bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of polyphenols in modern nutrition
Authors: Williamson G.
Published: August 2017

Polyphenols are found in plant‐based foods and beverages, notably apples, berries, citrus fruit, plums, broccoli, cocoa, tea and coffee and many others. There is substantial epidemiological evidence that a diet high in polyphenol‐rich fruit, vegetables, cocoa and beverages protects against developing cardiovascular disease and type 2 diabetes. The absorption and metabolism of these compounds have been well described and, for many, the gut microbiota play a critical role in absorption; taking into consideration the parent compound and the metabolites from colon bacteria catabolism, more than 80% of a dose can be absorbed and ultimately excreted in the urine. Common polyphenols in the diet are flavanols (cocoa, tea, apples, broad beans), flavanones (hesperidin in citrus fruit), hydroxycinnamates (coffee, many fruits), flavonols (quercetin in onions, apples and tea) and anthocyanins (berries). Many intervention studies, mechanistic in vitro data and epidemiological studies support a role for polyphenols against the development of chronic diseases. For example, flavanols decrease endothelial dysfunction, lower blood pressure and cholesterol, and modulate energy metabolism. Coffee and tea both reduce the risk of developing type 2 diabetes, through action of their constituent polyphenols. Despite extensive research, the exact mechanisms of action of polyphenols in the human body have not been decisively proven, but there is strong evidence that some targets such as nitric oxide metabolism, carbohydrate digestion and oxidative enzymes are important for health benefits. Consumption of polyphenols as healthy dietary components is consistent with the advice to eat five or more portions of fruit and vegetables per day, but it is currently difficult to recommend what ‘doses’ of specific polyphenols should be consumed to derive maximum benefit.
Serum low‐density lipoprotein as a dietary responsive biomarker of cardiovascular disease risk: Consensus and confusion
Authors: Griffin B. A.
Published: August 2017

The replacement of saturated fatty acids (SFA) has been the mainstay of our dietary guidelines to help prevent cardiovascular disease (CVD) for over 30 years. However, the underlying evidence to support this guideline is now held in contentious disrepute on the grounds of an apparent lack of evidence, largely from meta‐analyses, for a direct relationship between saturated fat and CVD mortality. This can be explained by the fact that the relationship between dietary SFA and CVD is not direct, but indirect and mediated through the low‐density lipoprotein cholesterol (LDL‐C) raising effects of certain SFA, in certain foods. There is over 100 years of evidence to link raised serum cholesterol with CVD and to support the current consensus that serum LDL is causally related to CVD morbidity and mortality. Nevertheless, the role of LDL as a biomarker of CVD risk, as measured by its cholesterol content (LDL‐C), is often confused with its contribution to cardio‐metabolic risk by its conversion into small and dense LDL particles with increased potential to cause CVD. The clinical utility of serum LDL is outstanding as a biomarker for CVD, albeit through an increase in its cholesterol mass (LDL‐C), its small particle size or over‐abundance of these particles. What is of overriding importance is to identify and modify these characteristics in LDL at the earliest stage of their development and to reduce the associated CVD risk through appropriate and sustained changes in diet and lifestyle.
Platelet transfusion to reverse antiplatelet therapy before decompressive surgery in patients with intracranial haemorrhage
Authors: Baschin M. , Selleng S. , Zeden J.‐P. , Westphal A. , Kohlmann T. , Schroeder H. W. , Greinacher A. , Thiele T.
Published: August 2017

Background

Platelet concentrates (PC) are transfused to improve primary haemostasis before urgent neurosurgery in patients with intracranial haemorrhage (ICH) receiving antiplatelet therapy (APT). It is unresolved, whether PCs increase the risk for major cardio‐ and cerebrovascular adverse events. We evaluated a standardized transfusion regimen to reverse APT in patients with ICH who required decompressive neurosurgery.

Methods

Analysed were consecutive patients between 2012 and 2014. The primary outcome was the frequency of new arterial thrombotic complications. The secondary outcome was the frequency of recurrent ICH.

Results

Of 72 patients, 14 received acetylsalicylic acid and a P2Y12 inhibitor, 53 received acetylsalicylic acid and five clopidogrel. No acute coronary syndrome (95% CI: 0–5·07) and one ischaemic stroke occurred (1·4%; 95% CI: 0·25–7·46). In contrast, 26·4% of patients developed recurrent ICH (95% CI: 17·59–37·58). The risk of bleeding was significantly higher compared to the risk of arterial thrombosis (P < 0·00001) and was increased for patients with chronic ICH (OR: 4·78; 95% CI: 1·57–14·55) and those receiving clopidogrel (OR: 2·78; 95% CI: 0·90–8·57).

Conclusion

Platelet concentrate transfusion before cranial decompressive surgery in patients with ICH complicating APT showed a low risk for cardio‐cerebral thrombotic complications. However, the risk of rebleeding remains high, especially in patients with chronic ICH and those pretreated with clopidogrel.
An engineered S1P chaperone attenuates hypertension and ischemic injury
Authors: Swendeman Steven L. , Xiong Yuquan , Cantalupo Anna , Yuan Hui , Burg Nathalie , Hisano Yu , Cartier Andreane , Liu Catherine H. , Engelbrecht Eric , Blaho Victoria , Zhang Yi , Yanagida Keisuke , Galvani Sylvain , Obinata Hideru , Salmon Jane E. , Sanchez Teresa , Di Lorenzo Annarita , Hla Timothy
Published: August 2017

Cardiovascular diseases could be treated by chaperones that deliver the lipid mediator S1P that promotes endothelial function.
Papers of note in
Science Translational Medicine
9
(402)
Authors: Ferrarelli Leslie K.
Published: August 2017

This week’s articles describe a way to prevent a major side effect of chemotherapy, paths of endocrine therapy resistance in breast cancer, and a new treatment for type 1 diabetes.
Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats
Authors: Lin Yu-Wei , Zhou Qi Tony , Hu Yang , Onufrak Nikolas J. , Sun Siping , Wang Jiping , Forrest Alan , Chan Hak-Kim , Li Jian
Published: August 2017

Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10−4liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.
Drug Susceptibility and Replicative Capacity of Multidrug-Resistant Recombinant Human Cytomegalovirus Harboring Mutations in
UL56
and
UL54
Genes
Authors: Piret Jocelyne , Goyette Nathalie , Boivin Guy
Published: August 2017

Letermovir is an investigational antiviral agent with a novel mechanism of action involving the viral terminase (pUL56). We evaluated the impact of the V236M mutation in the
UL56
gene alone and in combination with the E756K mutation in the
UL54
gene on drug susceptibility and viral replicative capacity of recombinant human cytomegalovirus. The double mutant exhibited at least borderline resistance to all antivirals tested (ganciclovir, foscarnet, cidofovir, brincidofovir, and letermovir) and replicated less efficiently than the wild-type virus
in vitro
.
Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection
Authors: Berube Bryan J. , Murphy Katherine R. , Torhan Matthew C. , Bowlin Nicholas O. , Williams John D. , Bowlin Terry L. , Moir Donald T. , Hauser Alan R.
Published: August 2017

Pseudomonas aeruginosa
is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or microabscess formation. The rising incidence of multidrug resistance among
P. aeruginosa
isolates has increased both the economic burden and the morbidity and mortality associated with
P. aeruginosa
disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells
in vitro
. In this study, we used a mouse model of
P. aeruginosa
abscess formation to test the
in vivo
efficacy of these compounds against the
P. aeruginosa
type III secretion system (T3SS). Bacteria used the T3SS to intoxicate infiltrating neutrophils to establish abscesses. Despite this antagonism, sufficient numbers of functioning neutrophils remained for proper containment of the abscesses, as neutrophil depletion resulted in an increased abscess size, the formation of dermonecrotic lesions on the skin, and the dissemination of
P. aeruginosa
to internal organs. Consistent with the specificity of the T3SS-neutrophil interaction,
P. aeruginosa
bacteria lacking a functional T3SS were fully capable of causing abscesses in a neutropenic host. Phenoxyacetamide inhibitors attenuated abscess formation and aided in the immune clearance of the bacteria. Finally, a
P. aeruginosa
strain resistant to the phenoxyacetamide compound was fully capable of causing abscess formation even in the presence of the T3SS inhibitors. Together, our results further define the role of type III secretion in murine abscess formation and demonstrate the
in vivo
efficacy of phenoxyacetamide inhibitors in
P. aeruginosa
infection.
Mediator Tail Module Is Required for Tac1-Activated
CDR1
Expression and Azole Resistance in Candida albicans
Authors: Liu Zhongle , Myers Lawrence C.
Published: August 2017

The human fungal pathogen
Candida albicans
develops drug resistance after long-term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of-function (GOF) mutations in the transcription factor Tac1 and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which
C. albicans
acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C terminus of Tac1. GOF mutations within the Tac1 TAD, outside the context of full-length Tac1, generally do not enhance its absolute potential as a transcriptional activator. Negative regulation of the Tac1 TAD by the Tac1 middle region is necessary for the activating effect of GOF mutations or fluphenazine to be realized. We have found that full-length Tac1, when hyperactivated by xenobiotics or GOF mutations, facilitates the recruitment of the Mediator coactivator complex to the
CDR1
promoter. Azole resistance and the activation of Tac1 target genes, such as
CDR1
, are dependent on the Tac1 TAD and subunits of the Mediator tail module. The dependence of different Tac1 target promoters on the Mediator tail module, however, varies widely. Lastly, we show that hyperactivation of Tac1 is correlated with its Mediator-dependent phosphorylation, a potentially useful biomarker for Tac1 hyperactivation. The role of Mediator in events downstream of Tac1 hyperactivation in fluconazole-resistant clinical isolates is complex and provides opportunities and challenges for therapeutic intervention.
Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced
MDR1
Expression and Fluconazole Resistance
Authors: Liu Zhongle , Myers Lawrence C.
Published: August 2017

Long-term azole treatment of patients with chronic
Candida albicans
infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation of
MDR1
, a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We identified the Swi/Snf chromatin remodeling complex as a key coactivator for Mrr1, which is required to maintain basal and induced open chromatin, and Mrr1 occupancy, at the
MDR1
promoter. Deletion of
snf2
, the catalytic subunit of Swi/Snf, largely abrogates the increases in
MDR1
expression and fluconazole MIC observed in
MRR1
GOF
mutant strains. Mediator positively and negatively regulates key Mrr1 target promoters. Deletion of the Mediator tail module
med3
subunit reduces, but does not eliminate, the increased
MDR1
expression and fluconazole MIC conferred by
MRR1
GOF
mutations. Eliminating the kinase activity of the Mediator Ssn3 subunit suppresses the decreased
MDR1
expression and fluconazole MIC of the
snf2
null mutation in
MRR1
GOF
strains. Ssn3 deletion also suppresses
MDR1
promoter histone displacement defects in
snf2
null mutants. The combination of this work with studies on other hyperactive zinc cluster transcription factors that confer azole resistance in fungal pathogens reveals a complex picture where the induction of drug efflux pump expression requires the coordination of multiple coactivators. The observed variations in transcription factor and target promoter dependence of this process may make the search for azole sensitivity-restoring small molecules more complicated.
Relationships of Vancomycin Pharmacokinetics to Body Size and Composition Using a Novel Pharmacomorphomic Approach Based on Medical Imaging
Authors: Pai Manjunath P. , Derstine Brian A. , Lichty Matt , Ross Brian E. , Sullivan June A. , Su Grace L. , Wang Stewart C.
Published: August 2017

Antibiotics such as vancomycin are empirically dosed on the basis of body weight, which may not be optimal across the expanding adult body size distribution. Our aim was to compare the relationships between morphomic parameters generated from computed tomography images to conventional body size metrics as predictors of vancomycin pharmacokinetics (PK). This single-center retrospective study included 300 patients with 1,622 vancomycin concentration (52% trough) measurements. Bayesian estimation was used to compute individual vancomycin volume of distribution of the central compartment (Vc) and clearance (CL). Approximately 45% of patients were obese with an overall median (5th, 95th percentile) weight and body mass index of 87.2 (54.7, 123) kg and 28.8 (18.9, 43.7) kg/m
2
, respectively. Morphomic parameters of body size such as body depth, total body area, and torso volume of the twelfth thoracic through fourth lumbar vertebrae (T12 to L4) correlated with Vc. The relationship of vancomycin Vc was poorly predicted by body size but was stronger with T12-to-L4 torso volume (coefficient of determination [
R
2
] = 0.11) than weight (
R
2
= 0.04). No relationships between vancomycin CL and traditional body size metrics could be discerned; however, relationships with skeletal muscle volume and total psoas area were found. Vancomycin CL independently correlated with total psoas area and inversely correlated with age. Thus, vancomycin CL was significantly related to total psoas area over age (
R
2
= 0.23,
P
< 0.0001). This proof-of-concept study suggests a potential role for translation of radiographic information into parameters predictive of drug pharmacokinetics. Prediction of individual antimicrobial pharmacokinetic parameters using analytic morphomics has the potential to improve antimicrobial dose selection and outcomes of obese patients.
RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus
Authors: Jain Ira , Miller Eric W. , Danger Jessica L. , Pflughoeft Kathryn J. , Sumby Paul
Published: August 2017

Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease. This is true for the group A
Streptococcus
(GAS), a pathogen that causes both invasive (e.g., necrotizing fasciitis) and noninvasive (e.g., pharyngitis) diseases. The
c
ontrol
o
f
v
irulence (CovRS) two-component system has a major role in regulating GAS virulence factor expression. The
r
egulator
o
f
c
ov (RocA) protein, which is a predicted kinase, functions in an undetermined manner through CovRS to alter gene expression and reduce invasive disease virulence. Here, we show that the ectopic expression of a truncated RocA derivative, harboring the membrane-spanning domains but not the dimerization or HATPase domain, is sufficient to complement a
rocA
mutant strain. Coupled with a previous bioinformatic study, the data are consistent with RocA being a pseudokinase. RocA reduces the ability of serotype M1 GAS isolates to express capsule and to evade killing in human blood, phenotypes that are not observed for M3 or M18 GAS due to isolates of these serotypes naturally harboring mutant
rocA
alleles. In addition, we found that varying the RocA concentration attenuates the regulatory activity of Mg
2+
and the antimicrobial peptide LL-37, which positively and negatively regulate CovS function, respectively. Thus, we propose that RocA is an accessory protein to the CovRS system that influences the ability of GAS to modulate gene expression in response to host factors. A model of how RocA interacts with CovRS, and of the regulatory consequences of such activity, is presented.
Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection
Authors: Bhowmick Rudra , Clark Stacie , Bonventre Joseph V. , Leong John M. , McCormick Beth A.
Published: August 2017

Pulmonary infection byStreptococcus pneumoniaeis characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A3(HXA3) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge withS. pneumoniae. As phospholipase A2(PLA2) promotes the release of AA, we investigated the role of PLA2in local and systemic disease duringS. pneumoniaeinfection. The group IVA cytosolic isoform of PLA2(cPLA2α) was activated uponS. pneumoniaeinfection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blockedS. pneumoniae-induced PMN transepithelial migrationin vitro. Genetic ablation of the cPLA2isoform cPLA2α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge withS. pneumoniae. The cPLA2α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA2α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection followingS. pneumoniaelung challenge.
Listeria monocytogenes Has Both Cytochrome
bd
-Type and Cytochrome
aa
3
-Type Terminal Oxidases, Which Allow Growth at Different Oxygen Levels, and Both Are Important in Infection
Authors: Corbett David , Goldrick Marie , Fernandes Vitor E. , Davidge Kelly , Poole Robert K. , Andrew Peter W. , Cavet Jennifer , Roberts Ian S.
Published: August 2017

Listeria monocytogenes
is a foodborne pathogen responsible for a number of life-threatening infections of humans. During an infection, it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here, we demonstrate that
L. monocytogenes
has two terminal oxidases, a cytochrome
bd
-type (CydAB) and a cytochrome
aa
3
-type menaquinol (QoxAB) oxidase, and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB
bd
-type oxidase is essential for aerobic respiration and intracellular replication, and
cydAB
mutants are highly attenuated in mice. In contrast, the QoxAB
aa
3
-type oxidase is required neither for aerobic respiration in air nor for intracellular growth. However, the
qoxAB
mutants are attenuated in mice, with a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB
aa
3
-type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (vol/vol), both oxidases are functional, and the presence of either is sufficient for aerobic respiration and intracellular replication. However, at 0.2% (vol/vol), both oxidases are necessary for maximum growth. These findings are consistent with the ability of
L. monocytogenes
to switch between terminal oxidases under different oxygen conditions, providing exquisite adaptation to different conditions encountered within the infected host.
Meeting Report on the ASM Conference on Mechanisms of Interbacterial Cooperation and Competition
Authors: Lories Bram , Parijs Ilse , Foster Kevin R. , Steenackers Hans P.
Published: August 2017

The American Society for Microbiology Conference on Mechanisms of Interbacterial Cooperation and Competition was held in Washington, DC, from 1 to 4 March 2017. The conference provided an international forum for sociomicrobiologists from different disciplines to present and discuss new findings. The meeting covered a wide range of topics, spanning molecular mechanisms, ecology, evolution, computation, and manipulation of interbacterial interactions, and encompassed social communities in medicine, the natural environment, and industry. This report summarizes the presentations and emerging themes.
Bacteriophages of
Gordonia
spp. Display a Spectrum of Diversity and Genetic Relationships
Authors: Pope Welkin H. , Mavrich Travis N. , Garlena Rebecca A. , Guerrero-Bustamante Carlos A. , Jacobs-Sera Deborah , Montgomery Matthew T. , Russell Daniel A. , Warner Marcie H. ,   Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES), Hatfull Graham F.
Published: August 2017

The global bacteriophage population is large, dynamic, old, and highly diverse genetically. Many phages are tailed and contain double-stranded DNA, but these remain poorly characterized genomically. A collection of over 1,000 phages infecting
Mycobacterium smegmatis
reveals the diversity of phages of a common bacterial host, but their relationships to phages of phylogenetically proximal hosts are not known. Comparative sequence analysis of 79 phages isolated on
Gordonia
shows these also to be diverse and that the phages can be grouped into 14 clusters of related genomes, with an additional 14 phages that are “singletons” with no closely related genomes. One group of six phages is closely related to Cluster A mycobacteriophages, but the other
Gordonia
phages are distant relatives and share only 10% of their genes with the mycobacteriophages. The
Gordonia
phage genomes vary in genome length (17.1 to 103.4 kb), percentage of GC content (47 to 68.8%), and genome architecture and contain a variety of features not seen in other phage genomes. Like the mycobacteriophages, the highly mosaic
Gordonia
phages demonstrate a spectrum of genetic relationships. We show this is a general property of bacteriophages and suggest that any barriers to genetic exchange are soft and readily violable.

IMPORTANCE
Despite the numerical dominance of bacteriophages in the biosphere, there is a dearth of complete genomic sequences. Current genomic information reveals that phages are highly diverse genomically and have mosaic architectures formed by extensive horizontal genetic exchange. Comparative analysis of 79 phages of
Gordonia
shows them to not only be highly diverse, but to present a spectrum of relatedness. Most are distantly related to phages of the phylogenetically proximal host
Mycobacterium smegmatis
, although one group of
Gordonia
phages is more closely related to mycobacteriophages than to the other
Gordonia
phages. Phage genome sequence space remains largely unexplored, but further isolation and genomic comparison of phages targeted at related groups of hosts promise to reveal pathways of bacteriophage evolution.
Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer
Authors: Balyasnikova Svetlana , Read James , Wotherspoon Andrew , Rasheed S , Tekkis Paris , Tait Diana , Cunningham David , Brown G
Published: August 2017

Introduction

Early rectal cancer (ERC) assessment should include prediction of the potential excision plane to safely remove lesions with clear deep margins and feasibility of organ preservation.

Method

MRI accuracy for differentiating ≤T1sm2 (partially preserved submucosa) or ≤T2 (partially preserved muscularis) versus >T2 tumours was compared with the gold standard of pT stage T1sm1/2 versus ≤pT2 versus >pT2. N stage was also compared. The MRI protocol employed a standard surface phased array coil with a high resolution (0.6×0.6×3 mm resolution). The staging data were analysed from a prospectively recorded database of all ERC (≤mrT3b) treated by primary surgery.

Results

Of 65 <mrT3b tumours, 45 were ≤pT2 and 14 were ≤pT1sm2. MRI accuracy for ≤T1sm2 was 89% (95% CI 63% to 87%), positive predictive value (PPV) 77% and negative predictive value (NPV) 92%, and for ≤T2 89% (95% CI 79% to 95%), PPV 93% and NPV 81%. Interobserver agreement between two experienced radiologists was >0.7 suggesting good agreement. 44 out of 65 patients underwent radical surgery and 22 out of 44 were ≤mrT2. MRI accuracy to predict lymph node status was 84% (95% CI 70% to 92%), PPV 71% and NPV 90%. Among the 21 out of 65 (32%) patients undergoing local excision or TEM, 20 out of 21 were staged as MR≤T2 and confirmed as such by pathology. On follow-up, none had relapse. If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment, a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95% CI 9% to 35%).

Conclusions

MRI is a useful tool for multidisciplinary teams (MDTs) wishing to optimise treatment options for ERC; these study findings will be validated in a prospective multicentre trial.
Single-nucleotide polymorphism data describe contemporary population structure and diversity in allochronic lineages of pink salmon (Oncorhynchus gorbuscha)
Authors: Tarpey Carolyn M. , Seeb James E. , McKinney Garrett J. , Templin William D. , Bugaev Alexander , Sato Shunpei , Seeb Lisa W.
Published: August 2017

Pink salmon, the most abundant Pacific salmon, have an obligate 2-year life cycle that leads to reproductively isolated even- and odd-year lineages. Using new and existing data, we examined the genetic structure of both lineages across their distributional range by genotyping 16 681 single-nucleotide polymorphisms for 383 individuals originating from seven pairs of even- and odd-year populations. Distinct differences in standing pools of genetic variation were identified between the lineages; we observed higher levels of heterozygosity, allelic richness, and significantly more private alleles in the odd-year lineage. However, the patterns of population structure were concordant between lineages: the Asian and northern Alaska populations displayed little differentiation but differed significantly from populations in southcentral Alaska and the Pacific Northwest. Our population structure results, in the context of known paleoecological information, suggest that both lineages occupied a northern Beringial refugium as well as a Cascadian refugium in North America during the Last Glacial Maximum. These results highlight the influence of historical patterns of habitat availability on contemporary population structure and support the hypothesis of a pre-glacial origin of the lineages.
Systematic reassessment of the first Jurassic pterosaur from Thailand
Authors: Unwin David M. , Martill David M.
Published: August 2017

A pterosaur humerus (PRC 64) from the Upper Jurassic of Thailand was initially assigned to the Azhdarchoidea, an important clade of edentulous Cretaceous pterodactyloid pterosaurs. Here it is reassigned, on the basis of morphological comparisons and a phylogenetic analysis, to the Rhamphorhynchidae, a widely distributed clade of small to medium-sized seemingly piscivorous basal pterosaurs. This record extends the geographical range of rhamphorhynchids and confirms recent findings that these pterosaurs inhabited continental as well as marginal marine ecosystems.
The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity
Authors: Burmeister Melissa A. , Brown Jacob D. , Ayala Jennifer E. , Stoffers Doris A. , Sandoval Darleen A. , Seeley Randy J. , Ayala Julio E.
Published: August 2017

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.
Effect of Propane and NaCl-SDS Solution on Nucleation Process of Mine Gas Hydrate
Authors: Zhang Qiang , Wu Qiang , Zhang Hui
Published: August 2017

In order to explore the method of accelerating hydration separation process to recover methane from mine gas, propane hydrate phase equilibrium was used to measure the equilibrium points of three kinds of mine gas in NaCl solution. Driving force was set as 1 MPa on this basis and high-pressure experimental apparatus of mine gas hydrate was used to carry out the nucleation kinetics experiments of mine gas hydrate for three gas samples in different concentrations of sodium chloride (NaCl) and sodium dodecyl sulfate (SDS) compound systems, which was to study the effect of propane and NaCl-SDS solution on nucleation process of mine gas hydrate. The results showed that induction time of multicomponent mine gas hydrate formation was shortened with the decrease of methane concentration and increase of propane concentration. The induction time of mine gas hydrate formation was shortened with the reduction of NaCl concentration and the increase of SDS concentration. It was found that methane and propane in multicomponent mine gas nucleated collaboratively, which simplified its nucleation process compared with the single component. NaCl has two kinds of functions.
Reliability Optimization and Importance Analysis of Circular‐Consecutive k‐out‐of‐n System
Authors: Zhang Shuai , Zhao Jiang-bin , Li Hong-guang , Wang Ning
Published: August 2017

The circular‐consecutive k‐out‐of‐n:F(G) system (Cir/Con/k/n:F(G) system) usually consists of n components arranged in a circle where the system fails (works) if consecutive k components fail (work). The optimization of the Cir/Con/k/n system is a typical case in the component assignment problem. In this paper, the Birnbaum importance‐based genetic algorithm (BIGA), which takes the advantages of genetic algorithm and Birnbaum importance, is introduced to deal with the reliability optimization for Cir/Con/k/n system. The detailed process and property of BIGA are put forward at first. Then, some numerical experiments are implemented, whose results are compared with two classic Birnbaum importance‐based search algorithms, to evaluate the effectiveness and efficiency of BIGA in Cir/Con/k/n system. Finally, three typical cases of Cir/Con/k/n systems are introduced to demonstrate the relationships among the component reliability, optimal permutation, and component importance.
Short-Term Regulation of FcγR-Mediated Phagocytosis by TLRs in Macrophages: Participation of 5-Lipoxygenase Products
Authors: Pinheiro Carla da S. , Monteiro Ana Paula T. , Dutra Fabiano F. , Bozza Marcelo T. , Peters-Golden Marc , Benjamim Claudia F. , Canetti Claudio
Published: August 2017

TLRs recognize a broad spectrum of microorganism molecules, triggering a variety of cellular responses. Among them, phagocytosis is a critical process for host defense. Leukotrienes (LTs), lipid mediators produced from 5-lipoxygenase (5-LO) enzyme, increase FcγR-mediated phagocytosis. Here, we evaluated the participation of TLR2, TLR3, TLR4, and TLR9 in FcγR-mediated phagocytosis and whether this process is modulated by LTs. Rat alveolar macrophages (AMs), murine bone marrow-derived macrophages (BMDMs), and peritoneal macrophages (PMs) treated with TLR2, TLR3, and TLR4 agonists, but not TLR9, enhanced IgG-opsonized sheep red blood cell (IgG-sRBC) phagocytosis. Pretreatment of AMs or BMDMs with drugs that block LT synthesis impaired the phagocytosis promoted by TLR ligands, and TLR potentiation was also abrogated in PMs and BMDMs from 5-LO−/−mice. LTB4production induced by IgG engagement was amplified by TLR ligands, while cys-LTs were amplified by activation of TLR2 and TLR4, but not by TLR3. We also noted higher ERK1/2 phosphorylation in IgG-RBC-challenged cells when preincubated with TLR agonists. Furthermore, ERK1/2 inhibition by PD98059 reduced the phagocytic activity evoked by TLR agonists. Together, these data indicate that TLR2, TLR3, and TLR4 ligands, but not TLR9, amplify IgG-mediated phagocytosis by a mechanism which requires LT production and ERK-1/2 pathway activation.
Programming for Stimulation-Induced Transient Nonmotor Psychiatric Symptoms after Bilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson’s Disease
Authors: Wu Xi , Qiu Yiqing , Simfukwe Keith , Wang Jiali , Chen Jianchun , Hu Xiaowu
Published: August 2017

Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (p=1.000). Conclusion. The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective.
Stereospecific Assay of (R)- and (S)-Goitrin in Commercial Formulation of Radix Isatidis by Reversed Phase High-Performance Liquid Chromatography
Authors: Nie Lixing , Dai Zhong , Ma Shuangcheng
Published: August 2017

Radix isatidis(Banlangen) is a widely used traditional Chinese medicine for treating fever and removing toxic heat. Pharmacological studies have indicated that (R)-goitrin (epigoitrin) is one of the main constituents accounting for its antiviral activity, while (S)-goitrin (goitrin) is known as an antithyroid factor. To better control the quality ofradix isatidisand its formulations, it is imperative to enantiomerically determine the contents of R- and S-goitrin. In this study, an enantioselective method based on reversed phase chromatography was developed for the assay of (R, S)-goitrin enantiomers. Optimum separation was obtained on an S-Chiral A column (4.6 mm × 250 mm, 5 μm) using methanol/water (30 : 70, v/v) as the mobile phase. After validation, the method was applied to quantify the enantiomers in Banlangen granules, which is the most prescribed commercial formulation ofradix isatidis. Compared to enantioselective resolution approaches based on normal phase chromatography, the new method could be conveniently performed using regular reversed phase high-performance liquid chromatography (RP-HPLC) equipment and was found to be more suitable for the enantioselective quality control of water-extracted and soluble medicines.
Efficacy of Blood Sources and Artificial Blood Feeding Methods in Rearing of Aedes aegypti (Diptera: Culicidae) for Sterile Insect Technique and Incompatible Insect Technique Approaches in Sri Lanka
Authors: Gunathilaka Nayana , Ranathunge Tharaka , Udayanga Lahiru , Abeyewickreme Wimaladharma
Published: August 2017

Introduction. Selection of the artificial membrane feeding technique and blood meal source has been recognized as key considerations in mass rearing of vectors. Methodology. Artificial membrane feeding techniques, namely, glass plate, metal plate, and Hemotek membrane feeding method, and three blood sources (human, cattle, and chicken) were evaluated based on feeding rates, fecundity, and hatching rates of Aedes aegypti. Significance in the variations among blood feeding was investigated by one-way ANOVA, cluster analysis of variance (ANOSIM), and principal coordinates (PCO) analysis. Results. Feeding rates of Ae. aegypti significantly differed among the membrane feeding techniques as suggested by one-way ANOVA (p<0.05). The metal plate method was identified as the most efficient and cost-effective feeding technique. Blood feeding rate of Ae. aegypti was higher with human blood followed by cattle and chicken blood, respectively. However, no significant difference was observed from the mosquitoes fed with cattle and human blood, in terms of fecundity, oviposition rate, and fertility as suggested by one-way ANOVA (p>0.05). Conclusions. Metal plate method could be recommended as the most effective membrane feeding technique for mass rearing of Ae. aegypti, due to its high feeding rate and cost effectiveness. Cattle blood could be recommended for mass rearing Ae. aegypti.
Methylene Blue Effectiveness as Local Analgesic after Anorectal Surgery: A Literature Review
Authors: Fransiska Dewi , Jeo Wifanto Saditya , Moenadjat Yefta , Friska Dewi
Published: August 2017

Background. Methylene blue (MB) has been found to have unique analgesic property through temporary disruption of sensory nerve conduction. In anorectal surgery, MB is widely used as a biologic stain but the analgesic effect has never been studied. Thus, a literature review completed with critical appraisal is required to find out its efficacy. Methods. A review has been run to find out its efficacy. Literature search proceeded in database sites, namely, PubMed, EBSCO, Cochrane, Wiley, and ProQuest using the following keywords: “anorectal” OR “hemorrhoid” OR “anal fistula” OR “anal fissure” OR “anal abscess” OR “anal pruritus” AND “methylene blue” AND “analgesic”; then the critical appraisal and its implication were discussed. Result. There were 491 articles in full text found, and four studies met the inclusion criteria. Two studies were focused on the evaluation of VAS in hemorrhoid surgery whereas the rest were focused on the evaluation of symptom score in anal pruritus. Conclusions. A study with level of evidence 2 on VAS showed the efficacy. The rest showed insufficient evidence due to variations of anorectal surgery and the methods and techniques of MB application. A further prospective clinical study is required.
Ex Vivo Expansion of Human Limbal Epithelial Cells Using Human Placenta-Derived and Umbilical Cord-Derived Mesenchymal Stem Cells
Authors: Nam Sang Min , Maeng Yong-Sun , Kim Eung Kweon , Seo Kyoung Yul , Lew Helen
Published: August 2017

Ex vivo culture of human limbal epithelial cells (LECs) is used to treat limbal stem cell (LSC) deficiency, a vision loss condition, and suitable culture systems using feeder cells or serum without animal elements have been developed. This study evaluated the use of human umbilical cord or placenta mesenchymal stem cells (C-MSCs or P-MSCs, resp.) as feeder cells in an animal/serum-free coculture system with human LECs. C-/P-MSCs stimulated LEC colony formation of the stem cell markers (p63, ABCG2) and secreted known LEC clonal growth factors (keratinocyte growth factor, β-nerve growth factor). Transforming growth factor-β-induced protein (TGFBIp), an extracellular matrix (ECM) protein, was produced by C-/P-MSCs and resulted in an increase in p63+ ABCG2+ LEC colonies. TGFBIp-activated integrin signaling molecules (FAK, Src, and ERK) were expressed in LECs, and TGFBIp-induced LEC proliferation was effectively blocked by a FAK inhibitor. In conclusion, C-/P-MSCs enhanced LEC culture by increasing growth of the LSC population by secreting growth factors and the ECM protein TGFBIp, which is suggested to be a novel factor for promoting the growth of LECs in culture. C-/P-MSCs may be useful for the generation of animal-free culture systems for the treatment of LSC deficiency.
Computational and Mathematical Methods to Estimate the Basic Reproduction Number and Final Size for Single-Stage and Multistage Progression Disease Models for Zika with Preventative Measures
Authors: Padmanabhan P. , Seshaiyer P.
Published: August 2017

We present new mathematical models that include the impact of using selected preventative measures such as insecticide treated nets (ITN) in controlling or ameliorating the spread of the Zika virus. For these models, we derive the basic reproduction number and sharp estimates for the final size relation. We first present a single-stage model which is later extended to a new multistage model for Zika that incorporates more realistic incubation stages for both the humans and vectors. For each of these models, we derive a basic reproduction number and a final size relation estimate. We observe that the basic reproduction number for the multistage model converges to expected values for a standard Zika epidemic model with fixed incubation periods in both hosts and vectors. Finally, we also perform several computational experiments to validate the theoretical results obtained in this work and study the influence of various parameters on the models.
Immunological Reactivity Using Monoclonal and Polyclonal Antibodies of Autoimmune Thyroid Target Sites with Dietary Proteins
Authors: Kharrazian Datis , Herbert Martha , Vojdani Aristo
Published: August 2017

Many hypothyroid and autoimmune thyroid patients experience reactions with specific foods. Additionally, food interactions may play a role in a subset of individuals who have difficulty finding a suitable thyroid hormone dosage. Our study was designed to investigate the potential role of dietary protein immune reactivity with thyroid hormones and thyroid axis target sites. We identified immune reactivity between dietary proteins and target sites on the thyroid axis that includes thyroid hormones, thyroid receptors, enzymes, and transport proteins. We also measured immune reactivity of either target specific monoclonal or polyclonal antibodies for thyroid-stimulating hormone (TSH) receptor, 5′deiodinase, thyroid peroxidase, thyroglobulin, thyroxine-binding globulin, thyroxine, and triiodothyronine against 204 purified dietary proteins commonly consumed in cooked and raw forms. Dietary protein determinants included unmodified (raw) and modified (cooked and roasted) foods, herbs, spices, food gums, brewed beverages, and additives. There were no dietary protein immune reactions with TSH receptor, thyroid peroxidase, and thyroxine-binding globulin. However, specific antigen-antibody immune reactivity was identified with several purified food proteins with triiodothyronine, thyroxine, thyroglobulin, and 5′deiodinase. Laboratory analysis of immunological cross-reactivity between thyroid target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune thyroid disease.
Impacts of Smart Configuration in Pedelec-Sharing: Evidence from a Panel Survey in Madrid
Authors: Munkácsy András , Monzón Andrés
Published: August 2017

Despite the recently increasing research interest, this is one of the first studies employing a panel sample of users and nonusers to understand the bike-sharing phenomenon (N=205). On the basis of a novel surveying technique, a case study on the clients of the state-of-the-art bike-sharing scheme of Madrid (Spain) is presented. BiciMAD is a system of the latest generation, namely, multimodal demand responsive bike-sharing: a fleet of electric pedal-assisted bicycles (pedelecs) with an advanced technology and unique smart service configuration to tackle challenges that may hinder the promotion of cycling and bike-sharing in the city. A statistical test has verified that there is a moderate association between previous intention and actual use of bike-sharing (Cramer’s V = 0.25) and both barriers and motivators of further use have been identified. Indicators on mobility patterns show that although drawing primarily from other sustainable modes of transport, bike-sharing has increased mobility (total number and distance of trips) and especially active travel but decreased the perceived travel time.