bluuebunny/crossref_metadata_2025 huggingface dataset:
BoostGAPFILL: improving the fidelity of metabolic network reconstructions through integrated constraint and pattern-based methods
Authors: Oyetunde Tolutola , Zhang Muhan , Chen Yixin , Tang Yinjie , Lo Cynthia
Published: October 2016

Motivation

Metabolic network reconstructions are often incomplete. Constraint-based and pattern-based methodologies have been used for automated gap filling of these networks, each with its own strengths and weaknesses. Moreover, since validation of hypotheses made by gap filling tools require experimentation, it is challenging to benchmark performance and make improvements other than that related to speed and scalability.

Results

We present BoostGAPFILL, an open source tool that leverages both constraint-based and machine learning methodologies for hypotheses generation in gap filling and metabolic model refinement. BoostGAPFILL uses metabolite patterns in the incomplete network captured using a matrix factorization formulation to constrain the set of reactions used to fill gaps in a metabolic network. We formulate a testing framework based on the available metabolic reconstructions and demonstrate the superiority of BoostGAPFILL to state-of-the-art gap filling tools. We randomly delete a number of reactions from a metabolic network and rate the different algorithms on their ability to both predict the deleted reactions from a universal set and to fill gaps. For most metabolic network reconstructions tested, BoostGAPFILL shows above 60% precision and recall, which is more than twice that of other existing tools.

Availability and Implementation

MATLAB open source implementation (https://github.com/Tolutola/BoostGAPFILL)

Supplementary information

Supplementary data are available at Bioinformatics online.
Survival and dispersal variability of pelagic eggs and yolk-sac larvae of central and eastern baltic flounder (Platichthys flesus): application of biophysical models
Authors: Hinrichsen Hans-Harald , Petereit Christoph , Nissling Anders , Wallin Isa , Ustups Didzis , Florin Ann-Britt
Published: October 2016

A hydrodynamic model coupled with a Lagrangian particle tracking technique was utilized to simulate spatially and temporally resolved long-term environmentally related (i) size of habitat suitable for reproduction, (ii) egg/yolk-sac larval survival, (iii) separation of causes of mortality, and (iv) connectivity between spawning areas of Baltic flounder with pelagic eggs. Information on reproduction habitat requirements and mortality sources were obtained from field or laboratory studies. In our modelling study we only quantified physical processes generating heterogeneity in spatial distribution of eggs and yolk-sac larvae, as e.g. predation is not accounted for. The spatial extent of eggs and larvae represented as modelled particles is primarily determined by oxygen and salinity conditions. The reproduction habitat most suitable was determined for the Gdansk Deep, followed by the Bornholm Basin. Relatively low habitat suitability was obtained for the Arkona Basin and the Gotland Basin. The model runs also showed yolk-sac larval survival to be to a large extent affected by sedimentation. Eggs initially released in the Arkona Basin and Bornholm Basin are strongly affected by sedimentation compared with those released in the Gdansk Deep and Gotland Basin. Highest relative survival of eggs occurred in the Gdansk Deep and in the Bornholm Basin. Relatively low survival rates in the Gotland Basin were attributable to oxygen-dependent mortality. Oxygen content had almost no impact on survival in the Arkona Basin. For all spawning areas mortality caused by lethally low temperatures was only evident after severe winters. Buoyancy of eggs and yolk-sac larvae in relation to topographic features appear as a barrier for the transport of eggs and yolk-sac larvae and potentially limits the connectivity of early life stages between the different spawning areas.
Implementing “the IEA”: using integrated ecosystem assessment frameworks, programs, and applications in support of operationalizing ecosystem-based management
Authors: Harvey Chris J. , Kelble Christopher R. , Schwing Franklin B.
Published: October 2016

The Integrated Ecosystem Assessment (IEA) approach was designed to assimilate scientific knowledge in the ideal format for providing advice to inform marine Ecosystem-Based Management (EBM). As such, IEAs were envisioned as the cornerstone integrated science product for the US National Oceanic and Atmospheric Administration (NOAA) that would maximize efficiencies and synergies across the agency’s ecosystem science efforts. This led to the development of a NOAA IEA Program that would oversee regional implementation of the national IEA framework. As implementation proceeded, uptake by management entities was slower than anticipated, in part because EBM was not quickly embraced and applied to achieve management objectives. This slow movement to EBM in conjunction with the need to develop scientific analyses and methods to properly implement IEA resulted in the IEA process being viewed as its own endpoint. This commonly led to referring to “the IEA” when variously discussing the IEA framework, program, products, and process. Now that IEA and EBM are maturing, we need to be specific with what we are referring to when discussing IEAs, in order to develop reasonable expectations for applying IEA tools. We also now recognize the need to implement multiple IEA processes at varying geographic and complexity scales within an ecosystem to effectively meet the scientific requirements for operational EBM rather than viewing an IEA application as a single regional science product.
Meningococcal Disease in Patients With Human Immunodeficiency Virus Infection: A Review of Cases Reported Through Active Surveillance in the United States, 2000–2008
Authors: Harris Christine M. , Wu Henry M. , Li Jianmin , Hall H. Irene , Lee Adria , Zell Elizabeth , Harrison Lee H. , Petit Susan , Farley Monica M. , Lynfield Ruth , Miller Lisa , Nichols Megin , Reingold Arthur , Schaffner William , Thomas Ann , MacNeil Jessica R. , Clark Thomas A. , Cohn Amanda C.
Published: October 2016

Background

Although human immunodeficiency virus (HIV) infection is an established risk factor for several bacterial infections, the association between HIV infection and meningococcal disease remains unclear.

Methods

Expanded chart reviews were completed on persons with meningococcal disease and HIV infection reported from 2000 through 2008 from 9 US sites participating in an active population-based surveillance system for meningococcal disease. The incidence of meningococcal disease among patients meeting Centers for Disease Control and Prevention acquired immune deficiency syndrome (AIDS) surveillance criteria was estimated using data from the National HIV Surveillance System for the participating sites.

Results

Thirty-three cases of meningococcal disease in individuals with HIV infection were reported from participating sites, representing 2.0% of all reported meningococcal disease cases. Most (75.8%) persons with HIV infection were adult males aged 25 to 64 years old. Among all meningococcal disease cases aged 25 to 64 years old, case fatality ratios were similar among HIV-infected and HIV-uninfected persons (13.3% vs 10.6%; P = .6). The cumulative, mean incidence of meningococcal disease among patients aged 25 to 64 years old with HIV infection ever classified as AIDS was 3.5 cases per 100000 person years (95% confidence interval [CI], 2.1–5.6), compared with 0.3 cases per 100000 person years (95% CI, 0.3–0.3) for persons of the same age group not reported to have AIDS (relative risk = 12.9; 95% CI, 7.9–20.9).

Conclusions

Individuals with HIV infection meeting the AIDS surveillance case definition have a higher incidence of meningococcal disease compared with the general adult population.
Antiretroviral Therapy as Prevention of … Pneumococcal Infections?
Authors: Lesourd Anaïs , Leporrier Jérémie , Delbos Valérie , Unal Guillemette , Honoré Patricia , Etienne Manuel , Bouchaud Olivier , Caron François
Published: October 2016

Background

Despite antiretroviral therapy, it is generally believed that the risk for pneumococcal infections (PnIs) is high among patients infected with human immunodeficiency virus (HIV). However, most studies in this field have been conducted before 2010, and the proportion of virologically suppressed patients has drastically increased in these latter years thanks to larger indications and more effective antiretroviral regimens. This study aimed to re-evaluate the current risk of PnI among adult patients infected with HIV.

Methods

The incidence of PnI was evaluated between 1996 and 2014 in 2 French regional hospitals. The 80 most recent cases of PnI (2000–2014) were retrospectively compared with 160 controls (HIV patients without PnI) to analyze the residual risk factors of PnI.

Results

Among a mean annual follow-up cohort of 1616 patients, 116 PnIs were observed over 18 years. The risk factors of PnI among patients infected with HIV were an uncontrolled HIV infection or “classic” risk factors of PnI shared by the general population such as addiction, renal or respiratory insufficiency, or hepatitis B or C coinfection. Pneumococcal vaccination coverage was low and poorly targeted, because only 5% of the cases had been previously vaccinated. The incidence of invasive PnIs among HIV patients with a nonvirologically suppressed infection or comorbidities was 12 times higher than that reported in the general population at the country level (107 vs 9/100000 patients), whereas the incidence among virologically suppressed HIV patients without comorbidities was lower (7.6/100000 patients).

Conclusions

Human immunodeficiency virus infection no longer per se seems to be a significant risk factor for PnI, suggesting a step-down from a systematic to an “at-risk patient” targeted pneumococcal vaccination strategy.
Exploring NICU Nurses' Affective Responses to End-of-Life Care
Authors: Lewis Stephanie Lacefield
Published: October 2016

Background:

The survival rate for infants born with life-threatening problems has improved greatly over the last few decades. Nevertheless, infants still die in neonatal intensive care units (NICUs) every day. Despite existing standards of care, some aspects of end-of-life care (EOLC) are still not delivered consistently. Little is known about how NICU nurses' individual experiences affect EOLC.

Purpose:

The purpose of this study was to explore, through lived and told stories, the affective, interactional, and meaning-related responses that NICU nurses have while caring for dying infants and their families. Coping strategies and changes in practice were also explored.

Methods:

Thirty-six members of the National Association of Neonatal Nurses submitted written narratives about an EOLC experience during which the nurse experienced strong emotions.

Findings:

Narrative analysis revealed many affective responses, but 3 were the most frequent: responsibility, moral distress, and identification. Coping methods included healthy and less healthy strategies, such as colleague support, informal and formal debriefing, practicing intentional gratefulness, avoidance, and compartmentalization. Changes in practice identified were universally described as professional growth through the use of reflective practice.

Implications for Practice & Research:

Educators should discuss the range of emotions experienced by caregivers related to EOLC and healthy coping strategies and encourage the use of reflective practice as a facilitator of professional growth. Nurse leaders should promote supportive environments in NICUs and ensure debriefing opportunities for nurses who have recently cared for a dying infant. Future research should focus on formulating interventions to utilize debriefing with NICU nurses and perhaps the development of EOLC mentors.
Change in Psychosocial Health Status Over 5 Years in Relation to Adults’ Hearing Ability in Noise
Authors: Stam Mariska , Smit Jan H. , Twisk Jos W. R. , Lemke Ulrike , Smits Cas , Festen Joost M. , Kramer Sophia E.
Published: October 2016

Objectives:

The aim of this study was to establish the longitudinal relationship between hearing ability in noise and psychosocial health outcomes (i.e., loneliness, anxiety, depression, distress, and somatization) in adults aged 18 to 70 years. An additional objective was to determine whether a change in hearing ability in noise over a period of 5 years was associated with a change in psychosocial functioning. Subgroup effects for a range of factors were investigated.

Design:

Longitudinal data of the web-based Netherlands Longitudinal Study on Hearing (NL-SH) (N = 508) were analyzed. The ability to recognize speech in noise (i.e., the speech-reception-threshold [SRTn]) was measured with an online digit triplet test at baseline and at 5-year follow-up. Psychosocial health status was assessed by online questionnaires. Multiple linear regression analyses and longitudinal statistical analyses (i.e., generalized estimating equations) were performed.

Results:

Poorer SRTn was associated longitudinally with more feelings of emotional and social loneliness. For participants with a high educational level, the longitudinal association between SRTn and social loneliness was significant. Changes in hearing ability and loneliness appeared significantly associated only for specific subgroups: those with stable pattern of hearing aid nonuse (increased emotional and social loneliness), who entered matrimony (increased social loneliness), and low educational level (less emotional loneliness). No significant longitudinal associations were found between hearing ability and anxiety, depression, distress, or somatization.

Conclusions:

Hearing ability in noise was longitudinally associated with loneliness. Decline in hearing ability in noise was related to increase in loneliness for specific subgroups of participants. One of these subgroups included participants whose hearing deteriorated over 5 years, but who continued to report nonuse of hearing aids. This is an important and alarming finding that needs further investigation.
Database studies: an increasing trend in the United States orthopaedic literature
Authors: Sivasundaram Lakshmanan , Pannell William , Heckmann Nathanael , Alluri Ram K. , Omid Reza , “Rick” Hatch George F.
Published: October 2016

Background:

There has been a recent increase in the number of orthopaedic publications using large-scale databases. The purpose of this study was to examine current database publication trends in the United States orthopaedic literature. In addition, we briefly discuss the strengths and limitations of the most utilized databases.

Methods:

PubMed was queried, and all abstracts and text were screened by two authors to insure that they reported on an orthopaedic topic using database findings. Studies from international databases, single-center databases, specialty-specific registries, and review articles were excluded. Annual and subspecialty trends were analyzed using Spearman correlation. Significance was set at P<0.05.

Results:

Our initial search yielded 1080 articles, of which 306 met inclusion criteria. There was a significant increase in the number of database studies published from 2004 to 2014, and an almost two-fold increase in the number of published studies from 2013 to 2014. The Journal of Bone and Joint Surgery, Spine (Phila Pa 1976), and Clinical Orthopaedics and Related Research had the most database publications over the period examined. Spine, joints, and sports subspecialties published the most database studies.

Conclusions:

There has been a large increase in the number of database studies published in United States orthopaedic literature, with the most dramatic increase observed between 2013 and 2014. Understanding the general strengths and limitations of these databases, as well as the differences between the various types of databases, is essential to fully understand this medium of orthopaedic research.
Systemic therapy for bone sarcomas
Authors: Portnoy David C. , VanderWalde Ari M.
Published: October 2016

Bone sarcomas comprise less than 0.2% of all malignancies and are divided into several subtypes with varying sensitivities to systemic therapy. While the role of adjuvant chemotherapy in the management of soft-tissue sarcomas is controversial, perioperative chemotherapy has greatly improved the survival of nonmetastatic Ewing sarcoma and osteosarcoma. However, metastatic unresectable Ewing sarcoma and osteosarcoma are still associated with a poor prognosis. Giant cell tumor of bone and chordoma are refractory to conventional cytotoxic chemotherapy, but in recent years targeted therapy has been shown to be able to provide a degree of control of unresectable disease. Conventional chondrosarcoma remains refractory to systemic therapy, although the less common subtypes, dedifferentiated and mesenchymal chondrosarcomas, can be sensitive to chemotherapy but still have a poor prognosis.
Surgical and Radiographic Outcomes After Pedicle Subtraction Osteotomy According to Surgeon's Experience
Authors: Choi Ho Yong , Hyun Seung-Jae , Kim Ki-Jeong , Jahng Tae-Ahn , Kim Hyun-Jib
Published: October 2016

Study Design.

Retrospective case series.

Objective.

The aim of this study was to evaluate and compare the surgical, radiographic, and clinical outcomes of pedicle subtraction osteotomy (PSO) according to surgeon's experience.

Summary of Background Data.

Although PSO has been widely used to correct spinal deformities, it still remains technically demanding procedure with high complications.

Methods.

Comparative analysis of 40 consecutive patients treated with lumbar PSOs was performed. According to time period, the former and latter 20 patients were divided into group 1 and group 2, respectively. Patients’ demographic data, operative, radiographic/clinical outcomes, and complications were compared between the groups.

Results.

Baseline characteristics and preoperative radiographic parameters were not different between the groups. Significant reductions of operative time (569.6 vs. 392.0 minutes, P = 0.000), surgical bleeding (1777.5 vs. 949.5 mL, P = 0.002), and transfused volume of red blood cell (1232.6 vs. 864.1 mL, P = 0.041) in group 2 were observed. Postoperative sagittal vertical axis was significantly different between the groups (40.1 and –3.6 mm, groups 1 and 2, respectively, P = 0.008), and the difference was sustained to the ultimate follow-up (59.4 vs. 13.2 mm, P = 0.003). There was a difference regarding the amount of curve correction by PSO, which was significantly greater in group 2 (25.7° vs. 35.8°, P = 0.023). Intraoperative complications (7 vs. 1, P = 0.019) were significantly lower in group 2. Total complications (20 vs. 10, P = 0.070), postoperative transient neurologic deficit (2 vs. 1), and revision surgery (4 vs. 3) were also lower in group 2, without statistical significance. The amount of the improvement of SRS-22 score was not different between the groups (P = 0.395).

Conclusion.

PSO may be performed in patients with fixed sagittal imbalance with an acceptable rate of complications after about 20 cases. With acquisition of surgical experiences, surgeons could perform PSO more effectively and safely.

Level of Evidence: 4
Lumbar Fusion in Utah Workers’ Compensation Patients
Authors: Cuneo Jessica G. , DeBerard M. Scott , Wheeler Anthony J.
Published: October 2016

Study Design.

This study was a retrospective-cohort design involving a review of patient medical and cost records and a 2-year postsurgery follow-up outcome survey.

Objective.

To evaluate the functional and cost outcomes associated with recent lumbar fusion surgeries in Utah workers and compare these outcomes with a comparable prior study cohort.

Summary of Background Data.

Lumbar fusion performed on injured workers has dramatically increased over the past 2 decades and this likely coincided with the increased use of more advanced surgical instrumentation. Considering the recent changes in lumbar fusion surgery, there is a need to identify how patient outcomes have changed among injured workers.

Materials and Methods.

Retrospective chart review and 2-year postsurgery follow-up survey of patient outcomes were performed. Postsurgical outcomes for this sample were compared with established norms for back pain patients and a previous cohort of compensated lumbar fusion patients obtained from Workers’ Compensation Fund of Utah.

Results.

The current cohort evidenced a solid fusion rate of 89% and significant increase in the use of surgical instrumentation, particularly titanium fusion cages. Despite increased solid fusion rates, injured workers who have undergone lumbar fusion in Utah demonstrated equivalent and in some cases worse outcomes than those documented a decade ago. Specifically, there were significant increases in back pain dysfunction and narcotic medication usage in the current versus the past cohort. Medical and compensation costs for compensated lumbar fusion patients in Utah also significantly increased since the mid-1990s.

Conclusion.

Over the past decade, injured workers who have undergone lumbar fusion in Utah showed an increase in solid fusion rates and costs without a corresponding improvement in patient outcomes.

Level of Evidence.

3
Necrotizing Infundibular Crystalline Folliculitis (NICF) Induced by Anti-Tumoral Therapies: Report of 2 Cases
Authors: Fattouh Kinda , Collet-Benzaquen Diane , Provensal Anne M. , Desseigne Françoise , Castillo Christine , Combemale Patrick , de la Fouchardière Arnaud
Published: October 2016

Necrotizing Infundibular Crystalline Folliculitis (NICF) is rare entity of unknown pathogenesis presenting as follicular crystalline papules arising in seborrheic areas. We report 2 cases of NICF in patients under targeted therapy for metastatic adenocarcinoma. In one case, the lesions reappeared cyclically every 3 weeks after each injection and in the other case, lesions persisted until disruption of the continuous oral therapy. Punch-biopsies demonstrated folliculitis with a plugging crystalline material associated with either bacteria or yeast. These are the first descriptions of drug-induced NICF.
Lymphocyte–monocyte ratio at admission predicts possible outcomes in patients with acute-on-chronic liver failure
Authors: Zhu ShaoMing , Waili Yulituzi , Qi XiaoTing , Chen YueMei , Lou YuFeng
Published: October 2016

Background

The lymphocyte–monocyte ratio (LMR) in the peripheral blood is suggested to be a potential biomarker for predicting the clinical outcomes of several diseases. We aimed to evaluate the relative efficiency of LMR for predicting 3-month mortality in patients with acute-on-chronic liver failure (AoCLF).

Patients and methods

In this study, 74 chronic hepatitis B patients, 90 AoCLF patients, and 70 healthy controls were followed up for 4 months. The primary endpoint was 3-month in-hospital mortality. Hematological and virological parameters as well as liver biochemistry were determined using blood samples ordered upon admission. A panel of clinical and biochemical variables were analyzed for potential associations with outcomes using Cox proportional hazards and multiple regression models.

Results

A significantly lower LMR was detected in AoCLF patients than in healthy controls and chronic hepatitis B groups (both P=0.001). The LMR inversely correlated with model for end-stage liver disease scores, and a lower LMR was associated with increased 3-month mortality. Multivariate analysis suggested that both LMR and model for end-stage liver disease scores were independent predictors of 3-month mortality (P<0.01).

Conclusion

A low LMR measured at admission is predictive of a poor prognosis in AoCLF patients.
Assessing the Attitudes of Nutrition Professionals on MyPlate
Authors: Combs Sarah , Gamble Jadra
Published: October 2016

Visuals are becoming mainstream as a way to increase the public's awareness on a variety of subjects. MyPlate has risen in popularity since its release. However, some questions still exist about the visual educational material. The intention of this survey was to determine the attitudes of nutrition professionals about MyPlate and its visual appeal. The majority of the 142 participants thought MyPlate was easy to use (n = 83 [58.9%]), but over half (n = 75 [52.8%]) also thought that information was missing. Findings indicate that nutrition professionals consider MyPlate a good starting educational material but prefer to use supplemental materials to further counsel patients.
Measuring Patient Dietary Intake Using Visual Estimation Methods in Japanese Hospitals
Authors: Kawasaki Yui , Kojima Yui , Akamatsu Rie
Published: October 2016

Visual estimation is an easy-to-perform technique commonly used in hospitals to measure patients' dietary intake. We performed qualitative research with nurses and dietitians to assess this practice. In September 2014, we conducted individual interviews with 10 dietitians and 10 clinical nurses in Tokyo, Japan. The interviews were recorded, transcribed, and analyzed using qualitative methods. Three main practices emerged: measurement, data input, and training for raters. Each consisted of 4 parts: Practitioners, Subjects, Situations, and Methods. This study demonstrated the current status of rater training.
Snake fungal disease: an emerging threat to wild snakes
Authors: Lorch Jeffrey M. , Knowles Susan , Lankton Julia S. , Michell Kathy , Edwards Jaime L. , Kapfer Joshua M. , Staffen Richard A. , Wild Erik R. , Schmidt Katie Z. , Ballmann Anne E. , Blodgett Doug , Farrell Terence M. , Glorioso Brad M. , Last Lisa A. , Price Steven J. , Schuler Krysten L. , Smith Christopher E. , Wellehan James F. X. , Blehert David S.
Published: October 2016

Since 2006, there has been a marked increase in the number of reports of severe and often fatal fungal skin infections in wild snakes in the eastern USA. The emerging condition, referred to as snake fungal disease (SFD), was initially documented in rattlesnakes, where the infections were believed to pose a risk to the viability of affected populations. The disease is caused by
Ophidiomyces ophiodiicola
, a fungus recently split from a complex of fungi long referred to as the
Chrysosporium
anamorph of
Nannizziopsis vriesii
(CANV). Here we review the current state of knowledge about
O. ophiodiicola
and SFD. In addition, we provide original findings which demonstrate that
O. ophiodiicola
is widely distributed in eastern North America, has a broad host range, is the predominant cause of fungal skin infections in wild snakes and often causes mild infections in snakes emerging from hibernation. This new information, together with what is already available in the scientific literature, advances our knowledge of the cause, pathogenesis and ecology of SFD. However, additional research is necessary to elucidate the factors driving the emergence of this disease and develop strategies to mitigate its impacts.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Modelling coffee leaf rust risk in Colombia with climate reanalysis data
Authors: Bebber Daniel P. , Castillo Ángela Delgado , Gurr Sarah J.
Published: October 2016

Many fungal plant diseases are strongly controlled by weather, and global climate change is thus likely to have affected fungal pathogen distributions and impacts. Modelling the response of plant diseases to climate change is hampered by the difficulty of estimating pathogen-relevant microclimatic variables from standard meteorological data. The availability of increasingly sophisticated high-resolution climate reanalyses may help overcome this challenge. We illustrate the use of climate reanalyses by testing the hypothesis that climate change increased the likelihood of the 2008–2011 outbreak of Coffee Leaf Rust (CLR,Hemileia vastatrix) in Colombia. We develop a model of germination and infection risk, and drive this model using estimates of leaf wetness duration and canopy temperature from the Japanese 55-Year Reanalysis (JRA-55). We model germination and infection as Weibull functions with different temperature optima, based upon existing experimental data. We find no evidence for an overall trend in disease risk in coffee-growing regions of Colombia from 1990 to 2015, therefore, we reject the climate change hypothesis. There was a significant elevation in predicted CLR infection risk from 2008 to 2011 compared with other years. JRA-55 data suggest a decrease in canopy surface water after 2008, which may have helped terminate the outbreak. The spatial resolution and accuracy of climate reanalyses are continually improving, increasing their utility for biological modelling. Confronting disease models with data requires not only accurate climate data, but also disease observations at high spatio-temporal resolution. Investment in monitoring, storage and accessibility of plant disease observation data are needed to match the quality of the climate data now available.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Ploidy dynamics and evolvability in fungi
Authors: Wertheimer Noa Blutraich , Stone Neil , Berman Judith
Published: October 2016

Rapid responses to acute stresses are essential for stress survival and are critical to the ability of fungal pathogens to adapt to new environments or hosts. The rapid emergence of drug resistance is used as a model for how fungi adapt and survive stress conditions that inhibit the growth of progenitor cells. Aneuploidy and loss of heterozygosity (LOH), which are large-scale genome shifts involving whole chromosomes or chromosome arms, occur at higher frequency than point mutations and have the potential to mediate stress survival. Furthermore, the stress of exposure to an antifungal drug can induce elevated levels of LOH and can promote the formation of aneuploids. This occurs via mitotic defects that first produce tetraploid progeny with extra spindles, followed by chromosome mis-segregation. Thus, drug exposure induces elevated levels of aneuploidy, which can alter the copy number of genes that improve survival in a given stress or drug. Selection then acts to increase the proportion of adaptive aneuploids in the population. Because aneuploidy is a common property of many pathogenic fungi, including those posing emerging threats to plants, animals and humans, we propose that aneuploid formation and LOH often accompanying it contribute to the rapid generation of diversity that can facilitate the emergence of fungal pathogens to new environmental niches and/or new hosts, as well as promote antifungal drug resistance that makes emerging fungal infections ever more difficult to contain.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Medical mycology and fungal immunology: new research perspectives addressing a major world health challenge
Authors: Gow Neil A. R. , Netea Mihai G.
Published: October 2016

Fungi cause more than a billion skin infections, more than 100 million mucosal infections, 10 million serious allergies and more than a million deaths each year. Global mortality owing to fungal infections is greater than for malaria and breast cancer and is equivalent to that owing to tuberculosis (TB) and HIV. These statistics evidence fungal infections as a major threat to human health and a major burden to healthcare budgets worldwide. Those patients who are at greatest risk of life-threatening fungal infections include those who have weakened immunity or have suffered trauma or other predisposing infections such as HIV. To address these global threats to human health, more research is urgently needed to understand the immunopathology of fungal disease and human disease susceptibility in order to augment the advances being made in fungal diagnostics and drug development. Here, we highlight some recent advances in basic research in medical mycology and fungal immunology that are beginning to inform clinical decisions and options for personalized medicine, vaccine development and adjunct immunotherapies.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Food system consequences of a fungal disease epidemic in a major crop
Authors: Godfray H. Charles J. , Mason-D'Croz Daniel , Robinson Sherman
Published: October 2016

Fungal diseases are major threats to the most important crops upon which humanity depends. Were there to be a major epidemic that severely reduced yields, its effects would spread throughout the globalized food system. To explore these ramifications, we use a partial equilibrium economic model of the global food system (IMPACT) to study a hypothetical severe but short-lived epidemic that reduces rice yields in the countries affected by 80%. We modelled a succession of epidemic scenarios of increasing severity, starting with the disease in a single country in southeast Asia and ending with the pathogen present in most of eastern Asia. The epidemic and subsequent crop losses led to substantially increased global rice prices. However, as long as global commodity trade was unrestricted and able to respond fast enough, the effects on individual calorie consumption were, to a large part, mitigated. Some of the worse effects were projected to be experienced by poor net-rice importing countries in sub-Saharan Africa, which were not affected directly by the disease but suffered because of higher rice prices. We critique the assumptions of our models and explore political economic pressures to restrict trade at times of crisis. We finish by arguing for the importance of ‘stress-testing’ the resilience of the global food system to crop disease and other shocks.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Microevolutionary traits and comparative population genomics of the emerging pathogenic fungus
Cryptococcus gattii
Authors: Farrer Rhys A. , Voelz Kerstin , Henk Daniel A. , Johnston Simon A. , Fisher Matthew C. , May Robin C. , Cuomo Christina A.
Published: October 2016

Emerging fungal pathogens cause an expanding burden of disease across the animal kingdom, including a rise in morbidity and mortality in humans. Yet, we currently have only a limited repertoire of available therapeutic interventions. A greater understanding of the mechanisms of fungal virulence and of the emergence of hypervirulence within species is therefore needed for new treatments and mitigation efforts. For example, over the past decade, an unusual lineage of
Cryptococcus gattii
, which was first detected on Vancouver Island, has spread to the Canadian mainland and the Pacific Northwest infecting otherwise healthy individuals. The molecular changes that led to the development of this hypervirulent cryptococcal lineage remain unclear. To explore this, we traced the history of similar microevolutionary events that can lead to changes in host range and pathogenicity. Here, we detail fine-resolution mapping of genetic differences between two highly related
Cryptococcus gattii
VGIIc isolates that differ in their virulence traits (phagocytosis, vomocytosis, macrophage death, mitochondrial tubularization and intracellular proliferation). We identified a small number of single site variants within coding regions that potentially contribute to variations in virulence. We then extended our methods across multiple lineages of
C. gattii
to study how selection is acting on key virulence genes within different lineages.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Rapid emergence of pathogens in agro-ecosystems: global threats to agricultural sustainability and food security
Authors: McDonald Bruce A. , Stukenbrock Eva H.
Published: October 2016

Agricultural ecosystems are composed of genetically depauperate populations of crop plants grown at a high density and over large spatial scales, with the regional composition of crop species changing little from year to year. These environments are highly conducive for the emergence and dissemination of pathogens. The uniform host populations facilitate the specialization of pathogens to particular crop cultivars and allow the build-up of large population sizes. Population genetic and genomic studies have shed light on the evolutionary mechanisms underlying speciation processes, adaptive evolution and long-distance dispersal of highly damaging pathogens in agro-ecosystems. These studies document the speed with which pathogens evolve to overcome crop resistance genes and pesticides. They also show that crop pathogens can be disseminated very quickly across and among continents through human activities. In this review, we discuss how the peculiar architecture of agro-ecosystems facilitates pathogen emergence, evolution and dispersal. We present four example pathosystems that illustrate both pathogen specialization and pathogen speciation, including different time frames for emergence and different mechanisms underlying the emergence process. Lastly, we argue for a re-design of agro-ecosystems that embraces the concept of dynamic diversity to improve their resilience to pathogens. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Mitigating amphibian chytridiomycoses in nature
Authors: Garner Trenton W. J. , Schmidt Benedikt R. , Martel An , Pasmans Frank , Muths Erin , Cunningham Andrew A. , Weldon Che , Fisher Matthew C. , Bosch Jaime
Published: October 2016

Amphibians across the planet face the threat of population decline and extirpation caused by the disease chytridiomycosis. Despite consensus that the fungal pathogens responsible for the disease are conservation issues, strategies to mitigate their impacts in the natural world are, at best, nascent. Reducing risk associated with the movement of amphibians, non-amphibian vectors and other sources of infection remains the first line of defence and a primary objective when mitigating the threat of disease in wildlife. Amphibian-associated chytridiomycete fungi and chytridiomycosis are already widespread, though, and we therefore focus on discussing options for mitigating the threats once disease emergence has occurred in wild amphibian populations. All strategies have shortcomings that need to be overcome before implementation, including stronger efforts towards understanding and addressing ethical and legal considerations. Even if these issues can be dealt with, all currently available approaches, or those under discussion, are unlikely to yield the desired conservation outcome of disease mitigation. The decision process for establishing mitigation strategies requires integrated thinking that assesses disease mitigation options critically and embeds them within more comprehensive strategies for the conservation of amphibian populations, communities and ecosystems.

This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
Mice deficient ofMycsuper-enhancer region reveal a differential control mechanism between normal and pathological growth
Authors: Dave Kashyap , Sur Inderpreet , Yan Jian , Zhang Jilin , Kaasinen Eevi , Zhong Fan , Blaas Leander , Li Xiaoze , Månsson Robert , Taipale Jussi
Published: October 2016

The gene desert upstream of theMyconcogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multipleMYCenhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entireMYCupstream super-enhancer region in mice results in 50 to 80% decrease inMYCexpression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but notin vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.
The presence or absence alone of miRNA isoforms (isomiRs) successfully discriminate amongst the 32 TCGA cancer types
Authors: Telonis Aristeidis G. , Magee Rogan , Loher Phillipe , Chervoneva Inna , Londin Eric , Rigoutsos Isidore
Published: October 2016

Previously, we demonstrated that miRNA isoforms (isomiRs) are constitutive and their expression profiles depend on tissue, tissue state, and disease subtype. We have now extended our isomiR studies to The Cancer Genome Atlas (TCGA) repository. Specifically, we studied whether isomiR profiles can distinguish amongst the 32 cancers. We analyzed 10,271 datasets from 32 cancers and found 7,466 isomiRs from 807 miRNA hairpin-arms to be expressed above threshold. Using the top 20% most abundant isomiRs, we built a classifier that relied on “binary” isomiR profiles: isomiRs were simply represented as ‘present’ or ‘absent’ and, unlike previous methods, all knowledge about their expression levels was ignored. The classifier could label tumor samples with an average sensitivity of 93% and a False Discovery Rate of 3%. Notably, its ability to classify well persisted even when we reduced the set of used features (=isomiRs) by a factor of 10. A counterintuitive finding of our analysis is that the isomiRs and miRNA loci with the highest ability to classify tumors arenotthe ones that have been attracting the most research attention in the miRNA field. Our results provide a framework in which to study cancer-type-specific isomiRs and explore their potential uses as cancer biomarkers
Characterization of Dependencies Between Growth and Division in Budding Yeast
Authors: Mayhew Michael B. , Iversen Edwin S. , Hartemink Alexander J.
Published: October 2016

Cell growth and division are processes vital to the proliferation and development of life. Coordination between these two processes has been recognized for decades in a variety of organisms. In the budding yeastSaccharomyces cerevisiae, this coordination or ‘size control’ appears as an inverse correlation between cell size and the rate of cell-cycle progression, routinely observed in G1prior to cell division commitment. Beyond this point, cells are presumed to complete S/G2/M at similar rates and in a size-independent manner. As such, studies of dependence between growth and division have focused on G1. Moreover, coordination between growth and division has commonly been analyzedwithinthe cycle of a single cell without accounting for correlations in growth and division characteristicsbetweencycles of related cells. In a comprehensive analysis of three published time-lapse microscopy datasets, we analyze both intra-and inter-cycle dependencies between growth and division, revisiting assumptions about the coordination between these two processes. Interestingly, we find evidence (1) that S/G2/M durations are systematically longer in daughters than in mothers, (2) of dependencies between S/G2/M and size at budding that echo the classical G1dependencies, and, (3) in contrast with recent bacterial studies, of negative dependencies between size at birth and size accumulated during the cell cycle. In addition, we develop a novel hierarchical model to uncover inter-cycle dependencies, and we find evidence for such dependencies in cells growing in sugar-poor environments. Our analysis highlights the need for experimentalists and modelers to account for new sources of cell-to-cell variation in growth and division, and our model provides a formal statistical framework for the continued study of dependencies between biological processes.
The molecular mechanism of the type IVa pilus motors
Authors: McCallum Matthew , Tammam Stephanie , Khan Ahmad , Burrows Lori L. , Howell P. Lynne
Published: October 2016

Type IVa pili are protein filaments essential for virulence in many bacterial pathogens; they extend and retract from the surface of bacterial cells to pull the bacteria forward with unprecedented force. They are used for attachment, swarming and twitching motility, biofilm formation, up-regulation of other virulence factors, and natural competence. The pilus is assembled by the motor subcomplex which consists of the inner membrane protein PilC and the cytoplasmic ATPase PilB. How PilB catalyzes this process is unknown, due in part to the lack of high-resolution structural information. Phylogenetic analysis of PilB-like ATPases, including GspE, PilT, BfpD, FlaI, and archaeal GspE2 revealed highly conserved residues essential for function in this family of ATPases. Here we report the structure of the core ATPase domains ofGeobacter metalloreducensPilB bound to ADP and the non-hydrolysable ATP analogue, AMPPNP, at 3.4 and 2.3Å, respectively. Importantly, these structures were determined in non-saturating nucleotide conditions, revealing important differences in nucleotide binding between chains. Analysis of these differences revealed the sequential turnover of nucleotide by the chains, and the corresponding domain movements. Our data indicate a clockwise rotation of movement in PilB, which would support the assembly of a right-handed helical pilus. Conversely, our analysis suggests a counterclockwise rotation in PilT that would enable right-handed pilus disassembly. The proposed model provides insight into how this family of ATPases can power pilus extension and retraction with extraordinary forces.
Ontology-based workflow extraction from texts using word sense disambiguation
Authors: Halioui Ahmed , Valtchev Petko , Diallo Abdoulaye Baniré
Published: October 2016

This paper introduces a method for automatic workflow extraction from texts using Process-Oriented Case-Based Reasoning (POCBR). While the current workflow management systems implement mostly different complicated graphical tasks based on advanced distributed solutions (e.g.cloud computing and grid computation), workflow knowledge acquisition from texts using case-based reasoning represents more expressive and semantic cases representations. We propose in this context, an ontology-based workflow extraction framework to acquire processual knowledge from texts. Our methodology extends classic NLP techniques to extract and disambiguate tasks in texts. Using a graph-based representation of workflows and a domain ontology, our extraction process uses a context-based approach to recognize workflow components : data and control flows. We applied our framework in a technical domain in bioinformatics : i.e. phylogenetic analyses. An evaluation based on workflow semantic similarities on a gold standard proves that our approach provides promising results in the process extraction domain. Both data and implementation of our framework are available in :http://labo.bioinfo.uqam.ca/tgrowler.