bluuebunny/crossref_metadata_2025 huggingface dataset:
A Single Amino Acid Change in the Response Regulator PhoP, Acquired during Yersinia pestis Evolution, Affects PhoP Target Gene Transcription and Polymyxin B Susceptibility
Authors: Fukuto Hana S. , Vadyvaloo Viveka , McPhee Joseph B. , Poinar Hendrik N. , Holmes Edward C. , Bliska James B.
Published: February 2018

Yersinia pestis
, the causative agent of plague, evolved from the closely related pathogen
Yersinia pseudotuberculosis
. During its emergence,
Y. pestis
is believed to have acquired its unique pathogenic characteristics through numerous gene gains/losses, genomic rearrangements, and single nucleotide polymorphism (SNP) changes. One such SNP creates a single amino acid variation in the DNA binding domain of PhoP, the response regulator in the PhoP/PhoQ two-component system.
Y. pseudotuberculosis
and the basal human-avirulent strains of
Y. pestis
harbor glycines at position 215 of PhoP, whereas the modern human-virulent strains (e.g., KIM and CO92) harbor serines at this residue. Since PhoP plays multiple roles in the adaptation of
Y. pestis
to stressful host conditions, we tested whether this amino acid substitution affects PhoP activity or the ability of
Y. pestis
to survive in host environments. Compared to the parental KIM6+ strain carrying the modern allele of
phoP
(
phoP-S215
), a derivative carrying the basal allele (
phoP-G215
) exhibited slightly defective growth under a low-Mg
2+
condition and decreased transcription of a PhoP target gene,
ugd
, as well as an ∼8-fold increase in the susceptibility to the antimicrobial peptide polymyxin B. The
phoP-G215
strain showed no apparent defect in flea colonization, although a
phoP
-null mutant showed decreased flea infectivity in competition experiments. Our results suggest that the amino acid variation at position 215 of PhoP causes subtle changes in the PhoP activity and raise the possibility that the change in this residue have contributed to the evolution of increased virulence in
Y. pestis
.

IMPORTANCE
Y. pestis
acquired a single nucleotide polymorphism (SNP) in
phoP
when the highly human-virulent strains diverged from less virulent basal strains, resulting in an amino acid substitution in the DNA binding domain of the PhoP response regulator. We show that
Y. pestis
carrying the modern
phoP
allele has an increased ability to induce the PhoP-regulated
ugd
gene and resist antimicrobial peptides compared to an isogenic strain carrying the basal allele. Given the important roles PhoP plays in host adaptation, the results raise an intriguing possibility that this amino acid substitution contributed to the evolution of increased virulence in
Y. pestis
. Additionally, we present the first evidence that
phoP
confers a survival fitness advantage to
Y. pestis
inside the flea midgut.
Structural Basis of a Thiol-Disulfide Oxidoreductase in the Hedgehog-Forming Actinobacterium Corynebacterium matruchotii
Authors: Luong Truc Thanh , Tirgar Reyhaneh , Reardon-Robinson Melissa E. , Joachimiak Andrzej , Osipiuk Jerzy , Ton-That Hung
Published: February 2018

The actinobacterium
Corynebacterium matruchotii
has been implicated in nucleation of oral microbial consortia leading to biofilm formation. Due to the lack of genetic tools, little is known about basic cellular processes, including protein secretion and folding, in this organism. We report here a survey of the
C. matruchotii
genome, which encodes a large number of exported proteins containing paired cysteine residues, and identified an oxidoreductase that is highly homologous to the
Corynebacterium diphtheriae
thiol-disulfide oxidoreductase MdbA (MdbA
Cd
). Crystallization studies uncovered that the 1.2-Å resolution structure of
C. matruchotii
MdbA (MdbA
Cm
) possesses two conserved features found in actinobacterial MdbA enzymes, a thioredoxin-like fold and an extended α-helical domain. By reconstituting the disulfide bond-forming machine
in vitro
, we demonstrated that MdbA
Cm
catalyzes disulfide bond formation within the actinobacterial pilin FimA. A new gene deletion method supported that
mdbA
is essential in
C. matruchotii
. Remarkably, heterologous expression of MdbA
Cm
in the
C. diphtheriae
Δ
mdbA
mutant rescued its known defects in cell growth and morphology, toxin production, and pilus assembly, and this thiol-disulfide oxidoreductase activity required the catalytic motif CXXC. Altogether, the results suggest that MdbA
Cm
is a major thiol-disulfide oxidoreductase, which likely mediates posttranslocational protein folding in
C. matruchotii
by a mechanism that is conserved in
Actinobacteria
.

IMPORTANCE
The actinobacterium
Corynebacterium matruchotii
has been implicated in the development of oral biofilms or dental plaque; however, little is known about the basic cellular processes in this organism. We report here a high-resolution structure of a
C. matruchotii
oxidoreductase that is highly homologous to the
Corynebacterium diphtheriae
thiol-disulfide oxidoreductase MdbA. By biochemical analysis, we demonstrated that
C. matruchotii
MdbA catalyzes disulfide bond formation
in vitro
. Furthermore, a new gene deletion method revealed that deletion of
mdbA
is lethal in
C. matruchotii
. Remarkably,
C. matruchotii
MdbA can replace
C. diphtheriae
MdbA to maintain normal cell growth and morphology, toxin production, and pilus assembly. Overall, our studies support the hypothesis that
C. matruchotii
utilizes MdbA as a major oxidoreductase to catalyze oxidative protein folding.
Human Papillomaviruses Preferentially Recruit DNA Repair Factors to Viral Genomes for Rapid Repair and Amplification
Authors: Mehta Kavi , Laimins Laimonis
Published: February 2018

High-risk human papillomaviruses (HPVs) activate the ataxia telangiectasia mutated-dependent (ATM) DNA damage response as well as the ataxia telangiectasia mutated-dependent DNA-related (ATR) pathway in the absence of external DNA damaging agents for differentiation-dependent genome amplification. Through the use of comet assays and pulsed-field gel electrophoresis, our studies showed that these pathways are activated in response to DNA breaks induced by the viral proteins E6 and E7 alone and independently of viral replication. The majority of these virally induced DNA breaks are present in cellular DNAs and only minimally in HPV episomes. Treatment of HPV-positive cells with inhibitors of both ATM and ATR leads to the generation of DNA breaks and the fragmentation of viral episomes, indicating that DNA breaks are introduced into HPV genomes. These breaks, however, are rapidly repaired through the preferential recruitment of homologous recombination repair enzymes, such as RAD51 and BRCA1, to viral genomes at the expense of cellular DNAs. When HPV-positive cells are treated with hydroxyurea, this recruitment of RAD51 and BRCA1 to viral genomes is greatly enhanced with little recruitment to damaged cellular DNAs and with retention of the ability of viral genomes to amplify. Overall, our studies demonstrated that human papillomaviruses induce breaks into cellular and viral DNAs and that the preferential repair of these lesions in viral episomes leads to genome amplification.

IMPORTANCE
High-risk human papillomaviruses (HPVs) are the etiologic agents of cervical cancer and are linked to the development of many other anogenital and oropharyngeal cancers. Replication of high-risk HPVs requires the activation of the ataxia telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) DNA repair pathways. Our studies have shown that HPVs activate these pathways by inducing double-strand breaks primarily in cellular DNAs and minimally in viral genomes. Breaks are induced in viral genomes but are rapidly repaired through the preferential recruitment of homologous repair factors such as RAD51 and BRCA1 to HPV episomes. The preferential repair of breaks in viral genomes leads to amplification. Our study identified a novel mechanism by which human papillomaviruses manipulate DNA repair pathways to productively replicate viral genomes. The induction of genetic instability in cellular DNAs likely contributes to the generation of mutations that lead to the development of cancers.
A High-Throughput Approach for Identification of Nontuberculous Mycobacteria in Drinking Water Reveals Relationship between Water Age and
Mycobacterium avium
Authors: Haig Sarah-Jane , Kotlarz Nadine , LiPuma John J. , Raskin Lutgarde
Published: February 2018

Nontuberculous mycobacteria (NTM) frequently detected in drinking water (DW) include species associated with human infections, as well as species rarely linked to disease. Methods for improved the recovery of NTM DNA and high-throughput identification of NTM are needed for risk assessment of NTM infection through DW exposure. In this study, different methods of recovering bacterial DNA from DW were compared, revealing that a phenol-chloroform DNA extraction method yielded two to four times as much total DNA and eight times as much NTM DNA as two commercial DNA extraction kits. This method, combined with high-throughput, single-molecule real-time sequencing of NTM
rpoB
genes, allowed the identification of NTM to the species, subspecies, and (in some cases) strain levels. This approach was applied to DW samples collected from 15 households serviced by a chloraminated distribution system, with homes located in areas representing short (<24 h) and long (>24 h) distribution system residence times. Multivariate statistical analysis revealed that greater water age (i.e., combined distribution system residence time and home plumbing stagnation time) was associated with a greater relative abundance of
Mycobacterium avium
subsp.
avium
, one of the most prevalent NTM causing infections in humans. DW from homes closer to the treatment plant (with a shorter water age) contained more diverse NTM species, including
Mycobacterium abscessus
and
Mycobacterium chelonae
. Overall, our approach allows NTM identification to the species and subspecies levels and can be used in future studies to assess the risk of waterborne infection by providing insight into the similarity between environmental and infection-associated NTM.

IMPORTANCE
An extraction method for improved recovery of DNA from nontuberculous mycobacteria (NTM), combined with single-molecule real-time sequencing (PacBio) of NTM
rpoB
genes, was used for high-throughput characterization of NTM species and in some cases strains in drinking water (DW). The extraction procedure recovered, on average, eight times as much NTM DNA and three times as much total DNA from DW as two widely used commercial DNA extraction kits. The combined DNA extraction and sequencing approach allowed high-throughput screening of DW samples to identify NTM, revealing that the relative abundance of
Mycobacterium avium
subsp.
avium
increased with water age. Furthermore, the two-step barcoding approach developed as part of the PacBio sequencing method makes this procedure highly adaptable, allowing it to be used for other target genes and species.
Slowdown of Translational Elongation in
Escherichia coli
under Hyperosmotic Stress
Authors: Dai Xiongfeng , Zhu Manlu , Warren Mya , Balakrishnan Rohan , Okano Hiroyuki , Williamson James R. , Fredrick Kurt , Hwa Terence
Published: February 2018

In nature, bacteria frequently experience many adverse conditions, including heat, oxidation, acidity, and hyperosmolarity, which all tend to slow down if not outright stop cell growth. Previous work on bacterial stress mainly focused on understanding gene regulatory responses. Much less is known about how stresses compromise protein synthesis, which is the major driver of cell growth. Here, we quantitatively characterize the translational capacity of
Escherichia coli
cells growing exponentially under hyperosmotic stress. We found that hyperosmotic stress affects bacterial protein synthesis through reduction of the translational elongation rate, which is largely compensated for by an increase in the cellular ribosome content compared with nutrient limitation at a similar growth rate. The slowdown of translational elongation is attributed to a reduction in the rate of binding of tRNA ternary complexes to the ribosomes.

IMPORTANCE
Hyperosmotic stress is a common stress condition confronted by
E. coli
during infection of the urinary tract. It can significantly compromise the bacterial growth rate. Protein translation capacity is a critical component of bacterial growth. In this study, we find for the first time that hyperosmotic stress causes substantial slowdown in bacterial ribosome translation elongation. The slowdown of translation elongation originates from a reduced binding rate of tRNA ternary complex to the ribosomes.
CRISPR-Cas-Mediated Phage Resistance Enhances Horizontal Gene Transfer by Transduction
Authors: Watson Bridget N. J. , Staals Raymond H. J. , Fineran Peter C.
Published: February 2018

A powerful contributor to prokaryotic evolution is horizontal gene transfer (HGT) through transformation, conjugation, and transduction, which can be advantageous, neutral, or detrimental to fitness. Bacteria and archaea control HGT and phage infection through CRISPR-Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) adaptive immunity. Although the benefits of resisting phage infection are evident, this can come at a cost of inhibiting the acquisition of other beneficial genes through HGT. Despite the ability of CRISPR-Cas to limit HGT through conjugation and transformation, its role in transduction is largely overlooked. Transduction is the phage-mediated transfer of bacterial DNA between cells and arguably has the greatest impact on HGT. We demonstrate that in
Pectobacterium atrosepticum
, CRISPR-Cas can inhibit the transduction of plasmids and chromosomal loci. In addition, we detected phage-mediated transfer of a large plant pathogenicity genomic island and show that CRISPR-Cas can inhibit its transduction. Despite these inhibitory effects of CRISPR-Cas on transduction, its more common role in phage resistance promotes rather than diminishes HGT via transduction by protecting bacteria from phage infection. This protective effect can also increase transduction of phage-sensitive members of mixed populations. CRISPR-Cas systems themselves display evidence of HGT, but little is known about their lateral dissemination between bacteria and whether transduction can contribute. We show that, through transduction, bacteria can acquire an entire chromosomal CRISPR-Cas system, including
cas
genes and phage-targeting spacers. We propose that the positive effect of CRISPR-Cas phage immunity on enhancing transduction surpasses the rarer cases where gene flow by transduction is restricted.

IMPORTANCE
The generation of genetic diversity through acquisition of DNA is a powerful contributor to microbial evolution and occurs through transformation, conjugation, and transduction. Of these, transduction, the phage-mediated transfer of bacterial DNA, is arguably the major route for genetic exchange. CRISPR-Cas adaptive immune systems control gene transfer by conjugation and transformation, but transduction has been mostly overlooked. Our results indicate that CRISPR-Cas can impede, but typically enhances the transduction of plasmids, chromosomal genes, and pathogenicity islands. By limiting wild-type phage replication, CRISPR-Cas immunity increases transduction in both phage-resistant and -sensitive members of mixed populations. Furthermore, we demonstrate mobilization of a chromosomal CRISPR-Cas system containing phage-targeting spacers by generalized transduction, which might partly account for the uneven distribution of these systems in nature. Overall, the ability of CRISPR-Cas to promote transduction reveals an unexpected impact of adaptive immunity on horizontal gene transfer, with broader implications for microbial evolution.
Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial
Authors: de Vries Linda S , Groenendaal Floris , Liem Kian D , Heep Axel , Brouwer Annemieke J , van ’t Verlaat Ellen , Benavente-Fernández Isabel , van Straaten Henrica LM , van Wezel-Meijler Gerda , Smit Bert J , Govaert Paul , Woerdeman Peter A , Whitelaw Andrew
Published: February 2018

Objective

To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation.

Design

Multicentre randomised controlled trial (ISRCTN43171322).

Setting

14 neonatal intensive care units in six countries.

Patients

126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III–IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm).

Intervention

Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur.

Composite main outcome measure

VP shunt or death.

Results

19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05).

Conclusions

There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches.
I am currently working as a staff grade at the top of the pay scale with discretionary points. Will I have to take a pay cut if I apply for a specialist registrar rotation?
Authors: Eccles Simon
Published: February 2018

Got a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
Will prolonged study leave still be possible under the new general practitioner contract?
Authors: Irish Bill
Published: February 2018

Got a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
Trainer taming: part 2
Authors: Clarke Ray
Published: February 2018

In the second article in this series
Ray Clarke
explains how to get the best from your trainer when it comes to on-call, sick leave, making mistakes, and getting a reference
Effects of changes in eating speed on obesity in patients with diabetes: a secondary analysis of longitudinal health check-up data
Authors: Hurst Yumi , Fukuda Haruhisa
Published: February 2018

Objective

Few studies have examined the causal relationships between lifestyle habits and obesity. With a focus on eating speed in patients with type 2 diabetes, this study aimed to analyse the effects of changes in lifestyle habits on changes in obesity using panel data.

Methods

Patient-level panel data from 2008 to 2013 were generated using commercially available insurance claims data and health check-up data. The study subjects comprised Japanese men and women (n=59 717) enrolled in health insurance societies who had been diagnosed with type 2 diabetes during the study period. Body mass index (BMI) was measured, and obesity was defined as a BMI of 25 or more. Information on lifestyle habits were obtained from the subjects’ responses to questions asked during health check-ups. The main exposure of interest was eating speed (‘fast’, ‘normal’ and ‘slow’). Other lifestyle habits included eating dinner within 2 hours of sleeping, after-dinner snacking, skipping breakfast, alcohol consumption frequency, sleep adequacy and tobacco consumption. A generalised estimating equation model was used to examine the effects of these habits on obesity. In addition, fixed-effects models were used to assess these effects on BMI and waist circumference.

Results

The generalised estimating equation model showed that eating slower inhibited the development of obesity. The ORs for slow (0.58) and normal-speed eaters (0.71) indicated that these groups were less likely to be obese than fast eaters (P<0.001). Similarly, the fixed-effects models showed that eating slower reduced BMI and waist circumference. Relative to fast eaters, the coefficients of the BMI model for slow and normal-speed eaters were −0.11 and −0.07, respectively (P<0.001).

Discussion

Changes in eating speed can affect changes in obesity, BMI and waist circumference. Interventions aimed at reducing eating speed may be effective in preventing obesity and lowering the associated health risks.
Ready-made and custom-made eyeglasses in India: a cost-effectiveness analysis of a randomised controlled trial
Authors: Angell Blake , Ali Ferhina , Gandhi Monica , Mathur Umang , Friedman David S , Jan Stephen , Keay Lisa
Published: February 2018

Objective

Ready-made spectacles have been suggested as a less resource-intensive treatment for the millions of people living with uncorrected refractive error (URE) in low-income environments. In spite of this interest, there have been no published economic evaluations examining the cost-effectiveness of ready-made spectacles. This study aims to determine the relative cost-effectiveness of offering ready-made spectacles (RMS) relative to no intervention as well as the relative cost-effectiveness of custom-made spectacles (CS) relative to RMS to treat URE.

Methods and analysis

The relative cost-effectiveness of RMS relative to CS and no intervention was tested through a cost-effectiveness analysis from the health service provider perspective conducted alongside a double-masked randomised controlled trial in an urban hospital in Delhi, India. Participants were adults aged 18–45 years with ≥1 dioptre (D) of URE.

Results

There was no significant difference between the effectiveness of the CS and RMS interventions in improving visual acuity, but the CS was over four times the price of the RMS per patient (204 INR (US$2.42) and 792 INR (US$11.22)). The cost per unit improvement in logarithm of the minimum angle of resolution (logMAR) relative to baseline with the RMS intervention was 407 INR (US$4.35). Existing estimates of utility resulting from improvements in visual acuity result in incremental cost per quality-adjusted life years gained of between 212 INR and 1137 INR (US$0.44–US$23.74) depending on the source of the utility estimate and assumed expected life of the spectacles.

Conclusion

RMS represent a significantly cost-effective option for spectacle provision in low-resource settings. The RMS programme was substantially cheaper than an equivalent CS intervention while being effective in improving visual acuity for the majority of adults with refractive error in this setting. These findings provide further support for including RMS in programmes to address URE.

Trial registration number

NCT00657670, Results.
Management of non-variceal upper gastrointestinal bleeding: where are we in 2018?
Authors: Alzoubaidi Durayd , Lovat Laurence B , Haidry Rehan
Published: February 2018

Acute upper gastrointestinal bleeding (AUGIB) is one of the most common medical emergencies in the UK. Despite advancement in technology the management of AUGIB remains a challenge. The clinical community recognise the need for improvement in the treatment of these patients. AUGIB has a significant impact on resources. Endoscopic therapy is the gold standard treatment. The mortality in AUGIB is rarely related to the presenting bleed but significantly associated with concurrent comorbidities. The cost of blood transfusion in the management of patients with AUGIB is significant and misuse of blood products has been documented nationally. Risk stratification tools such as Glasgow-Blatchford Score, Rockall Score and the AIMS65 score have allowed clinicians to triage patients appropriately in order to deliver endoscopic therapy within a suitable time frame. Endoscopic therapeutic modalities such as epinephrine injection, heat thermocoagulation and mechanical clips have had a positive impact on patient’s management. However, in order to continue to improve patient’s outcomes, further developments are needed.
Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma
Authors: Arnes Luis , Liu Zhaoqi , Wang Jiguang , Maurer Carlo , Sagalovskiy Irina , Sanchez-Martin Marta , Bommakanti Nikhil , Garofalo Diana C , Balderes Dina A , Sussel Lori , Olive Kenneth P , Rabadan Raul
Published: February 2018

Objective

Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome.

Design

We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA.

Results

We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673andFAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines.

Conclusions

Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.
Mechanical thrombectomy of acute ischemic stroke with a new intermediate aspiration catheter: preliminary results
Authors: Sallustio Fabrizio , Pampana Enrico , Davoli Alessandro , Merolla Stefano , Koch Giacomo , Alemseged Fana , Panella Marta , D’Agostino Vittoria Carla , Mori Francesco , Morosetti Daniele , Konda Daniel , Fabiano Sebastiano , Diomedi Marina , Gandini Roberto
Published: February 2018

Background and purpose

To report clinical and procedural outcomes of acute ischemic stroke patients after endovascular treatment with the new thromboaspiration catheter AXS Catalyst 6.

Methods

Patients with anterior and posterior circulation stroke were selected. Successful reperfusion defined as a Thrombolysis in Cerebral Infarction (TICI) score ≥2 b and 3-month functional independence defined as a modified Rankin Scale (mRS) ≤2 were the main efficacy outcomes. Symptomatic intracranial hemorrhage and mortality were the main safety outcomes.

Results

107 patients were suitable for analysis. Mean age was 73.18±12.62 year and median baseline NIHSS was 17 (range: 3–32). The most frequent site of occlusion was the middle cerebral artery (MCA) (60.7%). 76.6% of patients were treated with AXS Catalyst 6 alone without the need for rescue devices or thromboaspiration catheters. Successful reperfusion was achieved in 84.1%, functional independence in 47.6%, symptomatic intracranial hemorrhage occurred in 3.7%, and mortality in 21.4%.

Conclusions

Endovascular treatment with AXS Catalyst 6 proved to be safe, technically feasible, and effective. Comparison analyses with other devices for mechanical thrombectomy are needed.
Cardiovascular effects among workers exposed to multiwalled carbon nanotubes
Authors: Kuijpers Eelco , Pronk Anjoeka , Kleemann Robert , Vlaanderen Jelle , Lan Qing , Rothman Nathaniel , Silverman Debra , Hoet Peter , Godderis Lode , Vermeulen Roel
Published: February 2018

Objectives

The increase in production of multiwalled carbon nanotubes (MWCNTs) has led to growing concerns about health risks. In this study, we assessed the association between occupational exposure to MWCNTs and cardiovascular biomarkers.

Methods

A cross-sectional study was performed among 22 workers of a company commercially producing MWCNTs (subdivided into lab personnel with low or high exposure and operators), and a gender and age-matched unexposed population (n=42). Exposure to MWCNTs and 12 cardiovascular markers were measured in participants’ blood (phase I). In a subpopulation of 13 exposed workers and six unexposed workers, these measures were repeated after 5 months (phase II). We analysed associations between MWCNT exposure and biomarkers of cardiovascular risk, adjusted for age, body mass index, sex and smoking.

Results

We observed an upward trend in the concentration of endothelial damage marker intercellular adhesion molecule-1 (ICAM-1), with increasing exposure to MWCNTs in both phases. The operator category showed significantly elevated ICAM-1 geometric mean ratios (GMRs) compared with the controls (phase I: GMR=1.40, P=1.30E-3; phase II: GMR=1.37, P=0.03). The trends were significant both across worker categories (phase I: P=1.50E-3; phase II: P=0.01) and across measured GM MWCNT concentrations (phase I: P=3.00E-3; phase II: P=0.01). No consistent significant associations were found for the other cardiovascular markers.

Conclusion

The associations between MWCNT exposure and ICAM-1 indicate endothelial activation and an increased inflammatory state in workers with MWCNT exposure.
Autoimmune necrotising myopathy and HMGCR antibodies
Authors: Karunaratne Kushan , Amiras Dimitri , Pickering Matthew C , Hofer Monika , Viegas Stuart
Published: February 2018

Statins lower serum cholesterol concentrations by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Muscle side effects are relatively common and include asymptomatic elevation of serum creatine kinase (CK), myalgia, proximal muscle weakness and rhabdomyolysis. More recently, a subset of cases of immune-mediated necrotising myopathy has been found to have antibodies against HMGCR. It is often an aggressive and debilitating myopathy and has a complex pathogenesis characterised by fibre necrosis, usually with minimal associated inflammation. Not all such patients are taking statins. The general consensus is that best treatment involves withdrawing the statin and giving immunosuppressive and immunomodulatory treatment. We describe three cases of HMGCR-related immune-mediated necrotising myopathy, detailing their clinical course and subsequent management, illustrating the spectrum of this disorder.
Effects of a matrix-coated organic acids and medium-chain fatty acids blend on performance, and in vitro fecal noxious gas emissions in growing pigs fed in-feed antibiotic-free diets
Authors: Hossain M.M. , Jayaraman B. , Kim S.C. , Lee K.Y. , Kim I.H. , Nyachoti C.M.
Published: February 2018

This study evaluated the efficacy of a matrix-coated organic acids and medium-chain fatty acids blend (MCOFA) in growing pigs. Ninety six pigs [(Yorkshire × Landrace) × Duroc] with an average body weight (BW) of 47.71 ± 3.73 kg were used in a 6 wk experiment. Pigs were allotted to diets containing 0 or 2 g kg−1 of MCOFA, and 0 or 2.5 g kg−1 of antibiotic growth promoters (AGP) according to a 2 × 2 factorial arrangement of treatments. Pigs fed diets supplemented with MCOFA had improved growth efficiency compared with those fed a diet without MCOFA (P < 0.05). Pigs receiving the diets supplemented with both AGP and MCOFA had higher apparent total tract digestibility of crude protein, dry matter, fat, and gross energy (P < 0.05). Pigs fed AGP × MCOFA diet had increased serum urea nitrogen (P < 0.05). Pigs fed diets supplemented with AGP had reduced fecal ammonia (NH3) gas emissions compared with those fed without AGP (P < 0.05). Moreover, pigs fed diets supplemented with MCOFA had reduced fecal NH3 and acetic acid gas emissions compared with those fed without MCOFA (P < 0.05). In conclusion, dietary supplementation with MCOFA improved performance in growing pigs.
Carcass characteristics of grass-fed crossbred bulls and steers slaughtered at two different ages
Authors: Pogorzelska-Przybyłek Paulina , Nogalski Zenon , Sobczuk-Szul Monika , Purwin Cezary , Momot Martyna
Published: February 2018

The aim of this study was to evaluate beef production potential and meat quality in young crossbred bulls and steers raised indoors and fed grass-based diets. One half of 96 bull calves were castrated at 2–3 wk of age. The calves were fed standard diets, and starting at 7 mo of age, they received grass silage supplemented with concentrates. At the end of the fattening period (18 and 21 mo of age), the animals were slaughtered, carcass quality was evaluated, and samples of musculus longissimus thoracis were collected to determine the proximate composition and meat quality. The semi-intensive feeding system contributed to higher daily gains (0.835 kg) in Holstein-Friesian (HF) × Hereford (HH) crosses. In comparison with steers, bulls were characterized by a higher dressing percentage (+1.33%), higher weight of five most valuable primal cuts (+6.7 kg), and higher lean meat content of three-rib cuts (+7.54%). Meat from steer carcasses, which had higher fat content was more tender and had desirable aroma, juiciness, and flavor. In semi-intensive production systems, steers performed better than bulls, and HF × HH crosses were more suitable than HF × Limousin (LM) and HF × Charolais (CH) crosses. Dairy-beef crosses should be slaughtered at 21 mo of age to improve carcass quality.
Coordination isomerism in N-heterocyclic phosphenium thiocyanates
Authors: Blum Markus , Gebhardt Jacqueline , Papendick Marius , Schlindwein Simon H. , Nieger Martin , Gudat Dietrich
Published: February 2018

Two N-heterocyclic phosphines with exocyclic SCN substituents were synthesised via metathesis of chlorophosphine precursors with KSCN and fully characterised. The crystallographic studies reveal that the products exhibit pronounced structural differences. The thiocyanato unit binds in one case via the nitrogen atom to yield a molecular structure with a slightly elongated P–N single bond and, in the other case, via the sulfur atom to form a structure that is best described as an ion pair and forms a one-dimensional coordination polymer in the crystal. DFT calculations suggest that the P–N and P…S interactions can be described as covalent and dative bonds, respectively, and that the structural differences correlate with the different cation stabilities of the individual phosphenium cation fragments.
Phytotherapeutic Activities of Sanguisorba officinalis and its Chemical Constituents: A Review
Authors: Jang Eungyeong , Inn Kyung-Soo , Jang Young Pyo , Lee Kyung-Tae , Lee Jang-Hoon
Published: February 2018

Sanguisorba officinalis Linne (S. officinalis, Rosaceae) has been used as a medicinal plant for the treatment of burns, hematemesis, melena, intestinal infections, and dermatitis for a long time in China, Korea, and Japan. The therapeutic efficacy of this herb is intimately associated with its anti-oxidant, anti-inflammatory, antiviral, antifungal, hemostatic, and anticancer activities. Its root contains triterpenoid saponins (zigyuglycoside I: C[Formula: see text]H[Formula: see text]O[Formula: see text] and ziyuglycoside II: C[Formula: see text]H[Formula: see text]O8) and tannins (sanguiin H-6: C[Formula: see text]H[Formula: see text]O[Formula: see text]). It has been recently revealed that these active constituents of S. officinalis possess antiwrinkle properties without cytotoxicity. They also have anticancer effects by inducing apoptosis and cell cycle arrest. Moreover, they can inhibit proliferative tumorigenesis. The underlying mechanism involved in the pharmacological actions of these active constituents is mainly related to p38 MAPK signaling. Although various studies have reported its therapeutic activities and major chemical components, review articles that extensively organize various properties of S. officinalis and its major constituents are still scarce. Taken together, the objective of this paper is to provide overall pharmacological and phytochemical profiles of S. officinalis and its constituents (including ziyuglycoside I, ziyuglycoside II, and sanguiin H-6), and their potential roles in clinical applications for the treatment of inflammatory diseases, bleeding disorders, and cancer.
The Protective Effects of Gardenia jasminoides (Fructus Gardenia) on Amyloid-β-Induced Mouse Cognitive Impairment and Neurotoxicity
Authors: Zang Cai-Xia , Bao Xiu-Qi , Li Lin , Yang Han-Yu , Wang Lu , Yu Yang , Wang Xiao-Liang , Yao Xin-Sheng , Zhang Dan
Published: February 2018

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed. Chinese herbs with thousand years of effective usage might be a good source for potential drugs. Gardenia jasminoides J. Ellis (Fructus Gardenia) is a common traditional Chinese medicine with tranquilizing effects, which is an important component of widely-used traditional Chinese medicine for dementia. GJ-4 is crocin richments extracted from Gardenia jasminoides J. Ellis. In our study, we attempted to observe the effects of GJ-4 on learning and memory injury induced by amyloid-[Formula: see text] 25-35 (A[Formula: see text] injection in mice. Treatment with GJ-4 dose-dependently enhanced the memory and cognition ability of A[Formula: see text]-injected mice. Preliminary mechanistic studies revealed the protective effect of GJ-4 was related to its protection of neurons and cholinergic dysfunction. The mechanistic results also indicated that GJ-4 could enhance antioxidant capacity and attenuate neuroinflammation. Our results implied that GJ-4 might be a promising drug to improve cognitive and memory impairment, with multiple targets.
Epimedium koreanum Ameliorates Oxidative Stress-Mediated Liver Injury by Activating Nuclear Factor Erythroid 2-Related Factor 2
Authors: Jung Ji Yun , Park Sang Mi , Ko Hae Li , Lee Jong Rok , Park Chung A , Byun Sung Hui , Ku Sae Kwang , Cho Il Je , Kim Sang Chan
Published: February 2018

Oxidative stress induced by reactive oxygen species is the main cause of various liver diseases. This study investigated the hepatoprotective effect of Epimedium koreanum Nakai water extract (EKE) against arachidonic acid (AA)[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells and carbon tetrachloride (CCl4-)-mediated acute liver injury in mice. Pretreatment with EKE (30 and 100[Formula: see text][Formula: see text]g/mL) significantly inhibited AA[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells by preventing changes in the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase. EKE attenuated hydrogen peroxide production, glutathione depletion, and mitochondrial membrane dysfunction. EKE also increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), transactivated anti-oxidant response element harboring luciferase activity, and induced the expression of anti-oxidant genes. Furthermore, the cytoprotective effect of EKE against AA[Formula: see text][Formula: see text][Formula: see text]iron was blocked in Nrf2 knockout cells. Ultra-performance liquid chromatography analysis showed that EKE contained icariin, icaritin, and quercetin; icaritin and quercetin were both found to protect HepG2 cells from AA[Formula: see text][Formula: see text][Formula: see text]iron via Nrf2 activation. In a CCl4-induced mouse model of liver injury, pretreatment with EKE (300[Formula: see text]mg/kg) for four consecutive days ameliorated CCl4-mediated increases in serum aspartate aminotransferase activity, histological activity index, hepatic parenchyma degeneration, and inflammatory cell infiltration. EKE also decreased the number of nitrotyrosine-, 4-hydroxynonenal-, cleaved caspase-3-, and cleaved poly(ADP-ribose) polymerase-positive cells in hepatic tissues. These results suggest EKE is a promising candidate for the prevention or treatment of oxidative stress-related liver diseases via Nrf2 activation.
EXPLICIT HESTON SOLUTIONS AND STOCHASTIC APPROXIMATION FOR PATH-DEPENDENT OPTION PRICING
Authors: KOURITZIN MICHAEL A.
Published: February 2018

New simulation approaches to evaluating path-dependent options without matrix inversion issues nor Euler bias are evaluated. They employ three main contributions: (1) stochastic approximation replaces regression in the LSM algorithm; (2) explicit weak solutions to stochastic differential equations are developed and applied to Heston model simulation; and (3) importance sampling expands these explicit solutions. The approach complements Heston [(1993) A closed-form solutions for options with stochastic volatility with applications to bond and currency options, Review of Financial Studies 6, 327–343] and Broadie & Kaya [(2006) Exact simulation of stochastic volatility and other affine jump diffusion processes, Operations Research 54 (2), 217–231] by handling the case of path-dependence in the option’s execution strategy. Numeric comparison against standard Monte Carlo methods demonstrates up to two orders of magnitude speed improvement. The general ideas will extend beyond the important Heston setting.
A New Balanced Particle Swarm Optimisation for Load Scheduling in Cloud Computing
Authors: Chaudhary Divya , Kumar Bijendra
Published: February 2018

The cloud computing is an augmentative and progressive paradigm that supports a huge amount of characteristics. It demands the optimal allocation of resources to the tasks present in the virtual machines (VMs) system using load scheduling algorithms. The basic objective of load scheduling is to avoid system overloading and thereby achieve higher throughput by maximising VM utilisation along with cost stabilisation. The first come first serve and min–min approaches allocate the load in a static manner and resources are left underutilised. The particle swarm optimisation obtains the motivation from the social behaviour of the flock of birds. It analyses various approaches for load scheduling. The paper proposes an improved balanced load scheduling approach based on particle swarm optimisation (BPSO) to minimise total transfer time and total cost stabilisation. The proposed BPSO approach is compared with the existing approaches used for load scheduling in cloudlets. The efficiency in terms of the transfer time and cost of the proposed algorithm is showcased with the help of simulation results. As evident from the results, the proposed algorithm reduces transfer time and cost than the prevalent algorithms thereby making a system with stable cost.
Pyridone substituted phthalocyanines: Photophysico-chemical properties and TD-DFT calculations
Authors: Abdurrahmanoğlu Şaziye , Canlıca Mevlüde , Mack John , Nyokong Tebello
Published: February 2018

4-(6-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yloxy)phthalonitrile has been used to prepare a novel Zn(II) phthalocyanines with four peripheral pyridone substituents. The compound has been characterized by UV-visible absorption, FT-IR and [Formula: see text]H-NMR spectroscopy, elemental analysis and MALDI-TOF mass spectroscopy. The fluorescence, triplet quantum and singlet oxygen quantum yields have been determined and TD-DFT calculations have been used to identify trends in the electronic structure.
Single Scan OCT-Based Retina Detection for Robot-Assisted Retinal Vein Cannulation
Authors: Borghesan G. , Ourak M. , Lankenau E. , Hüttmann G. , Schulz-Hildebrant H. , Willekens K. , Stalmans P. , Reynaerts D. , Vander Poorten E.
Published: February 2018

Vitreoretinal surgery concerns a set of particularly demanding minimal invasive micro-surgical interventions at the retina. Micro-surgeons are targeting sub-millimeter-sized structures here. Tiny vessels or wafer-thin membranes are to be cannulated or need to be peeled off. The greatest care is to be displayed not to damage these fragile structures or to inadvertently injure the underlying retina. Damage to the latter is mostly irreparable and might cause permanent loss of vision. Despite the availability over excellent stereo microscopes, wide-angle lenses and powerful light source visualization remains a problem. Especially, the limited depth perception is still perceived as a major bottle-neck whereas efforts have been conducted to integrate sensing capability in today’s state-of-the-art instruments, so far, little effort has been paid to process the obtained sensor data and turns this into a reliable source of information upon which robot assistive guidance schemes could be endowed upon. This paper proposes a number of processing techniques tailored to Optical Coherence Tomography (OCT) measurements. The first results of the proposed algorithms show that it is feasible to extract good and reliable distance estimates from this otherwise rather noisy signal and from a fairly limited dataset. The used data are the so-called A-scans. These are OCT measurements consisting of a single-line image that could be captured by an instrument-mounted fiber through which the OCT signal passes back-and-forth. However, in this work, we perform a pilot study whereby the employed A-scans are extracted from B-scans that are captured by a microscope-mounted OCT scanner, rather than obtained from a probe. The performance of a first embodiment of the algorithm that is based on an Unscented Kalman Filter (UKF) is compared to the performance of a second embodiment that relies on a Particle Filter (PF), focusing on the issues in filter initialization and the tracking quality. Finally, results of UKF and PF executions on a validation dataset are presented.
A Simheuristic Method for the Reversible Lanes Allocation and Scheduling Problem at Smart Container Terminal Gate
Authors: Wang Wenyuan , Jiang Ying , Peng Yun , Zhou Yong , Tian Qi
Published: February 2018

Under the constraints of limited spaces and imbalanced traffic volumes (for both in and out directions) of container gates, reversible lane layouts become an economical and practical way to improve the service level of container terminal systems and make the maximum use of the current terminal resources. Together with a consideration of minimized total costs (both construction and operating) of terminal gate system, this paper first developed an optimization model to decide the number and scheduling rules of the reversible lanes at a terminal gate. A metaheuristic algorithm was built to solve the optimal model. Meanwhile, to reflect the randomness and dynamics property of the terminal gate system in practice, parameters that cannot be calculated from conventional analytic methods are obtained through a simulation model. Finally, a hub container terminal in the northeast of China was employed to verify the effectiveness of the proposed method and provide a theoretical foundation for the construction and management of terminal gate systems.