bluuebunny/crossref_metadata_2025 huggingface dataset:
(p)ppGpp-Dependent Persisters Increase the Fitness of Escherichia coli Bacteria Deficient in Isoaspartyl Protein Repair
Authors: VandenBerg Kelsey E. , Ahn Sarah , Visick Jonathan E.
Published: July 2016

The
l
-isoaspartyl protein carboxyl methyltransferase (PCM) repairs protein damage resulting from spontaneous conversion of aspartyl or asparaginyl residues to isoaspartate and increases long-term stationary-phase survival of
Escherichia coli
under stress. In the course of studies intended to examine PCM function in metabolically inactive cells, we identified
pcm
as a gene whose mutation influences the formation of ofloxacin-tolerant persisters. Specifically, a Δ
pcm
mutant produced persisters for an extended period in stationary phase, and a Δ
glpD
mutation drastically increased persisters in a Δ
pcm
background, reaching 23% of viable cells. The high-persister double mutant showed much higher competitive fitness than the
pcm
mutant in competition with wild type during long-term stationary phase, suggesting a link between persistence and the mitigation of unrepaired protein damage. We hypothesized that reduced metabolism in the high-persister strain might retard protein damage but observed no gross differences in metabolism relative to wild-type or single-mutant strains. However, methylglyoxal, which accumulates in
glpD
mutants, also increased fitness, suggesting a possible mechanism. High-level persister formation in the Δ
pcm
Δ
glpD
mutant was dependent on guanosine pentaphosphate [(p)ppGpp] and polyphosphate. In contrast, persister formation in the Δ
pcm
mutant was (p)ppGpp independent and thus may occur by a distinct pathway. We also observed an increase in conformationally unstable proteins in the high-persister strain and discuss this as a possible trigger for persistence as a response to unrepaired protein damage.

IMPORTANCE
Protein damage is an important factor in the survival and function of cells and organisms. One specific form of protein damage, the formation of the abnormal amino acid isoaspartate, can be repaired by a nearly universally conserved enzyme, PCM. PCM-directed repair is associated with stress survival and longevity in bacteria, insects, worms, plants, mice, and humans, but much remains to be learned about the specific effects of protein damage and repair. This paper identifies an unexpected connection between isoaspartyl protein damage and persisters, subpopulations in bacterial cultures showing increased tolerance to antibiotics. In the absence of PCM, the persister population in
Escherichia coli
bacteria increased, especially if the metabolic gene
glpD
was also mutated. High levels of persisters in
pcm glpD
double mutants correlated with increased fitness of the bacteria in a competition assay, and the fitness was dependent on the signal molecule (p)ppGpp; this may represent an alternative pathway for responding to protein damage.
The Accessory Genome of Shiga Toxin-Producing Escherichia coli Defines a Persistent Colonization Type in Cattle
Authors: Barth Stefanie A. , Menge Christian , Eichhorn Inga , Semmler Torsten , Wieler Lothar H. , Pickard Derek , Belka Ariane , Berens Christian , Geue Lutz
Published: July 2016

Shiga toxin-producing
Escherichia coli
(STEC) strains can colonize cattle for several months and may, thus, serve as gene reservoirs for the genesis of highly virulent zoonotic enterohemorrhagic
E. coli
(EHEC). Attempts to reduce the human risk for acquiring EHEC infections should include strategies to control such STEC strains persisting in cattle. We therefore aimed to identify genetic patterns associated with the STEC colonization type in the bovine host. We included 88 persistent colonizing STEC (STEC
per
) (shedding for ≥4 months) and 74 sporadically colonizing STEC (STEC
spo
) (shedding for ≤2 months) isolates from cattle and 16 bovine STEC isolates with unknown colonization types. Genoserotypes and multilocus sequence types (MLSTs) were determined, and the isolates were probed with a DNA microarray for virulence-associated genes (VAGs). All STEC
per
isolates belonged to only four genoserotypes (O26:H11, O156:H25, O165:H25, O182:H25), which formed three genetic clusters (ST21/396/1705, ST300/688, ST119). In contrast, STEC
spo
isolates were scattered among 28 genoserotypes and 30 MLSTs, with O157:H7 (ST11) and O6:H49 (ST1079) being the most prevalent. The microarray analysis identified 139 unique gene patterns that clustered with the genoserotypes and MLSTs of the strains. While the STEC
per
isolates possessed heterogeneous phylogenetic backgrounds, the accessory genome clustered these isolates together, separating them from the STEC
spo
isolates. Given the vast genetic heterogeneity of bovine STEC strains, defining the genetic patterns distinguishing STEC
per
from STEC
spo
isolates will facilitate the targeted design of new intervention strategies to counteract these zoonotic pathogens at the farm level.

IMPORTANCE
Ruminants, especially cattle, are sources of food-borne infections by Shiga toxin-producing
Escherichia coli
(STEC) in humans. Some STEC strains persist in cattle for longer periods of time, while others are detected only sporadically. Persisting strains can serve as gene reservoirs that supply
E. coli
with virulence factors, thereby generating new outbreak strains. Attempts to reduce the human risk for acquiring STEC infections should therefore include strategies to control such persisting STEC strains. By analyzing representative genes of their core and accessory genomes, we show that bovine STEC with a persistent colonization type emerged independently from sporadically colonizing isolates and evolved in parallel evolutionary branches. However, persistent colonizing strains share similar sets of accessory genes. Defining the genetic patterns that distinguish persistent from sporadically colonizing STEC isolates will facilitate the targeted design of new intervention strategies to counteract these zoonotic pathogens at the farm level.
Effects of Specimen Collection Methodologies and Storage Conditions on the Short-Term Stability of Oral Microbiome Taxonomy
Authors: Luo Ting , Srinivasan Usha , Ramadugu Kirtana , Shedden Kerby A. , Neiswanger Katherine , Trumble Erika , Li Jiean J. , McNeil Daniel W. , Crout Richard J. , Weyant Robert J. , Marazita Mary L. , Foxman Betsy
Published: July 2016

Community profiling of the oral microbiome requires the recovery of quality sequences in order to accurately describe microbial community structure and composition. Our objective was to assess the effects of specimen collection method, storage medium, and storage conditions on the relative abundance of taxa in saliva and plaque identified using 16S rRNA genes. We also assessed short-term changes in taxon composition and relative abundance and compared the salivary and dental plaque communities in children and adults. Over a 2-week period, four successive saliva and dental plaque specimens were collected from four adults with no dental decay (108 samples), and two successive specimens were collected from six children with four or more erupted teeth (48 samples). There were minimal differences in community composition at the phylum and operational taxonomic unit levels between dental plaque collection using a scaler and collection using a CytoSoft brush. Plaque samples stored in OMNIgene medium showed higher within-sample Shannon diversity, were compositionally different, and were more similar to each other than plaque stored in liquid dental transport medium. Saliva samples stored in OMNIgene recovered similar communities for at least a week following storage at room temperature. However, the microbial communities recovered from plaque and saliva stored in OMNIgene were significantly different in composition from their counterparts stored in liquid dental transport medium. Dental plaque communities collected from the same tooth type over four successive visits from the same adult did not significantly differ in structure or composition.

IMPORTANCE
Large-scale epidemiologic studies require collection over time and space, often with multiple teams collecting, storing, and processing data. Therefore, it is essential to understand how sensitive study results are to modest changes in collection and storage protocols that may occur with variation in personnel, resources available at a study site, and shipping requirements. The research presented in this paper measures the effects of multiple storage parameters and collection methodologies on the measured ecology of the oral microbiome from healthy adults and children. These results will potentially enable investigators to conduct oral microbiome studies at maximal efficiency by guiding informed administrative decisions pertaining to the necessary field or clinical work.
A Small Number of Phylogenetically Distinct Clonal Complexes Dominate a Coastal Vibrio cholerae Population
Authors: Kirchberger Paul C. , Orata Fabini D. , Barlow E. Jed , Kauffman Kathryn M. , Case Rebecca J. , Polz Martin F. , Boucher Yan
Published: July 2016

Vibrio cholerae
is a ubiquitous aquatic microbe in temperate and tropical coastal areas. It is a diverse species, with many isolates that are harmless to humans, while others are highly pathogenic. Most notable among them are strains belonging to the pandemic O1/O139 serogroup lineage, which contains the causative agents of cholera. The environmental selective regimes that led to this diversity are key to understanding how pathogens evolve in environmental reservoirs. A local population of
V. cholerae
and its close relative
Vibrio metoecus
from a coastal pond and lagoon system was extensively sampled during two consecutive months across four size fractions (480 isolates). In stark contrast to previous studies, the observed population was highly clonal, with 60% of
V. cholerae
isolates falling into one of five clonal complexes, which varied in abundance in the short temporal scale sampled.
V. cholerae
clonal complexes had significantly different distributions across size fractions and the two environments sampled, the pond and the lagoon. Sequencing the genomes of 20 isolates representing these five
V. cholerae
clonal complexes revealed different evolutionary trajectories, with considerable variations in gene content with potential ecological significance. Showing genotypic differentiation and differential spatial distribution, the dominant clonal complexes are likely ecologically divergent. Temporal variation in the relative abundance of these complexes suggests that transient blooms of specific clones could dominate local diversity.

IMPORTANCE
Vibrio cholerae
is commonly found in coastal areas worldwide, with only a single group of this bacterium capable of causing severe cholera outbreaks. However, the potential to evolve the ability to cause disease exists in many strains of this species in its aquatic reservoir. Understanding how pathogenic bacteria evolve requires the study of their natural environments. By extensive sampling in a geographically restricted location in the United States, we found that most cells of a
V. cholerae
population belong to only a small number of strains. Analysis of their genome composition and spatial distribution indicates differential environmental adaptations between these strains. Other strains exist in smaller numbers, and the population was found to be temporally varied. This suggests frequent bloom and collapse cycles on a time scale of weeks. These population dynamics make it possible that more virulent strains could stochastically rise to large numbers, allowing for infection to occur.
A Rapid Method for Quantifying Viable Mycobacterium avium subsp. paratuberculosis in Cellular Infection Assays
Authors: Pooley Hannah B. , de Silva Kumudika , Purdie Auriol C. , Begg Douglas J. , Whittington Richard J. , Plain Karren M.
Published: July 2016

Determining the viability of bacteria is a key outcome of
in vitro
cellular infection assays. Currently, this is done by culture, which is problematic for fastidious slow-growing bacteria such as
Mycobacterium avium
subsp.
paratuberculosis
, where it can take up to 4 months to confirm growth. This study aimed to identify an assay that can rapidly quantify the number of viable
M. avium
subsp.
paratuberculosis
cells in a cellular sample. Three commercially available bacterial viability assays along with a modified liquid culture method coupled with high-throughput quantitative PCR growth detection were assessed. Criteria for assessment included the ability of each assay to differentiate live and dead
M. avium
subsp.
paratuberculosis
organisms and their accuracy at low bacterial concentrations. Using the culture-based method,
M. avium
subsp.
paratuberculosis
growth was reliably detected and quantified within 2 weeks. There was a strong linear association between the 2-week growth rate and the initial inoculum concentration. The number of viable
M. avium
subsp.
paratuberculosis
cells in an unknown sample was quantified based on the growth rate, by using growth standards. In contrast, none of the commercially available viability assays were suitable for use with samples from
in vitro
cellular infection assays.

IMPORTANCE
Rapid quantification of the viability of
Mycobacterium avium
subsp.
paratuberculosis
in samples from
in vitro
cellular infection assays is important, as it allows these assays to be carried out on a large scale.
In vitro
cellular infection assays can function as a preliminary screening tool, for vaccine development or antimicrobial screening, and also to extend findings derived from experimental animal trials. Currently, by using culture, it takes up to 4 months to obtain quantifiable results regarding
M. avium
subsp.
paratuberculosis
viability after an
in vitro
infection assay; however, with the quantitative PCR and liquid culture method developed, reliable results can be obtained at 2 weeks. This method will be important for vaccine and antimicrobial screening work, as it will allow a greater number of candidates to be screened in the same amount of time, which will increase the likelihood that a favorable candidate will be found to be subjected to further testing.
Socioeconomic status inequalities in low-grade inflammation during childhood
Authors: Schmeer Kammi K , Yoon Aimee
Published: July 2016

Background

Family socioeconomic status (SES) is an important source of child health disparities in the USA. Chronic stress is one way SES may impact children's physiology with implications for later health inequalities. These processes may work differently across childhood due to differences in exposure and susceptibility to stressors at different ages. We assess associations between family SES and one biomarker of chronic stress exposure—low-grade inflammation detected by elevated C reactive protein (CRP)—and evaluate differences in the associations by child age.

Methods

We used nationally representative data from the National Health and Nutrition Examination Survey and Tobit regression models to estimate SES associations with CRP and the moderating effects of age for children age 2–18 years. Our sample was limited to CRP ≤10 mg/l to focus on low-grade inflammation (N=13 165).

Results

Children whose parent had less than a high school degree had 35% higher CRP than those with a college graduate parent; and, poor children had 24% higher CRP than those with high family income, net of controls. When children's body mass index was accounted for, low education and poverty associations were reduced to 19% and 15%, respectively. Child age interactions were negative and significant for both parental education and family income.

Conclusions

This study provides new evidence that SES is associated with low-grade inflammation in children, and that these associations may be particularly strong during early and mid-childhood. Future research should further our understanding of stressors related to low family SES that may lead to immune system dysregulation during childhood.
Population attributable risk estimates for factors associated with non-use of postnatal care services among women in Nigeria
Authors: Agho K E , Ezeh O K , Issaka A I , Enoma A I , Baines S , Renzaho A M N
Published: July 2016

Objectives

To determine population attributable risks (PARs) estimates for factors associated with non-use of postnatal care (PNC) in Nigeria.

Design, setting and participants

The most recent Nigeria Demographic and Health Survey (NDHS, 2013) was examined. The study consisted of 20 467 mothers aged 15–49 years. Non-use of PNC services was examined against a set of demographic, health knowledge and social structure factors, using multilevel regression analysis. PARs estimates were obtained for each factor associated with non-use of PNC in the final multivariate logistic regression model.

Main outcome

PNC services.

Results

Non-use of PNC services was attributed to 68% (95% CI 56% to 76%) of mothers who delivered at home, 61% (95% CI 55% to 75%) of those who delivered with the help of non-health professionals and 37% (95% CI 31% to 45%) of those who lacked knowledge of delivery complications in the study population. Multiple variable analyses revealed that non-use of PNC services among mothers was significantly associated with rural residence, household poverty, no or low levels of mothers' formal education, small perceived size of neonate, poor knowledge of delivery-related complications, and limited or no access to the mass media.

Conclusions

PAR estimates for factors associated with non-use of PNC in Nigeria highlight the need for community-based interventions regarding maternal education and services that focus on mothers who delivered their babies at home. Our study also recommends financial support from the Nigerian government for mothers from low socioeconomic settings, so as to minimise the inequitable access to pregnancy and delivery healthcare services with trained healthcare personnel.
Differing expression profiles ofNotch/enterocyte andWnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours
Authors: Gui Xianyong , Meng Ziran , McConnell Yarrow J , Liu Shuhong , Falck Vincent G , Mack Lloyd A , Temple Walley J
Published: July 2016

Background

Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven byNotch-Hes1pathway, while secretory lineage is driven byWnt-Math1pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3for goblet cells,Gfi1-Sox9for Paneth cells andNgn3-Pdx1/Beta2/Pax4for enteroendocrine cells).

Methods

The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray.

Results

CCT showed reducedHes1/Elf3andSox9/Klf4coupled with elevatedMath1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higherKlf4and similarNgn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed aNotchsignalling similar to adenocarcinoma. Mucinous tumours showed lowerElf3than normal appendiceal epithelium and higherMath1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showedNotchsignalling similar to other glandular tumours, but lowerKlf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation.

Conclusions

Wnt/secretory lineage protein andNotch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.
Single best answer question-writing tips for clinicians
Authors: Walsh J L , Harris B H L , Smith P E
Published: July 2016

Assessment is essential for progression in medical careers. Thus, an important aspect of developing as a clinical teacher is the ability to produce high-quality assessments for junior colleagues. The single best answer (SBA) question format is becoming ubiquitous in the assessment of the application of knowledge in clinical medicine; writing this style of examination question can be a challenge. This concise guide highlights key SBA question-writing tips, aiming to help aspiring clinical teachers set high-quality knowledge assessments.
Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload
Authors: Xu Hong , van Deel Elza D. , Johnson Mark R. , Opić Petra , Herbert Bronwen R. , Moltzer Els , Sooranna Suren R. , van Beusekom Heleen , Zang Wang-Fu , Duncker Dirk J. , Roos-Hesselink Jolien W.
Published: July 2016

In Western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density, and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a trend towards normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced phosphoinositide 3-kinase phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size, and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.
Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero
Authors: Hooper Christopher W. , Delaney Cassidy , Streeter Taylor , Yarboro Michael T. , Poole Stanley , Brown Naoko , Slaughter James C. , Cotton Robert B. , Reese Jeff , Shelton Elaine L.
Published: July 2016

Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.
The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery
Authors: Darios Emma S. , Winner Brittany M. , Charvat Trevor , Krasinksi Antoni , Punna Sreenivas , Watts Stephanie W.
Published: July 2016

The adipokine chemerin causes arterial contraction and is implicated in blood pressure regulation, especially in obese subjects with elevated levels of circulating chemerin. Because chemerin is expressed in the perivascular adipose tissue (PVAT) that surrounds the sympathetic innervation of the blood vessel, we tested the hypothesis that chemerin (endogenous and exogenous) amplifies the sympathetic nervous system in mediating electrical field-stimulated (EFS) contraction. The superior mesenteric artery, with or without PVAT and with endothelium and sympathetic nerve intact, was mounted into isolated tissue baths and used for isometric contraction and stimulation. Immunohistochemistry validated a robust expression of chemerin in the PVAT surrounding the superior mesenteric artery. EFS (0.3–20 Hz) caused a frequency-dependent contraction in isolated arteries that was reduced by the chemerin receptor ChemR23 antagonist CCX832 alone (100 nM; with, but not without, PVAT), but not by the inactive congener CCX826 (100 nM). Exogenous chemerin-9 (1 μM)-amplified EFS-induced contraction in arteries (with and without PVAT) was blocked by CCX832 and the α-adrenergic receptor antagonist prazosin. CCX832 did not directly inhibit, nor did chemerin directly amplify, norepinephrine-induced contraction. Whole mount immunohistochemical experiments support colocalization of ChemR23 with the sympathetic nerve marker tyrosine hydroxylase in superior mesenteric PVAT and, to a lesser extent, in arteries and veins. These studies support the idea that exogenous chemerin modifies sympathetic nerve-mediated contraction through ChemR23 and that ChemR23 may be endogenously activated. This is significant because of the well-appreciated role of the sympathetic nervous system in blood pressure control.
Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression
Authors: Sasse Sarah K. , Altonsy Mohammed O. , Kadiyala Vineela , Cao Gaoyuan , Panettieri Reynold A. , Gerber Anthony N.
Published: July 2016

Airway smooth muscle is a major target tissue for glucocorticoid (GC)-based asthma therapies, however, molecular mechanisms through which the GC receptor (GR) exerts therapeutic effects in this key airway cell type have not been fully elucidated. We previously identified the nuclear factor-κB (NF-κB) inhibitor, A20 (TNFAIP3), as a mediator of cytokine repression by glucocorticoids (GCs) in airway epithelial cells and defined cooperative regulation of anti-inflammatory genes by GR and NF-κB as a key mechanistic underpinning of airway epithelial GR function. Here, we expand on these findings to determine whether a similar mechanism is operational in human airway smooth muscle (HASM). Using HASM cells derived from normal and fatal asthma samples as an in vitro model, we demonstrate that GCs spare or augment TNF-mediated induction of A20 ( TNFAIP3), TNIP1, and NFKBIA, all implicated in negative feedback control of NF-κB-driven inflammatory processes. We applied chromatin immunoprecipitation and reporter analysis to show that GR and NF-κB directly regulate A20 expression in HASM through cooperative induction of an intronic enhancer. Using overexpression, we show for the first time that A20 and its interacting partner, TNIP1, repress TNF signaling in HASM cells. Moreover, we applied small interfering RNA-based gene knockdown to demonstrate that A20 is required for maximal cytokine repression by GCs in HASM. Taken together, our data suggest that inductive regulation of A20 by GR and NF-κB contributes to cytokine repression in HASM.
Tumor necrosis factor regulates NMDA receptor-mediated airway smooth muscle contractile function and airway responsiveness
Authors: Anaparti Vidyanand , Pascoe Christopher D. , Jha Aruni , Mahood Thomas H. , Ilarraza Ramses , Unruh Helmut , Moqbel Redwan , Halayko Andrew J.
Published: July 2016

We have shown that N-methyl-d-aspartate receptors (NMDA-Rs) are receptor-operated calcium entry channels in human airway smooth muscle (HASM) during contraction. Tumor necrosis factor (TNF) augments smooth muscle contractility by influencing pathways that regulate intracellular calcium flux and can alter NMDA-R expression and activity in cortical neurons and glial cells. We hypothesized that NMDA-R-mediated Ca2+and contractile responses of ASM can be altered by inflammatory mediators, including TNF. In cultured HASM cells, we assessed TNF (10 ng/ml, 48 h) effect on NMDA-R subunit abundance by quantitative PCR, confocal imaging, and immunoblotting. We observed dose- and time-dependent changes in NMDA-R composition: increased obligatory NR1 subunit expression and altered regulatory NR2 and inhibitory NR3 subunits. Measuring intracellular Ca2+flux in Fura-2-loaded HASM cultures, we observed that TNF exposure enhanced cytosolic Ca2+mobilization and changed the temporal pattern of Ca2+flux in individual myocytes induced by NMDA, an NMDA-R selective analog of glutamate. We measured airway responses to NMDA in murine thin-cut lung slices (TCLS) from allergen-naive animals and observed significant airway contraction. However, NMDA acted as a bronchodilator in TCLS from house dust mice-challenged mice and in allergen-naive TCLS subjected to TNF exposure. All contractile or bronchodilator responses were blocked by a selective NMDA-R antagonist, (2R)-amino-5-phosphonopentanoate, and bronchodilator responses were prevented by NG-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) or indomethacin (cyclooxygenase inhibitor). Collectively, we show that TNF augments NMDA-R-mediated Ca2+mobilization in HASM cells, whereas in multicellular TCLSs allergic inflammation and TNF exposure leads to NMDA-R-mediated bronchodilation. These findings reveal the unique contribution of ionotrophic NMDA-R to airway hyperreactivity.
A Canonical Correlation Analysis of AIDS Restriction Genes and Metabolic Pathways Identifies Purine Metabolism as a Key Cooperator
Authors: Ye Hanhui , Yuan Jinjin , Wang Zhengwu , Huang Aiqiong , Liu Xiaolong , Han Xiao , Chen Yahong
Published: July 2016

Human immunodeficiency virus causes a severe disease in humans, referred to as immune deficiency syndrome. Studies on the interaction between host genetic factors and the virus have revealed dozens of genes that impact diverse processes in the AIDS disease. To resolve more genetic factors related to AIDS, a canonical correlation analysis was used to determine the correlation between AIDS restriction and metabolic pathway gene expression. The results show that HIV-1 postentry cellular viral cofactors from AIDS restriction genes are coexpressed in human transcriptome microarray datasets. Further, the purine metabolism pathway comprises novel host factors that are coexpressed with AIDS restriction genes. Using a canonical correlation analysis for expression is a reliable approach to exploring the mechanism underlying AIDS.
Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension
Authors: Rain Silvia , Andersen Stine , Najafi Aref , Gammelgaard Schultz Jacob , da Silva Gonçalves Bós Denielli , Handoko M. Louis , Bogaard Harm-Jan , Vonk-Noordegraaf Anton , Andersen Asger , van der Velden Jolanda , Ottenheijm Coen A.C. , de Man Frances S.
Published: July 2016

Background—

The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction.

Methods and Results—

By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction.

Conclusions—

RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness.
Otto Bauer and the Philosophy of Praxis – Then and Now
Authors: Blum Mark E.
Published: July 2016

Otto Bauer (1881–1938) has emerged once more in the thought of Western Marxists. The dominant theoretical voice of the Austrian Social Democrats in the late Austrian-Hungarian Empire and the First Austrian Republic, Bauer was re-examined in the 1970s and ’80s as ‘the third way’ was being explored in European politics by Eurocommunists. Bauer again is being discussed in the twenty-first century as not only a European ‘third way’, but as a model for nations across the globe. Bauer’s vision theoretically as well as tactically between 1919 and 1934, when Austrian fascism ended the political efforts of Austrian Social Democracy, was of a pluralist parliamentary governance that sought through party coalitions and the influence of social experiment a developing societal praxis whose socialist principles would realise eventually Marx’s understanding of a classless society. A gradualism in long-range strategy and tactics would lead democratically to greater collective coexistence embracing differing cultures within and beyond separate nations. Reviewed here are five publications between 2005 and 2011 which are either thoughtfully supportive or critically dismissive of Bauer’s multi-cultural models for the socialist coexistence of communities and nations. Two conference collections and three books on Bauer’s thought and political life enable the contemporary mind to evaluate the seminal promise of Bauer’s Marxist understanding, where for him Marxism was a social-scientific instrument to guide societal development.
Existential Psychotherapies: Similarities and Differences Among the Main Branches
Authors: Correia Edgar A. , Cooper Mick , Berdondini Lucia , Correia Karla
Published: July 2016

Authors agree that a range of different existential therapies exist. However, not much has been written about what is characteristic and distinctive of each existential therapy, and the few claims that have been made are mainly hypothetical. Practitioners from the four main branches of existential therapy were asked about the authors and texts that have most influenced their practice and the practices they considered most characteristic of existential therapy. From all over the world, 29 daseinsanalysts, 82 existential-humanistic, 573 existential-phenomenological, and 303 logotherapy and/or existential analysis practitioners participated in this study. Data show that the scope of influence of an author is pretty much limited to the branch he or she is related to and only a few authors, in particular Frankl and Yalom, influence practitioners from all four branches. Five categories of practice are shared among the main existential branches as the most characteristics of existential therapy, with phenomenological practices being the most shared category: But the frequency of each of these categories of practice differs significantly depending on respondents’ training or affiliated branch. Data corroborate the idea of different existential therapies, with logotherapy and/or existential analysis being the most markedly different branch of them all.
The Right to Health in Old Age
Authors: Bershtling Orit , Doron Israel , Werner Perla , Laish-Shamir Adva
Published: July 2016

Objectives

To develop a better understanding of the right to health in old age through the personal knowledge and experience of older persons and professionals in Israel.

Methods

A qualitative research method was adopted based on focus groups. Information was collected through four focus groups with 33 participants.

Results

Three main themes emerged: The first focused on the older persons’ self-positioning vis-à-vis the health-care system. The second illustrated the verbal means chosen by the participants to situate the health-care system itself. The third elaborated on the institutional and cultural processes involved in upholding health rights in old age.

Discussion

Future discussions regarding conceptualization of the right to health in old age should relate to its human aspects, that is, communication and interaction, and the older person’s knowledge, participation, and involvement in shaping the medical services that they receive.
The determinants of skills use and work pressure: A longitudinal analysis
Authors: Felstead Alan , Gallie Duncan , Green Francis , Henseke Golo
Published: July 2016

Employers, workers and governments all have a stake in improving intrinsic job quality since it can help to raise worker well-being and lower the social costs of ill-health. This article provides a unique insight into factors triggering changes to two key aspects of intrinsic job quality – the skills used and developed at work, and the pressures under which work is carried out. Using a rare two-wave panel dataset, the article assesses whether three predicted determinants – namely employee involvement, teamworking and computerisation – are good or bad for these aspects of intrinsic job quality.
Simple Tools to Facilitate Project Management of a Nursing Research Project
Authors: Aycock Dawn M. , Clark Patricia C. , Thomas-Seaton LaTeshia , Lee Shih-Yu , Moloney Margaret
Published: July 2016

Highly organized project management facilitates rigorous study implementation. Research involves gathering large amounts of information that can be overwhelming when organizational strategies are not used. We describe a variety of project management and organizational tools used in different studies that may be particularly useful for novice researchers. The studies were a multisite study of caregivers of stroke survivors, an Internet-based diary study of women with migraines, and a pilot study testing a sleep intervention in mothers of low-birth-weight infants. Project management tools were used to facilitate enrollment, data collection, and access to results. The tools included protocol and eligibility checklists, event calendars, screening and enrollment logs, instrument scoring tables, and data summary sheets. These tools created efficiency, promoted a positive image, minimized errors, and provided researchers with a sense of control. For the studies described, there were no protocol violations, there were minimal missing data, and the integrity of data collection was maintained.
Race-ing Queerness
Authors: Eguchi Shinsuke , Washington Myra S.
Published: July 2016

We argue that the representations of sex, love, and relationships in the television series Downtown Los Angeles (DTLA) mirrors existing racialized, gendered, sexualized, and classed hierarchies of masculinities among queer men. DTLA attempts to project a more inclusive ideology through its focus on typically marginalized groups but fails to offer a space for resisting or subverting those hierarchies. For that reason, we complicate DTLA’s representations as reproducing normative hierarchies. By doing so, we reimagine the potentiality of mediated spaces where the intersections and complexities of differences are embraced.
Locating Caribbean Studies in unending conversation
Authors: Noxolo Pat
Published: July 2016

This essay works through how seeing Caribbean Studies from my singular location – a Caribbean diaspora human geographer based in the UK but interested in the Caribbean as an area of study – leads to ‘conversations’ with a range of differently located academics, and locates Caribbean Studies in very particular ways. The particular concept of conversation comes through Hall’s (1993) Walter Rodney Memorial Lecture, published as ‘Negotiating Caribbean Identities’ in New Left Review. This routing leads to two critiques of defining one’s own cultural and disciplinary identity through Caribbean Studies, and also points to a renewal of Caribbean Studies, through unending conversations in and with the region.
Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: Results of a 2-year prospective study, including an additional 1-year follow-up
Authors: Kimura Hiroshi , Kanahara Nobuhisa , Sasaki Tsuyoshi , Komatsu Naoya , Ishige Minoru , Muneoka Katsumasa , Ino Hidetoshi , Yoshimura Kazuyuki , Yamanaka Hiroshi , Suzuki Tomotaka , Komatsu Hideki , Watanabe Hiroyuki , Shimizu Eiji , Iyo Masaomi
Published: July 2016

Dopamine supersensitivity psychosis (DSP) resulting from antipsychotic treatment is related to treatment-resistant schizophrenia (TRS), and its treatment has not been established to date. Maintaining thoroughly stable occupancy of the dopamine D2 receptor by risperidone long-acting injectable (RLAI) is one strategy for treatment. In this study, RLAI was given as an adjunctive medication to oral antipsychotic(s), which were switched partially and gradually to RLAI in 108 treatment-resistant patients for an additional 1-year follow-up in a 2-year study, and to compare the effects in 72 patients with a DSP history (DSP group) and 36 patients without this history (NonDSP group). Although both groups showed significant improvements in the total Brief Psychotic Rating Scale (BPRS) score during the follow-up period, greater improvement was observed for the DSP group than the NonDSP group. High doses (> 850 mg chlorpromazine-dose combined of oral antipsychotics and RLAI) did not significantly change in both groups throughout the study period; however, extrapyramidal symptoms, including tardive dyskinesia, were significantly improved only in the patients with DSP. This study strongly suggested that the RLAI treatment, even with only partial switching, provides relief from refractory symptoms, particularly for patients with a history of DSP.

Clinical trial registration: http://www.umin.ac.jp/:UMIN000008487
Senecavirus A
Authors: Segalés J. , Barcellos D. , Alfieri A. , Burrough E. , Marthaler D.
Published: July 2016

Senecavirus A (SVA) is the only member of the genus Senecavirus within the family Picornaviridae. This virus was discovered as a serendipitous finding in 2002 (and named Seneca Valley virus 001 [SVV-001]) while cultivating viral vectors in cell culture and has been proposed for use as an oncolytic virus to treat different types of human neoplasia. SVA was found in lesions in pigs affected by porcine idiopathic vesicular disease in Canada and the USA in 2008 and 2012, respectively. In 2014 and 2015, SVA infection was associated with outbreaks of vesicular disease in sows as well as neonatal pig mortality in Brazil and the USA. Phylogenetic analysis of the SVA VP1 indicates the existence of 3 clades of the virus. Clade I contains the historical strain SVV-001, clade II contains USA SVA strains identified between 1988 and 1997, and clade III contains global SVA strains from Brazil, Canada, China, and the USA identified between 2001 and 2015. The aim of this review is to draw the attention of veterinarians and researchers to a recently described infectious clinical-pathologic condition caused by a previously known agent (SVA). Apart from the intrinsic interest in a novel virus infecting pigs and causing economic losses, the major current concern is the similarity of the clinical picture to that of other swine diseases, because one of them—foot and mouth disease—is a World Organization for Animal Health–listed disease. Because the potential association of SVA with disease is rather new, there are still many questions to be resolved.
A Perspective on Veterinary Forensic Pathology and Medicine in the United Kingdom
Authors: Newbery S. G. , Cooke S. W. , Martineau H. M.
Published: July 2016

Internationally, forensic medicine and pathology are increasingly recognized as an important aspect of work done by veterinary clinicians and veterinary pathologists. In this article, a forensic veterinary clinician, a forensic veterinary pathologist in private practice, and a forensic veterinary pathologist at a veterinary school discuss the interactions among veterinary clinicians, veterinary pathologists, and law enforcement agencies and how future interactions can be improved. The focus is on the United Kingdom, but many of the principles, challenges, and suggestions are applicable to other jurisdictions. Clinicians and pathologists require forensic training to enable them to apply their veterinary knowledge to suspected cases of animal abuse and to subsequently present their findings and conclusions to a court of law in a concise, professional, and unbiased manner, and some opportunities for such advanced training in the United Kingdom are indicated. It is important that forensic veterinary clinicians and pathologists interact in an unbiased and collegial manner to answer the questions posed by courts of law. Opportunities for improved training, communication, and interaction among forensic veterinarians, forensic scientists, and law enforcement are discussed.
Pathogenesis of Renal Lesions in Chickens After Experimental Infection With 9a5b Newcastle Disease Virus Mutant Isolate
Authors: El-Bahrawy A. , Zaid A. , Sunden Y. , Sakurai M. , Ito H. , Ito T. , Morita T.
Published: July 2016

In this study, we investigated the pathogenesis of Newcastle disease virus (NDV) in the chicken kidney. Twenty-six 32-day-old specific pathogen-free chickens were intranasally inoculated with the 9a5b NDV mutant isolate. Kidney tissue samples, collected at 6 and 12 hours postinoculation (hpi) and 1, 2, 3, 5, and 10 days postinoculation (dpi), were analyzed by histopathology, immunohistochemistry (IHC), reverse transcription polymerase chain reaction (RT-PCR), and virus titration. Histopathologically, tubulointerstitial nephritis was detected in the renal cortex and predominantly in the medulla. Nephrotropism of 9a5b NDV was confirmed by IHC, RT-PCR, and virus isolation. Massive degenerative changes and infiltration of CD3-immunopositive cells accompanied replication of the 9a5b NDV isolate in chicken kidneys. In conclusion, pathological changes that were caused by NDV in chicken kidneys were similar to those caused by avian influenza virus, infectious bronchitis virus, and avian nephritis virus, and this highlights the importance of including NDV in the differential diagnosis of kidney disease in chickens.
James Dyson (1948) Shrinkage of Sperry and Grinnell Glaciers, Glacier National Park, Montana. Geographical Review 38(1): 95–103
Authors: Goff Paepin , Butler David R.
Published: July 2016

A warming climate is melting the namesake glaciers of Glacier National Park, Montana, USA. James Dyson’s 1948 paper was one of the earliest publications to emphasize climate change impacts to the cryosphere through an examination of Sperry and Grinnell Glaciers. This paper, combined with his subsequent works, acts as a pillar for current glacier monitoring efforts.