bluuebunny/crossref_metadata_2025 huggingface dataset:
Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia
Authors: Silva Talita M. , Chaar Laiali J. , Silva Reinaldo C. , Takakura Ana C. , Câmara Niels O. , Antunes Vagner R. , Moreira Thiago S.
Published: March 2018

New Findings

What is the central question of this study?

Microglia are presumed to be the source of inflammatory mediators that contribute to hypoxia‐induced neuroinflammation. However, the relationship between microglial activity during hypoxia and inflammatory responses in specific autonomic brain regions is not well understood. Therefore, we hypothesized that acute hypoxia initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control.

What is the main finding and its importance?

Acute hypoxia initiated neuroinflammatory mechanisms specifically in brain autonomic nuclei responsible for cardiorespiratory control, i.e. the rostral ventrolateral medulla and paraventricular nucleus of the hypothalamus. Our findings emphasize the importance of microglia for the maintenance of autonomic adjustments during physiological challenges, such as hypoxia, or during cardiorespiratory reflex activation elicited by the arterial chemoreceptors.

Prolonged and continuous exposure of mammals to a low oxygen environment (chronic hypoxia) elicits remarkable morphological and physiological adjustments. These include altered gene expression, increased peripheral chemosensitivity, enhanced respiratory drive and sympathoexcitation. The current study examines the hypothesis that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. Male Wistar rats pretreated with vehicle or minocycline (30 mg kg−1 day−1 for 5 days) were subjected to AH (8% O2, balance N2) or normoxia (21% O2) for 3 h. AH increased interleukin (IL)‐6, IL‐1β and matrix metalloprotease 9 (MMP9) mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) and rostral ventrolateral medulla (RVLM) and tumour necrosis factor α (TNFα) in the RVLM. Treatment with minocycline, an inhibitor of microglial activation, decreased IL‐1β, TNFα and MMP9 mRNA expression in the RVLM, and increased IL‐6 mRNA expression in the RVLM and PVH of rats exposed to AH. Minocycline treatment also elicited a decrease in the number of activated neurons in the RVLM/C1 neurons (expressed as Fos+/tyrosine hydroxylase+), the number of Fos‐activated neurons in the PVH and the increase in ventilation elicited by AH. When viewed together, these results suggest that AH modulates the expression of inflammatory mediators in autonomic brain nuclei that may be involved in the responses to chemoreceptor activation.
Age‐associated impairments in contraction‐induced rapid‐onset vasodilatation within the forearm are independent of mechanical factors
Authors: Hughes William E. , Kruse Nicholas T. , Casey Darren P.
Published: March 2018

New Findings

What is the central question of this study?

We examined whether the mechanical contribution to contraction‐induced rapid‐onset vasodilatation (ROV) differed with age and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults.

What is the main finding and its importance?

The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age‐related attenuations in ROV are not attributable to a mechanical component and that ROV responses are independent of peripheral artery stiffness.

Contraction‐induced rapid‐onset vasodilatation (ROV) is modulated by perfusion and transmural pressure in young adults; however, this effect remains unknown in older adults. The present study examined the mechanical contribution to ROV in young versus older adults, the influence of perfusion pressure and whether these responses are associated with arterial stiffness. Forearm vascular conductance (in millilitres per minute per 100 mmHg) was measured in 12 healthy young (24 ± 4 years old) and 12 older (67 ± 3 years old) adults during: (i) single dynamic contractions at 20% of maximal voluntary contraction; and (ii) single external mechanical compression of the forearm (200 mmHg) positioned above, at and below heart level. Carotid–radial pulse‐wave velocity characterized upper limb arterial stiffness. Total ROV responses to single muscle contractions and single external mechanical compressions were attenuated in older adults at heart level (P < 0.05); however, the relative mechanical contribution to contraction‐induced peak (46 ± 14 versus 40 ± 18%; P = 0.21) and total (37 ± 21 versus 32 ± 18%; P = 0.27) responses were not different between young and older adults. Reducing or enhancing perfusion pressure altered ROV responses to a similar extent between young and older adults (P < 0.05). Upper limb arterial stiffness was not associated with peak (r = 0.02; P = 0.93) or total vascular conductance (r = −0.01; P = 0.96) in the group as a whole. Our data suggest that: (i) age‐associated attenuations in ROV are not attributable to a mechanical component; (ii) enhancing perfusion pressure augments ROV to a similar extent between young and older adults; and (iii) basal upper limb arterial stiffness is not associated with the vasodilator responses after a single skeletal muscle contraction in young and older adults.
A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles
Authors: Xie Yeming , Han Koon Hee , Grainger Nathan , Li Wen , Corrigan Robert D. , Perrino Brian A.
Published: March 2018

Key points

Activation of focal adhesion kinase (FAK) by integrin signalling facilitates smooth muscle contraction by transmitting the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue.

Here we report that electrical field stimulation (EFS) of cholinergic motor neurons activates FAK in gastric fundus smooth muscles, and that FAK activation by EFS is atropine‐sensitive but nicardipine‐insensitive. PDBu and calyculin A contracted gastric fundus muscles Ca2+‐independently and also activated FAK.

Inhibition of FAK activation inhibits the contractile responses evoked by EFS, and inhibits CPI‐17 phosphorylation at T38.

This study indicates that mechanical force or tension is sufficient to activate FAK, and that FAK appears to be involved in the activation of the protein kinase C–CPI‐17 Ca2+ sensitization pathway in gastric fundus smooth muscles.

These results reveal a novel role for FAK in gastric fundus smooth muscle contraction by facilitating CPI‐17 phosphorylation.

Smooth muscle contraction involves regulating myosin light chain phosphorylation and dephosphorylation by myosin light chain kinase and myosin light chain phosphatase. C‐kinase potentiated protein phosphatase‐1 inhibitor of 17 kDa (CPI‐17) and myosin phosphatase targeting subunit of myosin light‐chain phosphatase (MYPT1) are crucial for regulating gastrointestinal smooth muscle contraction by inhibiting myosin light chain phosphatase. Integrin signalling involves the dynamic recruitment of several proteins, including focal adhesion kinase (FAK), to focal adhesions. FAK tyrosine kinase activation is involved in cell adhesion to the extracellular matrix via integrin signalling. FAK participates in linking the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here, we show that cholinergic stimulation activates FAK in gastric fundus smooth muscles. Electrical field stimulation in the presence of Nω‐nitro‐l‐arginine methyl ester and MRS2500 contracted gastric fundus smooth muscle strips and increased FAK Y397 phosphorylation (pY397). Atropine blocked the contractions and prevented the increase in pY397. The FAK inhibitor PF‐431396 inhibited the contractions and the increase in pY397. PF‐431396 also inhibited the electrical field stimulation‐induced increase in CPI‐17 T38 phosphorylation, and reduced MYPT1 T696 and T853, and myosin light chain S19 phosphorylation. Ca2+ influx was unaffected by PF‐431396. Nicardipine inhibited the contractions but had no effect on the increase in pY397. Phorbol 12,13‐dibutyrate or calyculin A contracted gastric fundus smooth muscle strips Ca2+ independently and increased pY397. Our findings suggest that FAK is activated by mechanical forces during contraction and reveal a novel role of FAK in the regulation of CPI‐17 phosphorylation.
The effect of resonance on transient microbubble acoustic response: Experimental observations and numerical simulations
Authors: Efthymiou K. , Pelekasis N. , Butler M. B. , Thomas D. H. , Sboros V.
Published: March 2018

A large number of acoustic signals from single lipid-shelled Definity® (Lantheus Medical Imaging, N. Billerica, MA) microbubbles have been measured using a calibrated microacoustic system, and a unique transient characteristic of resonance has been identified in the onset of scatter. Comparison of the numerically obtained response of microbubbles with acoustic measurements provides good agreement for a soft shell that is characterized by small area dilatation modulus and strain softening behavior, and identifies time to maximum radial excursion and scatter as a robust marker of resonance during transient response. As the sound amplitude increases a two-population pattern emerges in the time delay vs the fundamental acoustic scatter plots, consisting of an initial part pertaining to microbubbles with less than resonant rest radii, which corresponds to the weaker second harmonic resonance, and the dominant resonant envelope pertaining to microbubbles with resonant and greater than resonant rest radii, which corresponds to the primary and subharmonic resonances. Consequently, a wider resonant spectrum is observed. It is a result of the strain softening nature of soft lipid shells, based on which the microbubble sizes corresponding to the above resonances decrease as the sound amplitude increases. This bares an impact on the selection of an optimal microbubble size pertaining to subharmonic imaging.
Experimental characterization of the propagation of guided acoustic waves in pipe strings
Authors: Redissi Ahmed , Miller Scott
Published: March 2018

This paper experimentally characterizes the propagation of guided acoustic waves in pipe strings. It verifies through experiments the dispersion phenomenon in cylindrical waveguides and shows how it matches the expected theoretical results that were previously derived in the literature and also experimentally confirms that pipe strings have certain passbands and stopbands that will allow signals with certain frequencies to propagate and will inhibit others. The theoretical dispersion relation was computed for frequencies between 0 and 5 kHz. Then, an experimental testbed was used to produce measured results which were found to agree nicely with the theoretical results.
Environmental inversion using dispersion tracking in a shallow water environment
Authors: Michalopoulou Zoi-Heleni , Aunsri Nattapol
Published: March 2018

It has been previously shown using synthetic data that dispersion tracking with particle filtering can be used for sediment sound speed inversion. Here, dispersion tracking is performed with data collected in the Gulf of Mexico for sediment sound speed and thickness and water column depth estimation. In this experiment, sound that propagates a long distance from the source allows the identification of dispersion curves reflecting the different group velocities of modal frequencies within and across modes. Although the data are noisy, dispersion curves are tracked with sequential filtering and used for inversion. Probability density functions of the three unknown parameters are obtained. Water column depth is estimated with little uncertainty. The estimated sound speed is representative of sandy sediment and the sediment thickness matches to a large extent prior knowledge.
Cognitive disruption by noise-vocoded speech stimuli: Effects of spectral variation
Authors: Senan Toros Ufuk , Jelfs Sam , Kohlrausch Armin
Published: March 2018

The effect of irrelevant sounds on short-term memory was investigated in two experiments using noise-vocoded speech stimuli (NVSS). Speech samples were systematically modified by a noise-vocoder and a set of stimuli varying from amplitude-modulated white noise to intelligible speech was created. Eight NVSS conditions, composed of 1-, 2-, 4-, 6-, 9-, 12-, 15-, and 18-bands, were used as the distracting stimuli in a digit-recall task next to the speech and silence conditions. The results showed that performance decreased with the number of frequency bands up to the 6-bands condition, but there was no influence of number of bands on performance beyond six bands. The results were analyzed using four acoustic metrics proposed in the literature: the frequency domain correlation coefficient (FDCC), the fluctuation strength, the speech transmission index (STI), and the normalized covariance measure (NCM). None of the metrics successfully predicted the results. However, the parameter values of the FDCC, the STI, and the NCM indicated that a prediction model for irrelevant sound effect should account for both temporal and spectral features of the irrelevant sounds.
The Origin of Chromosomal Replication Is Asymmetrically Positioned on the Mycobacterial Nucleoid, and the Timing of Its Firing Depends on HupB
Authors: Hołówka Joanna , Trojanowski Damian , Janczak Mateusz , Jakimowicz Dagmara , Zakrzewska-Czerwińska Jolanta
Published: March 2018

The bacterial chromosome undergoes dynamic changes in response to ongoing cellular processes and adaptation to environmental conditions. Among the many proteins involved in maintaining this dynamism, the most abundant is the nucleoid-associated protein (NAP) HU. In mycobacteria, the HU homolog, HupB, possesses an additional C-terminal domain that resembles that of eukaryotic histones H1/H5. Recently, we demonstrated that the highly abundant HupB protein occupies the entirety of theMycobacterium smegmatischromosome and that the HupB-binding sites exhibit a bias from the origin (oriC) to the terminus (ter). In this study, we used HupB fused with enhanced green fluorescent protein (EGFP) to perform the first analysis of chromosome dynamics and to track theoriCand replication machinery directly on the chromosome during the mycobacterial cell cycle. We show that the chromosome is located in an off-center position that reflects the unequal division and growth of mycobacterial cells. Moreover, unlike the situation inE. coli, the sisteroriCregions ofM. smegmatismove asymmetrically along the mycobacterial nucleoid. Interestingly, in this slow-growing organism, the initiation of the next round of replication precedes the physical separation of sister chromosomes. Finally, we show that HupB is involved in the precise timing of replication initiation.

IMPORTANCEAlthough our view of mycobacterial nucleoid organization has evolved considerably over time, we still know little about the dynamics of the mycobacterial nucleoid during the cell cycle. HupB is a highly abundant mycobacterial nucleoid-associated protein (NAP) with an indispensable histone-like tail. It was previously suggested as a potential target for antibiotic therapy against tuberculosis. Here, we fused HupB with enhanced green fluorescent protein (EGFP) to study the dynamics of the mycobacterial chromosome in real time and to monitor the replication process directly on the chromosome. Our results reveal that, unlike the situation inEscherichia coli, the nucleoid of an apically growing mycobacterium is positioned asymmetrically within the cell throughout the cell cycle. We show that HupB is involved in controlling the timing of replication initiation. Since tuberculosis remains a serious health problem, studies concerning mycobacterial cell biology are of great importance.
Chemotaxis Arrays in Vibrio Species and Their Intracellular Positioning by the ParC/ParP System
Authors: Ringgaard Simon , Yang Wen , Alvarado Alejandra , Schirner Kathrin , Briegel Ariane
Published: March 2018

Most motile bacteria are able to bias their movement toward more favorable environments or to escape from obnoxious substances by a process called chemotaxis. Chemotaxis depends on a chemosensory system that is able to sense specific environmental signals and generate a behavioral response.
Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing
Authors: Shnayder Miri , Nachshon Aharon , Krishna Benjamin , Poole Emma , Boshkov Alina , Binyamin Amit , Maza Itay , Sinclair John , Schwartz Michal , Stern-Ginossar Noam
Published: March 2018

Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome RNA sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistencein vivois prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.

IMPORTANCEHuman cytomegalovirus is a prevalent pathogen, infecting most of the population worldwide and establishing lifelong latency in its hosts. Although reactivation from latency causes significant morbidity and mortality in immunocompromised hosts, our molecular understanding of the latent state remains limited. Here, we examine the viral gene expression during natural and experimental latent HCMV infection on a transcriptome-wide level. In contrast to the classical views on herpesvirus latency, we find no evidence for a restricted latency-associated viral gene expression program. Instead, we reveal that latency gene expression largely resembles a late lytic viral profile, albeit at much lower levels of expression. Taken together, our data transform the current view of HCMV persistence and suggest that latency is mainly governed by quantitative rather than qualitative changes in viral gene expression.
Predicting the Susceptibility of Meningococcal Serogroup B Isolates to Bactericidal Antibodies Elicited by Bivalent rLP2086, a Novel Prophylactic Vaccine
Authors: McNeil Lisa K. , Donald Robert G. K. , Gribenko Alexey , French Roger , Lambert Nathaniel , Harris Shannon L. , Jones Thomas R. , Li Sheng , Zlotnick Gary , Vogel Ulrich , Claus Heike , Abad Raquel , Vazquez Julio A. , Borrow Ray , Findlow Jamie , Taha Muhamed-Kheir , Deghmane Ala-Eddine , Caugant Dominique A. , Kriz Paula , Musilek Martin , Wang Xin , Vuong Jeni , Mayer Leonard W. , Pride Michael W. , Jansen Kathrin U. , Anderson Annaliesa S.
Published: March 2018

Bivalent rLP2086 (Trumenba), a vaccine for prevention of
Neisseria meningitidis
serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement-mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the
in vitro
fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates (
n
= 1,814,
n
= 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies.

IMPORTANCE
Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of
N. meningitidis
serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates.
Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
Authors: Doherty Matthew K. , Ding Tao , Koumpouras Charlie , Telesco Shannon E. , Monast Calixte , Das Anuk , Brodmerkel Carrie , Schloss Patrick D.
Published: March 2018

The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn’s disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects’ fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects’ baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated withFaecalibacteriumandEscherichiaorShigella. The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P= 0.020). Their baseline community structures were also significantly different (P= 0.017). Two OTUs affiliated withFaecalibacterium(P= 0.003) andBacteroides(P= 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P= 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.

IMPORTANCECD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especiallyFaecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.
Conditional Protein Splicing Switch in Hyperthermophiles through an Intein-Extein Partnership
Authors: Lennon Christopher W. , Stanger Matthew , Banavali Nilesh K. , Belfort Marlene
Published: March 2018

Inteins are intervening proteins that undergo an autocatalytic splicing reaction that ligates flanking host protein sequences termed exteins. Some intein-containing proteins have evolved to couple splicing to environmental signals; this represents a new form of posttranslational regulation. Of particular interest is RadA from the archaeon
Pyrococcus horikoshii
, for which long-range intein-extein interactions block splicing, requiring temperature and single-stranded DNA (ssDNA) substrate to splice rapidly and accurately. Here, we report that splicing of the intein-containing RadA from another archaeon,
Thermococcus sibericus
, is activated by significantly lower temperatures than is
P. horikoshii
RadA, consistent with differences in their growth environments. Investigation into variations between
T. sibericus
and
P. horikoshii
RadA inteins led to the discovery that a nonconserved region (NCR) of the intein, a flexible loop where a homing endonuclease previously resided, is critical to splicing. Deletion of the NCR leads to a substantial loss in the rate and accuracy of
P. horikoshii
RadA splicing only within native exteins. The influence of the NCR deletion can be largely overcome by ssDNA, demonstrating that the splicing-competent conformation can be achieved. We present a model whereby the NCR is a flexible hinge which acts as a switch by controlling distant intein-extein interactions that inhibit active site assembly. These results speak to the repurposing of the vestigial endonuclease loop to control an intein-extein partnership, which ultimately allows exquisite adaptation of protein splicing upon changes in the environment.

IMPORTANCE
Inteins are mobile genetic elements that interrupt coding sequences (exteins) and are removed by protein splicing. They are abundant elements in microbes, and recent work has demonstrated that protein splicing can be controlled by environmental cues, including the substrate of the intein-containing protein. Here, we describe an intein-extein collaboration that controls temperature-induced splicing of RadA from two archaea and how variation in this intein-extein partnership results in fine-tuning of splicing to closely match the environment. Specifically, we found that a small sequence difference between the two inteins, a flexible loop that likely once housed a homing endonuclease used for intein mobility, acts as a switch to control intein-extein interactions that block splicing. Our results argue strongly that some inteins have evolved away from a purely parasitic lifestyle to control the activity of host proteins, representing a new form of posttranslational regulation that is potentially widespread in the microbial world.
Mucolipin-2 Cation Channel Increases Trafficking Efficiency of Endocytosed Viruses
Authors: Rinkenberger Nicholas , Schoggins John W.
Published: March 2018

Receptor-mediated endocytosis is a cellular process commonly hijacked by viruses to enter cells. The stages of entry are well described for certain viruses, but the host factors that mediate each step are less well characterized. We previously identified endosomal cation channel mucolipin-2 (MCOLN2) as a host factor that promotes viral infection. Here, we assign a role for MCOLN2 in modulating viral entry. We show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require transport to late endosomes for infection, including influenza A virus, yellow fever virus, and Zika virus. We further identify a rare allelic variant of human
MCOLN2
that has a loss-of-function phenotype with respect to viral enhancement. These findings establish a mechanistic link between an endosomal cation channel and late stages of viral entry.

IMPORTANCE
Viruses must co-opt cellular processes to complete their life cycle. To enter cells, viruses frequently take advantage of cellular receptor-mediated endocytosis pathways. A growing number of host proteins are implicated in these viral uptake pathways. Here, we describe a new role for the gated cation channel MCOLN2 in viral entry. This endosomal protein modulates viral entry by enhancing the efficiency of viral trafficking through the endosomal system. Thus, MCOLN2-mediated enhancement of infection may represent a key vulnerability in the viral life cycle that could be targeted for therapeutic intervention.
Metagenomes Reveal Global Distribution of Bacterial Steroid Catabolism in Natural, Engineered, and Host Environments
Authors: Holert Johannes , Cardenas Erick , Bergstrand Lee H. , Zaikova Elena , Hahn Aria S. , Hallam Steven J. , Mohn William W.
Published: March 2018

Steroids are abundant growth substrates for bacteria in natural, engineered, and host-associated environments. This study analyzed the distribution of the aerobic 9,10-seco steroid degradation pathway in 346 publically available metagenomes from diverse environments. Our results show that steroid-degrading bacteria are globally distributed and prevalent in particular environments, such as wastewater treatment plants, soil, plant rhizospheres, and the marine environment, including marine sponges. Genomic signature-based sequence binning recovered 45 metagenome-assembled genomes containing a majority of 9,10-seco pathway genes. Only
Actinobacteria
and
Proteobacteria
were identified as steroid degraders, but we identified several alpha- and gammaproteobacterial lineages not previously known to degrade steroids. Actino- and proteobacterial steroid degraders coexisted in wastewater, while soil and rhizosphere samples contained mostly actinobacterial ones. Actinobacterial steroid degraders were found in deep ocean samples, while mostly alpha- and gammaproteobacterial ones were found in other marine samples, including sponges. Isolation of steroid-degrading bacteria from sponges confirmed their presence. Phylogenetic analysis of key steroid degradation proteins suggested their biochemical novelty in genomes from sponges and other environments. This study shows that the ecological significance as well as taxonomic and biochemical diversity of bacterial steroid degradation has so far been largely underestimated, especially in the marine environment.

IMPORTANCE
Microbial steroid degradation is a critical process for biomass decomposition in natural environments, for removal of important pollutants during wastewater treatment, and for pathogenesis of bacteria associated with tuberculosis and other bacteria. To date, microbial steroid degradation was mainly studied in a few model organisms, while the ecological significance of steroid degradation remained largely unexplored. This study provides the first analysis of aerobic steroid degradation in diverse natural, engineered, and host-associated environments via bioinformatic analysis of an extensive metagenome data set. We found that steroid-degrading bacteria are globally distributed and prevalent in wastewater treatment plants, soil, plant rhizospheres, and the marine environment, especially in marine sponges. We show that the ecological significance as well as the taxonomic and biochemical diversity of bacterial steroid degradation has been largely underestimated. This study greatly expands our ecological and evolutionary understanding of microbial steroid degradation.
Conversion of RpoS
−
Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS
+
Improves Their Resistance to Host Defense Barriers
Authors: Burda Whittney N. , Brenneman Karen E. , Gonzales Amanda , Curtiss Roy
Published: March 2018

Recombinant attenuated
Salmonella
vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of
Salmonella
to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS
+
derivative of Ty2 was better at inducing immune responses than its RpoS
−
counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against
S
. Typhi or in using
S
. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens.
A Novel
aadA
Aminoglycoside Resistance Gene in Bovine and Porcine Pathogens
Authors: Cameron Andrew , Klima Cassidy L. , Ha Reuben , Gruninger Robert J. , Zaheer Rahat , McAllister Tim A.
Published: March 2018

Aminoglycosides are important antimicrobials used worldwide for prophylaxis and/or therapy in multiple production animal species. The emergence of new resistance genes jeopardizes current pathogen detection and treatment methods. The risk of resistance gene transfer to other animal and human pathogens is elevated when resistance genes are carried by mobile genetic elements. This study identified a new variant of a spectinomycin/streptomycin resistance gene harbored in a self-transmissible mobile element. The gene was also present in four different bovine pathogen species.
Toxoplasma gondii LCAT Primarily Contributes to Tachyzoite Egress
Authors: Schultz Aric J. , Carruthers Vern B.
Published: March 2018

Toxoplasma gondii
is one of the most successful human pathogens, infecting an estimated 2.5 billion people across the globe. Pathogenesis seen during acute or reactivated toxoplasmosis has been closely tied to the parasite’s intracellular lytic life cycle, which culminates in an event called egress that results in the release of freshly replicated parasites from the infected host cell. Despite the highly destructive, cytolytic nature of this event and its downstream consequences, very little is known about how the parasite accomplishes this step. Previous work has suggested a role for a secreted phospholipase, LCAT, in
Toxoplasma
egress and roles in cell traversal and egress in the
Plasmodium
species orthologue. We confirm here that LCAT-deficient tachyzoites are unable to efficiently egress from infected monolayers, and we provide evidence that LCAT catalytic activity is required for its role in egress.
Ecosystem Microbiology of Coral Reefs: Linking Genomic, Metabolomic, and Biogeochemical Dynamics from Animal Symbioses to Reefscape Processes
Authors: Wegley Kelly Linda , Haas Andreas F. , Nelson Craig E.
Published: March 2018

Over the past 2 decades, molecular techniques have established the critical role of both free-living and host-associated microbial partnerships in the environment. Advancing research to link microbial community dynamics simultaneously to host physiology and ecosystem biogeochemistry is required to broaden our understanding of the ecological roles of environmental microbes.
Microbiomes
In Natura
: Importance of Invertebrates in Understanding the Natural Variety of Animal-Microbe Interactions
Authors: Petersen Jillian M. , Osvatic Jay
Published: March 2018

Animals evolved in a world teeming with microbes, which play pivotal roles in their health, development, and evolution. Although the overwhelming majority of living animals are invertebrates, the minority of “microbiome” studies focus on this group.
Microbial Eukaryotes: a Missing Link in Gut Microbiome Studies
Authors: Laforest-Lapointe Isabelle , Arrieta Marie-Claire
Published: March 2018

Human-associated microbial communities include prokaryotic and eukaryotic organisms across high-level clades of the tree of life. While advances in high-throughput sequencing technology allow for the study of diverse lineages, the vast majority of studies are limited to bacteria, and very little is known on how eukaryote microbes fit in the overall microbial ecology of the human gut.
Omics-Based Insights into Flavor Development and Microbial Succession within Surface-Ripened Cheese
Authors: Bertuzzi A. S. , Walsh A. M. , Sheehan J. J. , Cotter P. D. , Crispie F. , McSweeney P. L. H. , Kilcawley K. N. , Rea M. C.
Published: March 2018

Fermented foods, in particular, surface-ripened cheese, represent a model to explain the metabolic interactions which regulate microbial succession in complex environments. This study explains the role of individual species in a heterogeneous microbial environment, i.e., the exterior of surface-ripened cheese. Through whole-metagenome shotgun sequencing, it was possible to investigate the metabolic potential of the resident microorganisms and show how variations in the microbial populations influence important aspects of cheese ripening, especially flavor development. Overall, in addition to providing fundamental insights, this research has considerable industrial relevance relating to the production of fermented food with specific qualities.
Sports-related injuries in New Zealand: National Insurance (Accident Compensation Corporation) claims for five sporting codes from 2012 to 2016
Authors: King Doug , Hume Patria A , Hardaker Natalie , Cummins Cloe , Gissane Conor , Clark Trevor
Published: March 2018

Objectives

To provide epidemiological data and related costs for sport-related injuries of five sporting codes (cricket, netball, rugby league, rugby union and football) in New Zealand for moderate-to-serious and serious injury claims.

Methods

A retrospective analytical review using detailed descriptive epidemiological data obtained from the Accident Compensation Corporation (ACC) for 2012–2016.

Results

Over the 5 years of study data, rugby union recorded the most moderate-to-serious injury entitlement claims (25 226) and costs (New Zealand dollars (NZD$)267 359 440 (£139 084 749)) resulting in the highest mean cost (NZD$10 484 (£5454)) per moderate-to-serious injury entitlement claim. Rugby union recorded more serious injury entitlement claims (n=454) than cricket (t(4)=−66.6; P<0.0001); netball (t(4)=−45.1; P<0.0001); rugby league (t(4)=−61.4; P<0.0001) and football (t(4)=66.6; P<0.0001) for 2012–2016. There was a twofold increase in the number of female moderate-to-serious injury entitlement claims for football (RR 2.6 (95%CI 2.2 to 2.9); P<0.0001) compared with cricket, and a threefold increase when compared with rugby union (risk ratio (RR) 3.1 (95%CI 2.9 to 3.3); P<0.0001). Moderate-to-serious concussion claims increased between 2012 and 2016 for netball (RR 3.7 (95%CI 1.9 to 7.1); P<0.0001), rugby union (RR 2.0 (95% CI 1.6 to 2.4); P<0.0001) and football (RR 2.3 (95%CI 1.6 to 3.2); P<0.0001). Nearly a quarter of moderate-to-serious entitlement claims (23%) and costs (24%) were to participants aged 35 years or older.

Conclusions

Rugby union and rugby league have the highest total number and costs associated with injury. Accurate sport exposure data are needed to enable injury risk calculations.
Influence of military component and deployment-related experiences on mental disorders among Canadian military personnel who deployed to Afghanistan: a cross-sectional survey
Authors: Boulos David , Fikretoglu Deniz
Published: March 2018

Objective

The primary objective was to explore differences in mental health problems (MHP) between serving Canadian Armed Forces (CAF) components (Regular Force (RegF); Reserve Force (ResF)) with an Afghanistan deployment and to assess the contribution of both component and deployment experiences to MHP using covariate-adjusted prevalence difference estimates. Additionally, mental health services use (MHSU) was descriptively assessed among those with a mental disorder.

Design

Data came from the 2013 CAF Mental Health Survey, a cross-sectional survey of serving personnel (n=72 629). Analyses were limited to those with an Afghanistan deployment (population n=35 311; sampled n=4854). Logistic regression compared MHP between RegF and ResF members. Covariate-adjusted prevalence differences were computed.

Primary outcome measure

The primary outcomes were MHP, past-year mental disorders, identified using the WHO’s Composite International Diagnostic Interview, and past-year suicide ideation.

Results

ResF personnel were less likely to be identified with a past-year anxiety disorder (adjusted OR (AOR)=0.72 (95% CI 0.58 to 0.90)), specifically both generalised anxiety disorder and panic disorder, but more likely to be identified with a past-year alcohol abuse disorder (AOR=1.63 (95% CI 1.04 to 2.58)). The magnitude of the covariate-adjusted disorder prevalence differences for component was highest for the any anxiety disorder outcome, 2.8% (95% CI 1.0 to 4.6); lower for ResF. All but one deployment-related experience variable had some association with MHP. The ‘ever felt responsible for the death of a Canadian or ally personnel’ experience had the strongest association with MHP; its estimated covariate-adjusted disorder prevalence difference was highest for the any (of the six measured) mental disorder outcome (11.2% (95% CI 6.6 to 15.9)). Additionally, ResF reported less past-year MHSU and more past-year civilian MHSU.

Conclusions

Past-year MHP differences were identified between components. Our findings suggest that although deployment-related experiences were highly associated with MHP, these only partially accounted for MHP differences between components. Additional research is needed to further investigate MHSU differences between components.
Analysis of ground-based observations of some exoplanets
Authors: Püsküllü Çağlar , Soydugan Faruk
Published: March 2018

We present analyses of the transit light curves and transit time measurements of the exoplanets HAT-P-3b, HD 189733b, and WASP-43b. Transit light curves were collected at Çanakkale Onsekiz Mart University Observatory and TÜBİTAK National Observatory. The models were produced by WINFITTER code and stellar, planetary, and orbital properties were obtained and discussed. We searched for significant signals at the O-C diagrams generated with our transit times and additional data based on Exoplanet Transit Database.
The effect of global climate change on the future distribution of economically important macroalgae (seaweeds) in the northwest Atlantic
Authors: Khan Amina H. , Levac Elisabeth , Van Guelphen Lou , Pohle Gerhard , Chmura Gail L.
Published: March 2018

An increase in greenhouse gas emissions has led to a rise in average global air and ocean temperatures. Increased sea surface temperatures can cause changes in species’ distributions, particularly those species close to their thermal tolerance limits. We use a bioclimate envelope approach to assess potential shifts in the range of marine macroalgae harvested in North American waters: rockweed ( Fucus vesiculosus Linnaeus, 1753), serrated wrack ( Fucus serratus Linnaeus, 1753), knotted wrack ( Ascophyllum nodosum (Linnaeus) Le Jolis, 1863), carrageen moss ( Chondrus crispus Stackhouse, 1797), and three kelp species ( Laminaria digitata (Hudson) J.V. Lamouroux, 1813; Saccharina latissima (Linnaeus) C.E. Lane, C. Mayes, Druehl et G.W. Saunders, 2006; and Saccharina longicruris (Bachelot de la Pylaie) Kuntze, 1891). We determined species’ thermal limits from the current sea surface temperatures associated with their geographical distributions. Future distributions were based on sea surface temperatures projected for the year ∼2100 by four atmosphere-ocean general circulation models and earth system models for regional concentration pathways (RCPs) 4.5 and 8.5. Future distributions based on RCP 8.5 indicate that the presence of all but rockweed ( F. vesiculosus) is likely to be threatened by warming waters in the Gulf of St. Lawrence and along the Atlantic coast of Nova Scotia. Range retractions of macroalgae will have significant ecological and economic effects including impacts on commercial fisheries and harvest rates and losses of floral and faunal biodiversity and production, and should be considered in the designation of marine protected areas.
A fuzzy rumor spreading model based on transmission capacity
Authors: Zhang Yi , Xu Jiuping , Wu Yue
Published: March 2018

This paper proposes a rumor spreading model that considers three main factors: the event importance, event ambiguity, and the publics critical sense, each of which are defined by decision makers using linguistic descriptions and then transformed into triangular fuzzy numbers. To calculate the resultant force of these three factors, the transmission capacity and a new parameter category with fuzzy variables are determined. A rumor spreading model is then proposed which has fuzzy parameters rather than the fixed parameters in traditional models. As the proposed model considers the comprehensive factors affecting rumors from three aspects rather than examining special factors from a particular aspect. The proposed rumor spreading model is tested using different parameters for several different conditions on BA networks and three special cases are simulated. The simulation results for all three cases suggested that events of low importance, those that are only clarifying facts, and those that are strongly critical do not result in rumors. Therefore, the model assessment results were proven to be in agreement with reality. Parameters for the model were then determined and applied to an analysis of the 7.23 Yong–Wen line major transportation accident (YWMTA). When the simulated data were compared with the real data from this accident, the results demonstrated that the interval for the rumor spreading key point in the model was accurate, and that the key point for the YWMTA rumor spread fell into the range estimated by the model.