bluuebunny/crossref_metadata_2025 huggingface dataset:
Mineral nutrition and bone health in salmonids
Authors: Baeverfjord Grete , Antony Jesu Prabhu P. , Fjelldal Per Gunnar , Albrektsen Sissel , Hatlen Bjarne , Denstadli Vegard , Ytteborg Elisabeth , Takle Harald , Lock Erik‐Jan , Berntssen Marc H.G. , Lundebye Anne‐Katrine , Åsgård Torbjørn , Waagbø Rune
Published: May 2018

In the recent years, challenges faced in salmonid farming with regard to deformities have helped to improve our knowledge on skeletal biology and development of bone health in salmonids. Different nutritional, genetic and environmental factors are associated with skeletal deformities in salmonids and other fish species. Minerals are a group of essential nutrients having a vital role to play in skeletal development, growth and remodelling. The knowledge generated thus far on the structural and functional importance of minerals in salmonid bone health is largely restricted to phosphorus. A brief account of dietary phosphorus‐related bone deformities encountered in salmonids, critical life stages for the development of bone deformities, recent developments in the understanding of their aetiology and dietary phosphorus levels required to improve bone health are presented. The effect of increased dietary level of phosphorus in reducing bone health disorders under conditions of improved feed conversion efficiency and use of triploids in salmon farming are illustrated with help of metadata analysis from literature. With regard to the role of other essential minerals (macro‐ and micro‐) impacting bone health in salmonids, data available are extremely limited and hence information on other fish species and mammals is summarized in relation to bone development and incidence of deformities. The need to improve mineral bioavailability, utilization and reduce effluent mineral load is presented in brief with example from Norwegian salmon farming. Refinements in mineral requirement recommendations for salmonids and advanced methodologies for studying aetiology of skeletal anomalies, bone mineral status, skeletal development and deformities are also discussed.
How Safe Is Safe Enough for Self‐Driving Vehicles?
Authors: Liu Peng , Yang Run , Xu Zhigang
Published: May 2018

Self‐driving vehicles (SDVs) promise to considerably reduce traffic crashes. One pressing concern facing the public, automakers, and governments is “How safe is safe enough for SDVs?” To answer this question, a new expressed‐preference approach was proposed for the first time to determine the socially acceptable risk of SDVs. In our between‐subject survey (N = 499), we determined the respondents’ risk‐acceptance rate of scenarios with varying traffic‐risk frequencies to examine the logarithmic relationships between the traffic‐risk frequency and risk‐acceptance rate. Logarithmic regression models of SDVs were compared to those of human‐driven vehicles (HDVs); the results showed that SDVs were required to be safer than HDVs. Given the same traffic‐risk‐acceptance rates for SDVs and HDVs, their associated acceptable risk frequencies of SDVs and HDVs were predicted and compared. Two risk‐acceptance criteria emerged: the tolerable risk criterion, which indicates that SDVs should be four to five times as safe as HDVs, and the broadly acceptable risk criterion, which suggests that half of the respondents hoped that the traffic risk of SDVs would be two orders of magnitude lower than the current estimated traffic risk. The approach and these results could provide insights for government regulatory authorities for establishing clear safety requirements for SDVs.
Psychosocial status and cognitive achievement in Peru
Authors: Outes Ingo , Sánchez Alan , Molina Oswaldo
Published: May 2018

This paper assesses the importance of psychosocial status in the accumulation of cognitive skills during the transition from mid to late childhood. We use longitudinal data from a cohort of 700 Peruvian children drawn from a very rich dataset, the Young Lives Survey, to test the impact of children's perception of respect at the age of 8 on cognitive achievement 4 years later, controlling for cognitive skills at the age of 8, lagged child and household characteristics, and community fixed effects. This empirical specification is akin to estimating a conditional demand function for cognitive skills, which deals with some of the main pitfalls of skill endogeneity. We find that poorly respected children are linked to a lower rate of cognitive accumulation than their better‐respected counterparts. As expected, we also find that previously accumulated cognitive skills enable higher subsequent cognitive skill accumulation. We go one step further by testing and finding evidence of complementarities across skills. We show that cognitive differences amplify over time between children with low and high psychosocial skills. Overall, our results suggest that psychosocial status, an aspect little studied in the context of developing countries, plays an important role in the acquisition of cognitive skills during childhood.
Apriority, Necessity and the Subordinate Role of Empirical Warrant in Mathematical Knowledge
Authors: McEvoy Mark
Published: May 2018

In this article, I present a novel account of a priori warrant, which I then use to examine the relationship between a priori and a posteriori warrant in mathematics. According to this account of a priori warrant, the reason that a posteriori warrant is subordinate to a priori warrant in mathematics is because processes that produce a priori warrant are reliable independent of the contexts in which they are used, whereas this is not true for processes that produce a posteriori warrant. Following this, I show how this difference explains why a priori warranting processes, such as proof (and mathematical intuition) can, and a posteriori warranting processes cannot, definitively establish mathematical results. I then show why, in the event of a conflict between a priori and a posteriori warranting processes, the former undermine, and cannot be undermined by, the latter. Finally, I explain the connection between apriority and mathematical necessity, but do so in a way that allows for the existence of contingent a priori knowledge.
Combination therapy of canine osteosarcoma with canine bone marrow stem cells, bone morphogenetic protein and carboplatin in an in vivo model
Authors: Rici R. E. G. , Will S. E. A. L. , Luna A. C. L. , Melo L. F. , Santos A. C. , Rodrigues R. F. , Leandro R. M. , Maria D. A.
Published: May 2018

Osteosarcoma (OSA) is the most common malignant bone cancer in children and dogs. The therapeutic protocols adopted for dogs and humans are very similar, involving surgical options such as amputation. Besides surgical options, radiotherapy and chemotherapy also are adopted. However, hematologic, gastrointestinal and renal toxicity may occur because of chemotherapy treatments. Recent study clearly showed that mesenchymal stem cells (MSCs) combined with recombinant human bone morphogenetic protein (rhBMP‐2) may be associated with decreases of the tumorigenic potential of canine OSA. The aim of this study was to analyse the efficacy of chemotherapy with carboplatin and rhBMP‐2 with MSCs in a canine OSA in vivo model. Canine OSA cells were implanted in mice Balb‐c/nude with MSCs, rhBMP‐2 and carboplatin. Flow cytometry and PCR for markers involved in tumour suppression pathways were analysed. Results showed that the combination of MSCs and rhBMP‐2 reduced tumour mass and infiltration of neoplastic cells in tissues more efficiently than carboplatin alone. Thus it was demonstrated that the use of rhBMP‐2 and MSCs, in combination with conventional antineoplastic, may be an efficient treatment strategy.
DEVELOPMENT OF ANTIFOULING POLYETHERSULFONE (PES)-NANO ZnO MEMBRANE FOR PRODUCED WATER TREATMENT
Authors: Kusworo Tutuk Djoko , Aryanti Nita , Qudratun Qudratun , Tambunan Via Dolorosa , Rosa Simanjuntak Natalia
Published: May 2018

Produced water is the side product of the oil and gas processing. This water is different from any common water because it contains the dangerous chemical substances and matters in the oil and gas. The usage of produced water and unprocessed waste of produced water contains a lot of dangerous substances that can endanger the environmental stability. The right processing is all that it needs to make produced water that is drinkable or usable. The membrane technology is one of the alternative waste water treatment technologies. But, as in the usage, it still lacks in the field of fouling and cannot fulfilled the specification of usable water. Thus, this becomes the reason that bases this research. In this paper, there will be made a polyethersulfone membrane with an inversion phase method and an addition of Nano-antifouling compound, ZnO. The experimental results show that the TDS value of produced water decreased from 6600 into 1500 mg/L. Nano ZnO addition of 1.5 wt-% increase the permeate flux from 28 to 43 L/m2.hr. The UV irradiation on the membrane increase the initial flux from 28 to 48 L/m2.hr and also increase the TDS rejection from 16 to 25%. This shows that by using Polyethersulfone (PES)-ZnO membrane, we can increase the separation performance. Hence, this method is suitable for processing the produced water into usable water.
Transforming growth factor‐β signalling in renal fibrosis: from Smads to non‐coding RNAs
Authors: Tang Patrick Ming‐Kuen , Zhang Ying‐Ying , Mak Thomas Shiu‐Kwong , Tang Philip Chiu‐Tsun , Huang Xiao‐Ru , Lan Hui‐Yao
Published: May 2018

Transforming growth factor‐β (TGF‐β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF‐β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF‐β‐mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF‐β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF‐β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non‐coding RNAs at transcriptional levels. More importantly, disease‐specific Smad3‐dependent long non‐coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of TGF‐β‐driven renal fibrosis via non‐coding RNAs and their translational capacities will be discussed in detail.

image
Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity
Authors: Carter Heather N. , Kim Yuho , Erlich Avigail T. , Zarrin‐khat Dorrin , Hood David A.
Published: May 2018

Key points

A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy, but little is known about how mitophagy is altered with ageing and chronic exercise.

Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group.

Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories.

Mitophagy flux was significantly reduced as an adaptation to CCA suggesting that an improvement in organelle quality reduces the need for mitochondrial turnover.

CCA enhances lysosomal capacity and may ameliorate lysosomal dysfunction in aged muscle.

Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with ageing and chronic exercise. We assessed mitophagy flux using colchicine treatment in vivo following chronic contractile activity (CCA) of muscle in young and aged rats. CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle. Mitophagy flux was higher in aged muscle and was correlated with the enhanced expression of mitophagy receptors and upstream transcriptional regulators. CCA decreased mitophagy flux in both age groups, suggesting an improvement in organelle quality. CCA also reduced the exaggerated expression of TFEB evident in aged muscle, which may be promoting the age‐induced increase in lysosomal markers. Thus, aged muscle possesses an elevated drive for autophagy and mitophagy which may contribute to the decline in organelle content observed with age, but which may serve to maintain mitochondrial quality. CCA improves organelle integrity and reduces mitophagy, illustrating that chronic exercise is a modality to improve muscle quality in aged populations.
Electrolyte-insulator-semiconductor devices with different integrated reference electrodes for pH detection
Authors: César Rodrigo Reigota , Pascon Aline Maria , Doi Ioshiaki , Diniz José Alexandre
Published: May 2018

Electrolyte-insulator-semiconductor (EIS) devices were fabricated with different integrated reference electrodes, including aluminum (Al), alumina (Al2O3)/Al, titanium nitride (TiN), and graphene/TiN. A titanium oxide (TiO2) film as a gate dielectric and pH sensitive membrane was used in all EIS devices. Structural characterization by Raman spectroscopy indicated that the TiO2 film comprised 20% anatase and 80% rutile crystalline phases and was an appropriate gate dielectric for EIS and ion-sensitive field-effect transistor (ISFET) device applications. Capacitance versus voltage (C–V) measurements were carried out with solutions with pH values of 4, 7, and 10 dripped on the EIS devices. The C–V curves produced the flat-band voltages (VFB) for each solution, whose dependence on the pH value determined the pH sensitivity of EIS device. The best results in terms of the chemical stability and a pH sensitivity of 13 mV/pH were exhibited by the TiN reference electrode, which can be integrated in ISFET (or EIS) devices with monolithic complementary metal–oxide–semiconductor applications.
Remote plasma-enhanced atomic layer deposition of metallic TiN films with low work function and high uniformity
Authors: Zhu Yafeng , Li Fangsen , Huang Rong , Liu Tong , Zhao Yanfei , Shen Yang , Zhang Jian , Dingsun An , Guo Yun
Published: May 2018

Thermal stability of metal/n-GaN contact is critical for its applications in microelectronic and optoelectronic devices. Metal Ti is generally used to make Ohmic contact on n-GaN after high temperature annealing, and the key factor is to form TiN at the interface. To reduce the processing temperature and improve the reliability, metallic titanium nitride (TiN) thin film has been proposed to substitute traditional metals (such as Ti) in the contact structures, due to its low work function and high blocking effect. For this novel approach, the first step is to fabricate high quality TiN films. Here, the authors adopted remote plasma-enhanced atomic layer deposition method to deposit TiN films under well-controlled conditions. Stoichiometric TiN films (Ti:N ∼ 1:1) with low oxygen contamination (<5%) have been deposited uniformly on 2 in. substrates in a large temperature range of 250–400 °C. The work function of TiN films is quite low (∼3.7 ± 0.1 eV) compared to metal Ti (∼4.33 eV), and almost independent to the growth temperature and substrates. Strong Fermi edge and high conductivity indicate excellent metallic property of the TiN films. This study of TiN film growth paves the way to establish a low temperature process and improve the thermal stability of Ohmic contacts for wide band gap semiconductor-based devices.
Influence of suppression on restoration of spectral loudness summation in listeners with hearing loss
Authors: Rasetshwane Daniel M. , High Robin R. , Kopun Judy G. , Neely Stephen T. , Gorga Michael P. , Jesteadt Walt
Published: May 2018

Loudness depends on both the intensity and spectrum of a sound. Listeners with normal hearing perceive a broadband sound as being louder than an equal-level narrowband sound because loudness grows nonlinearly with level and is then summed across frequency bands. This difference in loudness as a function of bandwidth is reduced in listeners with sensorineural hearing loss (SNHL). Suppression, the reduction in the cochlear response to one sound by the simultaneous presentation of another sound, is also reduced in listeners with SNHL. Hearing-aid gain that is based on loudness measurements with pure tones may fail to restore normal loudness growth for broadband sounds. This study investigated whether hearing-aid amplification that mimics suppression can improve loudness summation for listeners with SNHL. Estimates of loudness summation were obtained using measurements of categorical loudness scaling (CLS). Stimuli were bandpass-filtered noises centered at 2 kHz with bandwidths in the range of 0.1–6.4 kHz. Gain was selected to restore normal loudness based on CLS measurements with pure tones. Gain that accounts for both compression and suppression resulted in better restoration of loudness summation, compared to compression alone. However, restoration was imperfect, suggesting that additional refinements to the signal processing and gain-prescription algorithms are needed.
In Vivo
and
In Vitro
Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci
Authors: Brown Gandt Autumn , Griffith Elizabeth C. , Lister Ida M. , Billings Lisa L. , Han Angel , Tangallapally Rajendra , Zhao Ying , Singh Aman P. , Lee Richard E. , LaFleur Michael D.
Published: May 2018

Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest.
Molecular and Functional Characterization of Fcγ Receptor IIIb-Ligand Interaction: Implications for Neutrophil-Mediated Immune Mechanisms in Malaria
Authors: Simtong Piyapong , Romphruk Amornrat V. , Traum Annalena , Burg-Roderfeld Monika , Bein Gregor , Jakubowski Konstantin , Dominik Andreas , Theisen Michael , Kana Ikhlaq Hussain , Sachs Ulrich J. , Santoso Sentot
Published: May 2018

The Fcγ receptor IIIb (FcγRIIIb) is a low-affinity receptor of IgG and is essential in neutrophil-mediated effector functions. Different allelic forms of FcγRIIIb carrying human neutrophil antigen (HNA-1a, -1b, -1c, and -1d) have been identified.
Legionella pneumophila Is Directly Sensitive to 2-Deoxyglucose-Phosphate via Its UhpC Transporter but Is Indifferent to Shifts in Host Cell Glycolytic Metabolism
Authors: Price Jordan V. , Jiang Kallie , Galantowicz Abigail , Freifeld Alana , Vance Russell E.
Published: May 2018

We explored the relationship between macrophage glycolysis and replication of an intracellular bacterial pathogen,
Legionella pneumophila
. Previous studies demonstrated that a glycolysis inhibitor, 2-deoxyglucose (2DG), blocks replication of
L. pneumophila
during infection of macrophages, leading to speculation that
L. pneumophila
may exploit macrophage glycolysis. We isolated
L. pneumophila
mutants resistant to the inhibitory effect of 2DG in macrophages, identifying a
L. pneumophila
hexose-phosphate transporter, UhpC, that is required for bacterial sensitivity to 2DG during infection. Our results reveal how a bacterial transporter mediates the direct antimicrobial effect of a toxic metabolite. Moreover, our results indicate that neither induction nor impairment of host glycolysis inhibits intracellular replication of
L. pneumophila
, which is consistent with a view of
L. pneumophila
as a metabolic generalist.
Pseudomonas aeruginosa Regulated Intramembrane Proteolysis: Protease MucP Can Overcome Mutations in the AlgO Periplasmic Protease To Restore Alginate Production in Nonmucoid Revertants
Authors: Delgado Camila , Florez Laura , Lollett Ivonne , Lopez Christine , Kangeyan Shiva , Kumari Hansi , Stylianou Marios , Smiddy Robert J. , Schneper Lisa , Sautter Robert T. , Smith David , Szatmari George , Mathee Kalai
Published: May 2018

Infection by the opportunistic pathogen
Pseudomonas aeruginosa
is the leading cause of morbidity and mortality seen in CF patients. Poor patient prognosis correlates with the genotypic and phenotypic change of the bacteria from a typical nonmucoid to a mucoid form in the CF lung, characterized by the overproduction of alginate. The expression of this exopolysaccharide is under the control an alternate sigma factor, AlgT/U, that is regulated posttranslationally by a series of proteases. A better understanding of this regulatory phenomenon will help in the development of therapies targeting alginate production, ultimately leading to an increase in the length and quality of life for those suffering from CF.
Diagnostic Performance of Pleural Fluid Adenosine Deaminase for Tuberculous Pleural Effusion in a Low-Incidence Setting
Authors: Blakiston Matthew , Chiu Weldon , Wong Conroy , Morpeth Susan , Taylor Susan
Published: May 2018

The challenges associated with diagnosing tuberculous pleural effusion have led to the use of pleural fluid adenosine deaminase (pfADA) as a biomarker for
Mycobacterium tuberculosis
infection. This study retrospectively reviewed the diagnostic performance of pfADA, the pleural fluid lactate dehydrogenase (LD)/ADA ratio, and combinations of these two parameters in 1,637 episodes of pleural effusion in the low-tuberculosis (TB)-incidence setting of Auckland, Aotearoa New Zealand, from between March 2008 and November 2014.
Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs
Authors: Houzet Laurent , Pérez-Losada Marcos , Matusali Giulia , Deleage Claire , Dereuddre-Bosquet Nathalie , Satie Anne-Pascale , Aubry Florence , Becker Emmanuelle , Jégou Bernard , Le Grand Roger , Keele Brandon F. , Crandall Keith A. , Dejucq-Rainsford Nathalie
Published: May 2018

The sexual transmission of viruses is responsible for the spread of multiple infectious diseases. Although the human immunodeficiency virus (HIV)/AIDS pandemic remains fueled by sexual contacts with infected semen, the origin of virus in semen is still unknown. In a substantial number of HIV-infected men, viral strains present in semen differ from the ones in blood, suggesting that HIV is locally produced within the genital tract. Such local production may be responsible for the persistence of HIV in semen despite effective antiretroviral therapy. In this study, we used single-genome amplification, amplicon sequencing (
env
gene), and phylogenetic analyses to compare the genetic structures of simian immunodeficiency virus (SIV) populations across all the male genital organs and blood in intravenously inoculated cynomolgus macaques in the chronic stage of infection. Examination of the virus populations present in the male genital tissues of the macaques revealed compartmentalized SIV populations in testis, epididymis, vas deferens, seminal vesicles, and urethra. We found genetic similarities between the viral strains present in semen and those in epididymis, vas deferens, and seminal vesicles. The contribution of male genital organs to virus shedding in semen varied among individuals and could not be predicted based on their infection or proinflammatory cytokine mRNA levels. These data indicate that rather than a single source, multiple genital organs are involved in the release of free virus and infected cells into semen. These findings have important implications for our understanding of systemic virus shedding and persistence in semen and for the design of eradication strategies to access viral reservoirs.

IMPORTANCE
Semen is instrumental for the dissemination of viruses through sexual contacts. Worryingly, a number of systemic viruses, such as HIV, can persist in this body fluid in the absence of viremia. The local source(s) of virus in semen, however, remains unknown. To elucidate the anatomic origin(s) of the virus released in semen, we compared viral populations present in semen with those in the male genital organs and blood of the Asian macaque model, using single-genome amplification, amplicon sequencing (
env
gene), and phylogenetic analysis. Our results show that multiple genital tissues harbor compartmentalized strains, some of them (i.e., from epididymis, vas deferens, and seminal vesicles) displaying genetic similarities with the viral populations present in semen. This study is the first to uncover local genital sources of viral populations in semen, providing a new basis for innovative targeted strategies to prevent and eradicate HIV in the male genital tract.
Secretion of Nonstructural Protein 1 of Dengue Virus from Infected Mosquito Cells: Facts and Speculations
Authors: Alcalá Ana C. , Palomares Laura A. , Ludert Juan E.
Published: May 2018

Dengue virus nonstructural protein 1 (NS1) is a multifunctional glycoprotein. For decades, the notion in the field was that NS1 is secreted exclusively from vertebrate cells and not from mosquito cells. However, recent evidence shows that mosquito cells also secrete NS1 efficiently. In this review, we discuss the evidence for secretion of NS1 of dengue virus, and of other flaviviruses, from mosquito cells, differences between NS1 secreted from mosquito and NS1 secreted from vertebrate cells, and possible roles of soluble NS1 in the insect flavivirus vector.
Herpes Simplex Virus 1 Tegument Protein VP22 Abrogates cGAS/STING-Mediated Antiviral Innate Immunity
Authors: Huang Jian , You Hongjuan , Su Chenhe , Li Yangxin , Chen Shunhua , Zheng Chunfu
Published: May 2018

Cytosolic DNA arising from intracellular pathogens is sensed by cyclic GMP-AMP synthase (cGAS) and triggers a powerful innate immune response. However, herpes simplex virus 1 (HSV-1), a double-stranded DNA virus, has developed multiple mechanisms to attenuate host antiviral machinery and facilitate viral infection and replication. In the present study, we found that HSV-1 tegument protein VP22 acts as an inhibitor of cGAS/stimulator of interferon genes (cGAS/STING)-mediated production of interferon (IFN) and its downstream antiviral genes. Our results showed that ectopic expression of VP22 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Infection with wild-type (WT) HSV-1, but not VP22-deficient virus (ΔVP22), inhibited immunostimulatory DNA (ISD)-induced activation of the IFN signaling pathway. Further study showed that VP22 interacted with cGAS and inhibited the enzymatic activity of cGAS. In addition, stable knockdown of cGAS facilitated the replication of ΔVP22 virus but not the WT. In summary, our findings indicate that HSV-1 VP22 acts as an antagonist of IFN signaling to persistently evade host innate antiviral responses.

IMPORTANCE
cGAS is very important for host defense against viral infection, and many viruses have evolved ways to target cGAS and successfully evade the attack by the immune system of their susceptible host. This study demonstrated that HSV-1 tegument protein VP22 counteracts the cGAS/STING-mediated DNA-sensing antiviral innate immunity signaling pathway by inhibiting the enzymatic activity of cGAS. The findings in this study will expand our understanding of the interaction between HSV-1 replication and the host DNA-sensing signaling pathway.
Loss of Upc2p-Inducible
ERG3
Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without Compromising Candida albicans Pathogenicity
Authors: Luna-Tapia Arturo , Willems Hubertine M. E. , Parker Josie E. , Tournu Hélène , Barker Katherine S. , Nishimoto Andrew T. , Rogers P. David , Kelly Steven L. , Peters Brian M. , Palmer Glen E.
Published: May 2018

Inactivation of sterol Δ
5,6
-desaturase (Erg3p) in the prevalent fungal pathogen
Candida albicans
is one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively few
erg3
-deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation upon
C. albicans
pathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While a
C. albicans
erg3
Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. The
erg3
Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducible
ERG3
transcription (rather than complete inactivation) is sufficient to confer
in vitro
fluconazole resistance, without compromising
C. albicans
stress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromising
C. albicans
pathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on both
C. albicans
pathogenicity and azole resistance.

IMPORTANCE
While conferring resistance to the azole antifungals
in vitro
, loss of sterol Δ
5,6
-desaturase (Erg3p) activity has also been shown to reduce
C. albicans
pathogenicity. Accordingly, it has been presumed that this mechanism may not be significant in the clinical setting. The results presented here challenge this assumption, revealing a more complex relationship between Erg3p activity, azole resistance,
C. albicans
pathogenicity, and the specific site of infection. Most importantly, we have shown that even modest changes in
ERG3
transcription are sufficient to confer azole resistance without compromising
C. albicans
fitness or pathogenicity. Given that previous efforts to assess the importance of
ERG3
as a determinant of clinical azole resistance have focused almost exclusively on detecting null mutants, its role may have been grossly underestimated. On the basis of our results, a more thorough investigation of the contribution of the
ERG3
gene to azole resistance in the clinical setting is warranted.
Conserved Responses in a War of Small Molecules between a Plant-Pathogenic Bacterium and Fungi
Authors: Spraker Joseph E. , Wiemann Philipp , Baccile Joshua A. , Venkatesh Nandhitha , Schumacher Julia , Schroeder Frank C. , Sanchez Laura M. , Keller Nancy P.
Published: May 2018

Small-molecule signaling is one major mode of communication within the polymicrobial consortium of soil and rhizosphere. While microbial secondary metabolite (SM) production and responses of individual species have been studied extensively, little is known about potentially conserved roles of SM signals in multilayered symbiotic or antagonistic relationships. Here, we characterize the SM-mediated interaction between the plant-pathogenic bacterium
Ralstonia solanacearum
and the two plant-pathogenic fungi
Fusarium fujikuroi
and
Botrytis cinerea
. We show that cellular differentiation and SM biosynthesis in
F. fujikuroi
are induced by the bacterially produced lipopeptide ralsolamycin (synonym ralstonin A). In particular, fungal bikaverin production is induced and preferentially accumulates in fungal survival spores (chlamydospores) only when exposed to supernatants of ralsolamycin-producing strains of
R. solanacearum
. Although inactivation of bikaverin biosynthesis moderately increases chlamydospore invasion by
R. solanacearum
, we show that other metabolites such as beauvericin are also induced by ralsolamycin and contribute to suppression of
R. solanacearum
growth
in vitro
. Based on our findings that bikaverin antagonizes
R. solanacearum
and that ralsolamycin induces bikaverin biosynthesis in
F. fujikuroi
, we asked whether other bikaverin-producing fungi show similar responses to ralsolamycin. Examining a strain of
B. cinerea
that horizontally acquired the bikaverin gene cluster from
Fusarium
, we found that ralsolamycin induced bikaverin biosynthesis in this fungus. Our results suggest that conservation of microbial SM responses across distantly related fungi may arise from horizontal transfer of protective gene clusters that are activated by conserved regulatory cues, e.g., a bacterial lipopeptide, providing consistent fitness advantages in dynamic polymicrobial networks.

IMPORTANCE
Bacteria and fungi are ubiquitous neighbors in many environments, including the rhizosphere. Many of these organisms are notorious as economically devastating plant pathogens, but little is known about how they communicate chemically with each other. Here, we uncover a conserved antagonistic communication between the widespread bacterial wilt pathogen
Ralstonia solanacearum
and plant-pathogenic fungi from disparate genera,
Fusarium
and
Botrytis
. Exposure of
Fusarium fujikuroi
to the bacterial lipopeptide ralsolamycin resulted in production of the antibacterial metabolite bikaverin specifically in fungal tissues invaded by
Ralstonia
. Remarkably, ralsolamycin induction of bikaverin was conserved in a
Botrytis cinerea
isolate carrying a horizontally transferred bikaverin gene cluster. These results indicate that horizontally transferred gene clusters may carry regulatory prompts that contribute to conserved fitness functions in polymicrobial environments.
Breaching Pathogeographic Barriers by the Bat White-Nose Fungus
Authors: Rhodes Johanna , Fisher Matthew C.
Published: May 2018

Bat white-nose syndrome has become associated with unparalleled mortality in bat species across the United States since 2006. In a recent article, Drees and colleagues (mBio 8:e01941-17, 2017,
https://doi.org/10.1128/mBio.01941-17
) utilized both whole-genome sequencing and microsatellite data to explore the origin and spread of the causative agent of bat white-nose syndrome,
Pseudogymnoascus destructans
. The research by Drees et al. supports the hypothesis that
P. destructans
was introduced into North America from Europe, with molecular dating suggesting a divergence from European isolates approximately 100 years ago. The approaches described in this study are an important contribution toward pinpointing the origins of this infection and underscore the need for more rigorous international biosecurity in order to stem the tide of emerging fungal pathogens.
Viromic Analysis of Wastewater Input to a River Catchment Reveals a Diverse Assemblage of RNA Viruses
Authors: Adriaenssens Evelien M. , Farkas Kata , Harrison Christian , Jones David L. , Allison Heather E. , McCarthy Alan J.
Published: May 2018

Enteric viruses cause gastrointestinal illness and are commonly transmitted through the fecal-oral route. When wastewater is released into river systems, these viruses can contaminate the environment. Our results show that we can use viromics to find the range of potentially pathogenic viruses that are present in the environment and identify prevalent genotypes. The ultimate goal is to trace the fate of these pathogenic viruses from origin to the point where they are a threat to human health, informing reference-based detection methods and water quality management.
Neighbourhood socioeconomic position and risks of major chronic diseases and all-cause mortality: a quasi-experimental study
Authors: Kim Daniel , Glazier Richard H , Zagorski Brandon , Kawachi Ichiro , Oreopoulos Philip
Published: May 2018

Objectives

This study estimated the health impacts of neighbourhood socioeconomic position (SEP) among public housing residents. Because applicants to public housing were assigned to housing projects primarily based on factors other than personal choice, we capitalised on a quasirandom source of variation in neighbourhood of residence to obtain more valid estimates of the health impacts of neighbourhood SEP.

Design

Quasiexperimental study.

Setting

Greater Metropolitan Toronto area, Canada.

Participants

Residents (24 019–28 858 adults age ≥30 years in 1994 for all outcomes except for asthma, for which the sample was expanded to 66 627 individuals age ≥4 years) of public housing on 1 January 1994.

Outcome measures

Incident hypertension, diabetes, asthma, and acute myocardial infarction (MI) and all-cause mortality between 1 January 1994 and 31 December 2006. We used multivariate Cox proportional hazards models to estimate hazard ratios (HRs) for the associations between the quartile of census tract-level SEP and the risk of diagnosis of each health outcome as well as death from any cause.

Results

Living in a public housing project in the second highest neighbourhood SEP quartile (Q3) was associated with lower hazards of acute MI (HR=0.76, 95% CI 0.54 to 1.07; P=0.11), incident asthma (HR=0.80, 95% CI 0.67 to 0.96; P=0.02) and all-cause mortality (HR=0.86, 95% CI 0.73 to 1.01; P=0.06) compared to living in the lowest neighbourhood SEP quartile (Q1), although only the trend for incident asthma reached statistical significance (P for trend=0.04). By contrast, the associations corresponding to living in the highest versus lowest quartile of median household income (Q4 vs Q1) were neither consistent in direction nor significant. The inconsistent associations may partly be attributed to selection and status incongruity.

Conclusion

This study provides new evidence compatible with protective influences of higher neighbourhood SEP on health outcomes, particularly asthma.
Teaching the relationship between health and climate change: a systematic scoping review protocol
Authors: Osama Tasnime , Brindley David , Majeed Azeem , Murray Kris A. , Shah Hiral , Toumazos Mel , Van Velthoven Michelle , Car Josip , Wells Glenn , Meinert Edward
Published: May 2018

Introduction

The observed and projected impacts of climate change on human health are significant. While climate change has gathered global momentum and is taught frequently, the extent to which the relationships between climate change and health are taught remains uncertain. Education provides an opportunity to create public engagement on these issues, but the extent to which historical implementation of climate health education could be leveraged is not well understood. To address this gap, we propose to conduct a scoping review of all forms of teaching that have been used to illustrate the health effects of climate change between 2005 and 2017, coinciding with a turning point in the public health and climate change agendas following the 2005 Group of 7/8 (G7/8) Summit.

Methods and analysis

Using Arksey/O’Malley’s and Levac’s methodological framework, MEDLINE/PubMed, Embase, Scopus, Education Resource Information Centre, Web of Science, Global Health, Health Management Information Consortium, Georef, Ebsco and PROSPERO will be systematically searched. Predetermined inclusion and exclusion criteria will be applied by two independent reviewers to determine study eligibility. Studies published in English and after 2005 only will be examined. Following selection of studies, data will be extracted and analysed.

Ethics and dissemination

No ethical approval is required as exclusively secondary data will be used. Our findings will be communicated to the European Institute of Innovation & Technology Health-Knowledge and Innovation Communities to assist in the development of a FutureLearn Massive Open Online Course on the health effects of climate change.
Induced endometrial trauma (endometrial scratch) in the mid-luteal menstrual cycle phase preceding first cycle IVF/ICSI versus usual IVF/ICSI therapy: study protocol for a randomised controlled trial
Authors: Pye Clare , Chatters Robin , Cohen Judith , Brian Kate , Cheong Ying C , Laird Susan , Mohiyiddeen Lamiya , Skull Jonathan , Walters Stephen , Young Tracey , Metwally Mostafa
Published: May 2018

Introduction

Endometrial trauma commonly known as endometrial scratch (ES) has been shown to improve pregnancy rates in women with a history of repeated implantation failure undergoing in vitro fertilisation (IVF), with or without intracytoplasmic sperm injection (ICSI). However, the procedure has not yet been fully explored in women having IVF/ICSI for the first time. This study aims to examine the effect of performing an ES in the mid-luteal phase prior to a first-time IVF/ICSI cycle on the chances of achieving a clinical pregnancy and live birth. If ES can influence this success rate, there would be a significant cost saving to the National Health Service through decreasing the number of IVF/ICSI cycles necessary to achieve a pregnancy, increase the practice of single embryo transfer and consequently have a large impact on risks and costs associated with multiple pregnancies.

Methods and analysis

This 30-month, UK, multicentre, parallel group, randomised controlled trial includes a 9-month internal pilot and health economic analysis recruiting 1044 women from 16 fertility units. It will follow up participants to identify if IVF/ICSI has been successful and live birth has occurred up to 6 weeks post partum. Primary analysis will be on an intention-to-treat basis. A substudy of endometrial samples obtained during the ES will assess the role of immune factors in embryo implantation. Main trial recruitment commenced on January 2017 and is ongoing.

Participants randomised to the intervention group will receive the ES procedure in the mid-luteal phase of the preceding cycle prior to first-time IVF/ICSI treatment versus usual IVF/ICSI treatment in the control group, with 1:1 randomisation. The primary outcome is live birth rate after completed 24 weeks gestation.

Ethics and dissemination

South Central—Berkshire Research Ethics Committee approved the protocol. Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences.

Trial registration number

ISRCTN23800982; Pre-results.
Effect of multimorbidity on survival of patients diagnosed with heart failure: a retrospective cohort study in Singapore
Authors: Kaur Palvinder , Saxena Nakul , You Alex Xiaobin , Wong Raymond C C , Lim Choon Pin , Loh Seet Yoong , George Pradeep Paul
Published: May 2018

Objective

Multimorbidity in patients with heart failure (HF) results in poor prognosis and is an increasing public health concern. We aim to examine the effect of multimorbidity focusing on type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) on all-cause and cardiovascular disease (CVD)-specific mortality among patients diagnosed with HF in Singapore.

Design

Retrospective cohort study.

Setting

Primary and tertiary care in three (out of six) Regional Health Systems in Singapore.

Participants

Patients diagnosed with HF between 2003 and 2016 from three restructured hospitals and nine primary care polyclinics were included in this retrospective cohort study.

Primary outcomes

All-cause mortality and CVD-specific mortality.

Results

A total of 34 460 patients diagnosed with HF from 2003 to 2016 were included in this study and were followed up until 31 December 2016. The median follow-up time was 2.1 years. Comorbidities prior to HF diagnosis were considered. Patients were categorised as (1) HF only, (2) T2DM+HF, (3) CKD+HF and (4) T2DM+CKD+HF. Cox regression model was used to determine the effect of multimorbidity on (1) all-cause mortality and (2) CVD-specific mortality. Adjusting for demographics, other comorbidities, baseline treatment and duration of T2DM prior to HF diagnosis, ‘T2DM+CKD+HF’ patients had a 56% higher risk of all-cause mortality (HR: 1.56, 95% CI 1.48 to 1.63) and a 44% higher risk of CVD-specific mortality (HR: 1.44, 95% CI 1.32 to 1.56) compared with patients diagnosed with HF only.

Conclusion

All-cause and CVD-specific mortality risks increased with increasing multimorbidity. This study highlights the need for a new model of care that focuses on holistic patient management rather than disease management alone to improve survival among patients with HF with multimorbidity.
Duty to provide care to Ebola patients: the perspectives of Guinean lay people and healthcare providers
Authors: Kpanake Lonzozou , Tonguino Tamba Kallas , Sorum Paul Clay , Mullet Etienne
Published: May 2018

Aim

To examine the views of Guinean lay people and healthcare providers (HCPs) regarding the acceptability of HCPs’ refusal to provide care to Ebola patients.

Method

From October to December 2015, lay people (n=252) and HCPs (n=220) in Conakry, Guinea, were presented with 54 sample case scenarios depicting a HCP who refuses to provide care to Ebola patients and were instructed to rate the extent to which this HCP’s decision is morally acceptable. The scenarios were composed by systematically varying the levels of four factors: (1) the risk of getting infected, (2) the HCP’s working conditions, (3) the HCP’s family responsibilities and (4) the HCP’s professional status.

Results

Five clusters were identified: (1) 18% of the participants expressed the view that HCPs have an unlimited obligation to provide care to Ebola patients; (2) 38% held that HCPs’ duty to care is a function of HCPs’ working conditions; (3) 9% based their judgments on a combination of risk level, family responsibilities and working conditions; (4) 23% considered that HCPs do not have an obligation to provide care and (5) 12% did not take a position.

Conclusion

Only a small minority of Guinean lay people and HCPs consider that HCPs’ refusal to provide care to Ebola patients is always unacceptable. The most commonly endorsed position is that HCPs’ duty to provide care to Ebola patients is linked to society’s reciprocal duty to provide them with the working conditions needed to fulfil their professional duty.
Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis
Authors: Akdemir Gülşah , Markusse Iris M , Bergstra Sytske Anne , Goekoop Robbert J , Molenaar Esmeralda T , van Groenendael Johannes H L M , Kerstens Pit J S M , Lems Willem F , Huizinga Tom W J , Allaart Cornelia F
Published: May 2018

Objectives

To compare outcomes of targeted treatment aimed at either low disease activity or remission in patients with early active rheumatoid arthritis (RA).

Methods

Five-year outcomes were compared in 133 patients with early active RA (1987), starting with methotrexate, sulfasalazine and tapered high dose of prednisone (arm 3 of the BehandelStrategieën (Treatment Strategies for Rheumatoid Arthritis) (BeSt) study), targeted at Disease Activity Score (DAS) ≤2.4 (low disease activity), and 175 patients with early RA, starting methotrexate and tapered high dose of prednisone, targeted at DAS <1.6 (selected from IMPROVED study who would have fulfilled inclusion criteria of the BeSt study). Association of treatment target with outcomes DAS <1.6, Boolean remission at year 1 and drug-free DAS remission (DFR) at year 5 were analysed by logistic regression analysis.

Results

At baseline, DAS <1.6 steered patients had a milder disease than DAS ≤2.4 steered patients (mean DAS 4.1±SD 0.7vs4.4±0.9, p=0.012) and less radiological damage. DAS decrease, functional ability and radiological damage progression over time were similar in both patient groups. DAS ≤2.4 was achieved in similar percentages in both patient groups, but more DAS <1.6 steered patients achieved DAS <1.6 and DFR. DAS <1.6 steered treatment was associated with achieving DAS <1.6 (OR 3.04 (95% CI 1.64 to 5.62)) and Boolean remission (3.03 (1.45 to 6.33)) at year 1 and DFR at year 5 (3.77 (1.51 to 9.43)).

Conclusions

In patients with early active RA who start with comparable disease-modifying antirheumatic drug+prednisone combination therapy, subsequent DAS <1.6 steered treatment is associated with similar clinical and radiological outcomes over time as DAS ≤2.4 steered treatment; however, in the DAS <1.6 steered group, more patients achieved remission and drug-free remission.