bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
AbstractSkeletal 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.
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

ABSTRACT

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

ABSTRACTDengue 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

ABSTRACT
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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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.
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

ObjectivesThis 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.DesignQuasiexperimental study.SettingGreater Metropolitan Toronto area, Canada.ParticipantsResidents (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 measuresIncident 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.ResultsLiving 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.ConclusionThis 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

IntroductionThe 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 analysisUsing 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 disseminationNo 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

IntroductionEndometrial 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 analysisThis 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 disseminationSouth 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 numberISRCTN23800982; 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

ObjectiveMultimorbidity 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.DesignRetrospective cohort study.SettingPrimary and tertiary care in three (out of six) Regional Health Systems in Singapore.ParticipantsPatients diagnosed with HF between 2003 and 2016 from three restructured hospitals and nine primary care polyclinics were included in this retrospective cohort study.Primary outcomesAll-cause mortality and CVD-specific mortality.ResultsA 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.ConclusionAll-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.