bluuebunny/crossref_metadata_2025 huggingface dataset:
Octapeptin C4 Induces Less Resistance and Novel Mutations in an Epidemic Carbapenemase-producingKlebsiella pneumoniaeST258 Clinical Isolate Compared to Polymyxins
Authors: Pitt Miranda E. , Cao Minh Duc , Butler Mark S. , Ramu Soumya , Ganesamoorthy Devika , Blaskovich Mark A. T. , Coin Lachlan J. M. , Cooper Matthew A.
Published: April 2018

Polymyxin B and E (colistin) have been pivotal in the treatment of extensively drug-resistant (XDR) Gram-negative bacterial infections, with increasing use over the past decade. Unfortunately, resistance to these antibiotics is rapidly emerging. The structurally-related octapeptin C4 (OctC4) has shown significant potency against XDR bacteria, including against polymyxin-resistant (Pmx-R) strains, but its mode of action remains undefined. We sought to compare and contrast the acquisition of XDRKlebsiella pneumoniae(ST258) resistancein vitrowith all three lipopeptides to help elucidate the mode of action of the drugs and potential mechanisms of resistance evolution. Strikingly, 20 days of exposure to the polymyxins resulted in a dramatic (1000-fold) increase in the minimum inhibitory concentration (MIC) for the polymyxins, reflecting the evolution of resistance seen in clinical isolates, whereas for OctC4 only a 4-fold increase was witnessed. There was no cross-resistance observed between the polymyxin - and octapeptin-induced resistant strains. Sequencing revealed previously known gene alterations for polymyxin resistance, includingcrrB,mgrB,pmrB,phoPQandyciM, and novel mutations inqseC. In contrast, mutations inmlaDFandpqiB, 1genes related to phospholipid transport, were found in octapeptin-resistant isolates. Mutation effects were validated via complementation assays. These genetic variations were reflected in phenotypic changes to lipid A. Pmx-R isolates increased 4-amino-4-deoxy-arabinose fortification to phosphate groups of lipid A, whereas OctC4 induced strains harbored a higher abundance of hydroxymyristate and palmitoylate. The results reveal a differing mode of action compared to polymyxins which provides hope for future therapeutics to combat the increasingly threat of XDR bacteria.
Corals sustain growth but not skeletal density across the Florida Keys Reef Tract despite ongoing warming
Authors: Rippe John , Baumann Justin H. , De Leener Daphne N. , Aichelman Hannah E. , Friedlander Eric B. , Davies Sarah W. , Castillo Karl D.
Published: April 2018

Through the continuous growth of their carbonate skeletons, corals record invaluable information about past environmental conditions and their effect on colony fitness. Here, we characterize century-scale growth records of inner and outer reef corals across ~200 km of the Florida Keys Reef Tract (FKRT) using skeletal cores extracted from two ubiquitous reef-building species, Siderastrea siderea and Pseudodiploria strigosa. We find that corals across the FKRT have sustained extension and calcification rates over the past century but have experienced a long-term reduction in skeletal density, regardless of reef zone. Notably, P. strigosa colonies exhibit temporary reef zone-dependent reductions in extension rate corresponding to two known extreme temperature events in 1969-70 and 1997-98. We propose that the subtropical climate of the FKRT may buffer corals from chronic growth declines associated with climate warming, though the significant reduction in skeletal density may indicate underlying vulnerability to present and future trends in ocean acidification.
DsbA is a redox-switchable mechanical chaperone
Authors: Eckels Edward C. , Chaudhuri Deep , Chakraborty Soham , Echelman Daniel J. , Haldar Shubhasis
Published: April 2018

DsbA is a ubiquitous bacterial oxidoreductase that associates with substrates during and after translocation, yet its involvement in protein folding and translocation remains an open question. Here we demonstrate a redox-controlled chaperone activity of DsbA, on both cysteine-containing and cysteine-free substrate, using a magnetic tweezers-based single molecule force spectroscopy that enables independent measurements of oxidoreductase activity and chaperone behavior. Interestingly we found, this chaperone activity is tuned by the oxidation state of DsbA; oxidized DsbA is a strong promoter of folding, but the effect is weakened by reduction of the catalytic CXXC motif. We further localize the chaperone binding site of DsbA using a seven-residue peptide which effectively blocks the chaperone activity. We calculated that DsbA assisted folding of proteins in the periplasm generates enough mechanical work to decrease the ATP consumption needed for periplasmic translocation by up to 33%. In turn, pharmacologic inhibition of this chaperone activity may open up a new class of anti-virulence agents.
Helicase Promotes Replication Re-initiation from an RNA Transcript
Authors: Sun Bo , Singh Anupam , Sultana Shemaila , Inman James T. , Patel Smita S. , Wang Michelle D.
Published: April 2018

To ensure accurate DNA replication, a replisome must effectively overcome numerous obstacles on its DNA substrate. After encountering an obstacle, a progressing replisome often aborts DNA synthesis but continues to unwind the DNA, resulting in a gap in the newly replicated DNA. However, little is known about how DNA synthesis is resumed downstream of an obstacle. Here, we examine the consequences of a non-replicating replisome collision with a co-directional RNA polymerase (RNAP). Using single-molecule and ensemble methods, we find that T7 helicase interacts strongly with a non-replicating T7 DNA polymerase (DNAP) at a replication fork. As the helicase advances the fork, the DNAP also moves forward processively, via its association with the helicase. The presence of the DNAP, in turn, increases both helicase’s processivity and unwinding rate. We show that such a DNAP, together with its helicase, is indeed able to actively disrupt a stalled transcription elongation complex, and then initiates replication using the RNA transcript as a primer. These observations exhibit T7 helicase’s novel role in replication re-initiation, independent of replication restart proteins or primase.
Creating Standards for Evaluating Tumour Subclonal Reconstruction
Authors: Salcedo Adriana , Tarabichi Maxime , Espiritu Shadrielle Melijah G. , Deshwar Amit G. , David Matei , Wilson Nathan M. , Dentro Stefan , Wintersinger Jeff A. , Liu Lydia Y. , Ko Minjeong , Sivanandan Srinivasan , Zhang Hongjiu , Zhu Kaiyi , Yang Tai-Hsien Ou , Chilton John M. , Buchanan Alex , Lalansingh Christopher M. , P’ng Christine , Anghel Catalina V. , Umar Imaad , Lo Bryan , Zou William ,   DREAM SMC-Het Participants, Simpson Jared T. , Stuart Joshua M. , Anastassiou Dimitris , Guan Yuanfang , Ewing Adam D. , Ellrott Kyle , Wedge David C. , Morris Quaid D. , Van Loo Peter , Boutros Paul C.
Published: April 2018

Tumours evolve through time and space. Computational techniques have been developed to infer their evolutionary dynamics from DNA sequencing data. A growing number of studies have used these approaches to link molecular cancer evolution to clinical progression and response to therapy. There has not yet been a systematic evaluation of methods for reconstructing tumour subclonality, in part due to the underlying mathematical and biological complexity and to difficulties in creating gold-standards. To fill this gap, we systematically elucidated the key algorithmic problems in subclonal reconstruction and developed mathematically valid quantitative metrics for evaluating them. We then created approaches to simulate realistic tumour genomes, harbouring all known mutation types and processes both clonally and subclonally. We then simulated 580 tumour genomes for reconstruction, varying tumour read-depth and benchmarking somatic variant detection and subclonal reconstruction strategies. The inference of tumour phylogenies is rapidly becoming standard practice in cancer genome analysis; this study creates a baseline for its evaluation.
The hydrolase LpqI primes mycobacterial peptidoglycan recycling
Authors: Moynihan Patrick J. , Cadby Ian T. , Veerapen Natacha , Jankute Monika , Crosatti Marialuisa , Mukamolova Galina V. , Lovering Andrew L. , Besra Gurdyal S.
Published: May 2018

Growth and division by most bacteria requires remodeling and cleavage of their cell wall. A byproduct of this process is the generation of free peptidoglycan (PG) fragments known as muropeptides. These muropeptides are recycled in many model organisms, where the bacteria can harness their unique nature as a signal for cell wall damage. These molecules also serve as important signals for hosts where binding to specific receptors reports on the presence of intracellular bacteria. Despite this critical role for muropeptides, it has long been thought that pathogenic mycobacteria such asMycobacterium tuberculosisdo not recycle their PG. Herein we show for the first time thatM. tuberculosisandMycobacterium bovisBCG are able to recycle components of their PG. We demonstrate that the core-mycobacterial genelpqI, encodes an authentic NagZ β-N-acetylglucosaminidase and that it is essential for PG-derived amino sugar recyclingviaan unusual pathway. By characterizing anM. bovisBCG strain lackinglpqIwe are also able to show that stem-peptide recycling proceeds independent of amino sugar recovery and loss oflpqIleads to antimicrobial resistancein vitro. Together these data provide a critical first step in understanding how mycobacteria recycle their peptidoglycan.
Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors
Authors: Dunkel Ying , Ear Jason , Mittal Yash , Lim Blaze B. C. , Liu Lawrence , Holda Magda K. , Nitsche Ulrich , Barbazán Jorge , Goel Ajay , Janssen Klaus-Peter , Aznar Nicolas , Ghosh Pradipta
Published: May 2018

Previously Aznar et al., showed that Daple enables Wnt/Frizzled receptors to transactivate trimeric G proteins during non-canonical Wnt signaling via a novel G-protein binding and activating (GBA) motif. By doing so, Daple serves as a double-edged sword; earlier during oncogenesis it suppresses neoplastic transformation and tumor growth, but later it triggers epithelial messenchymal transition (EMT). We have identified and characterized two isoforms of the human Daple/CCDC88c gene. While both isoforms cooperatively suppress tumor growth via their GBA motif, only the full-length transcript triggers EMT and invasion. Aspirin suppresses the full-length transcript and protein but upregulates the short isoform. Both isoforms are suppressed during colon cancer progression, and their reduced expression carries additive prognostic significance. These findings provide insights into the opposing roles of Daple during cancer progression and define the G protein regulatory GBA motif as one of the minimal modules essential for Daple’s role as a tumor suppressor.
Perceived threat bias and reduced hippocampal volume in combat veterans
Authors: Grupe Daniel W. , Hushek Benjamin A. , Ellis Kaley , Schoen Andrew J. , Wielgosz Joseph , Nitschke Jack B. , Davidson Richard J.
Published: May 2018

Background

Reduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the exact psychological processes associated with these alterations remain unclear. Given the role of the hippocampus in contextual representations of threat and memory, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans.

Methods

T1-weighted anatomical MRI scans were obtained from 52 male veterans with a broad range of PTSD symptoms. Hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. An index of perceived threat bias was calculated, reflecting the degree of discordance between subjective perceptions of threat while deployed and self-reported combat exposure. Hippocampal volume was regressed on perceived threat bias and PTSD symptoms on the Clinician-Administered PTSD Scale (CAPS).

Results

Perceived threat bias was unrelated to overall CAPS symptoms, but was positively correlated with CAPS avoidance/numbing symptoms and symptoms of depression, anxiety, and worry. The degree of perceived threat bias was inversely correlated with hippocampal volume. Hippocampal volume was also inversely related to avoidance/numbing CAPS symptoms.

Conclusions

These results indicate that volume of the hippocampus, a region involved in contextual threat processing and memory, is related to recalled associations between traumatic events and accompanying subjective threat appraisals. Future research should clarify the precise temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to exaggerated threat appraisal at the time of trauma, or in subsequently biased memories or appraisals of traumatic events.
Autophagy is essential for optimal Fe translocation to seeds in Arabidopsis
Authors: Pottier Mathieu , Dumont Jean , Masclaux-Daubresse Céline , Thomine Sébastien
Published: May 2018

Micronutrient deficiencies affect a large part of the world population. They are mostly due to the consumption of grains with insufficient content of Fe or Zn. Both de novo uptake by roots and recycling from leaves may provide seeds with nutrients. Autophagy, which is a conserved mechanism for nutrient recycling in eukaryotes, was shown to be involved in nitrogen remobilization to seeds. Here, we have investigated the role of this mechanism in micronutrient translocation to seeds. We found that several Arabidopsis thaliana plants impaired in autophagy display defects in nutrient remobilization to seeds. In atg5-1 mutant, which is completely defective in autophagy, the efficiency of Fe translocation from vegetative organs to seeds was severely decreased even when Fe was provided during seed formation. Combining atg5-1 with sid2 mutation that counteracts premature senescence associated to autophagy deficiency and using 57Fe pulse labeling, we could propose a two-step mechanism in which iron taken up de novo during seed formation is first accumulated in vegetative organs and subsequently remobilized to seeds. Finally, we showed that translocations of zinc and manganese to seeds are also dependent on autophagy. Fine tuning autophagy during seed formation opens therefore new possibilities to improve micronutrient remobilization to seeds.
Opsonin-free, real-time imaging of Cryptococcus neoformans capsule during budding
Authors: Paes Hugo Costa , Frazão Stefânia de Oliveira , Rosa Camila Pereira , Albuquerque Patrícia , Casadevall Arturo , Soares Felipe Maria Sueli , Nicola André Moraes
Published: May 2018

Cryptococcus neoformans is a unicellular fungal pathogen that causes meningoencephalitis, killing hundreds of thousands of patients each year. Its most distinctive characteristic is a polysaccharide capsule that envelops the whole cell. It is the major virulence attribute and the antigen for serologic diagnosis. We have developed a method for easy observation of the capsule and its growth dynamics using the cell-separation reagent Percoll and differential interference contrast (DIC) microscopy. Percoll suspension is far less disruptive of cell physiology than methods relying on antibody binding to the capsule, and measurements made with it are equivalent with India ink. Time-lapse microscopy observations using this method suggest that during budding, a dividing cell can regulate whether the capsule polysaccharide it produces is deposited on the capsule of the bud or on its own. This observation has important implications for our understanding of the C. neoformans capsule induction process during budding.

List of abbreviations and acronyms

CSF

Cerebrospinal fluid

DIC

Differential interference microscopy

NA

Numerical aperture

CCD

Charge-coupled device

MM

Minimal medium

CIM

CO2-independent medium

MOPS

3-Morpholinopropane-1-sulfonic acid

SD

Standard deviation
Identification of reference genes for real-time PCR gene expression studies during seed development and under abiotic stresses in Cyamopsis tetragonoloba (L.) Taub
Authors: Jaiswal Poonam Subhash , Kaur Navneet , Randhawa Gursharn Singh
Published: May 2018

Guar (Cyamopsis tetragonoloba) is an important industrial crop. The knowledge about genes of guar involved in various processes can help in developing improved varieties of this crop. qRT-PCR is a preferred technique for accurate quantification of gene expression data. This technique requires the use of appropriate reference genes from the crop to be studied. Such genes have not been yet identified in guar. The expression stabilities of the 10 candidate reference genes, viz., CYP, ACT 11, EF-1α, TUA, TUB, ACT 7, UBQ 10, UBC 2, GAPDH and 18S rRNA were evaluated in various tissues of guar under normal and abiotic stress conditions. Four different algorithms, geNorm, NormFinder, BestKeeper and ∆Ct approach, were used to assess the expression stabilities and the results obtained were integrated into comprehensive stability rankings. The most stable reference genes were found to be CYP and ACT 11(tissues), ACT 11, UBC 2 and ACT 7 (seed development), ACT 7 and TUB (drought stress), TUA, UBC 2 and CYP (nitrogen stress), TUA and UBC 2 (cold stress), GAPDH and ACT 7 (heat stress) and GAPDH and EF-1a (salt stress). These results indicated the necessity of identifying a suitable reference gene for each experimental condition. Four selected reference genes were validated by normalizing the expression of CtMT1 gene. To the best of our knowledge this is the first report on the identification of reference genes in guar. These findings are likely to provide a boost to the gene expression studies in this important crop.
The Pseudomonas aeruginosa complement of lactate dehydrogenases enables use of D- and L-lactate and metabolic crossfeeding
Authors: Lin Yu-Cheng , Cornell William-Cole , Price-Whelan Alexa , Dietrich Lars E.P.
Published: May 2018

Pseudomonas aeruginosa is the most common cause of chronic, biofilm-based lung infections in patients with cystic fibrosis (CF). Sputum from patients with CF has been shown to contain oxic and hypoxic subzones as well as millimolar concentrations of lactate. Here, we describe the physiological roles and expression patterns of P. aeruginosa lactate dehydrogenases in the contexts of different growth regimes. P. aeruginosa produces four enzymes annotated as lactate dehydrogenases, three of which are known to contribute to anaerobic or aerobic metabolism in liquid cultures. These three are LdhA, which reduces pyruvate to D-lactate during anaerobic survival, and LldE and LldD, which oxidize D-lactate and L-lactate, respectively, during aerobic growth. We demonstrate that the fourth enzyme, LldA, performs redundant L-lactate oxidation during growth in aerobic cultures in both a defined MOPS-based medium and synthetic CF sputum medium. However, LldA differs from LldD in that its expression is induced specifically by the L-enantiomer of lactate. We also show that all four enzymes perform functions in colony biofilms that are similar to their functions in liquid cultures. Finally, we provide evidence that the enzymes LdhA and LldE have the potential to support metabolic cross-feeding in biofilms, where LdhA can catalyze the production of D-lactate in the anaerobic zone that is then used as a substrate in the aerobic zone. Together, these observations further our understanding of the metabolic pathways that can contribute to P. aeruginosa growth and survival during CF lung infection.

IMPORTANCE

Lactate is thought to serve as a carbon and energy source during chronic infections. Sites of bacterial colonization can contain two enantiomers of lactate: the L-form, generally produced by the host, and the D-form, which is usually produced by bacteria including the pulmonary pathogen Pseudomonas aeruginosa. Here, we characterize P. aeruginosa’s set of four enzymes that it can use to interconvert pyruvate and lactate, the functions of which depend on the availability of oxygen and specific enantiomers of lactate. We also show that anaerobic pyruvate fermentation triggers production of the aerobic D-lactate dehydrogenase in both liquid cultures and biofilms, thereby enabling metabolic cross-feeding of lactate over time and space between subpopulations of cells. These metabolic pathways could contribute to P. aeruginosa growth and survival in the lung.
Switch costs in inhibitory control and voluntary behavior: A computational study of the antisaccade task
Authors: Aponte Eduardo A. , Stephan Klaas E. , Heinzle Jakob
Published: May 2018

An integral aspect of human cognition is the ability to inhibit habitual responses in order to initiate complex, rule-guided actions. Moreover, humans have also the ability to alternate between different sets of rules or tasks, at the cost of degraded performance when compared to repeating the same task, a phenomenon called the ‘task switch cost’. While it is recognized that switching between tasks requires often to inhibit habitual responses, the interaction between these two forms of cognitive control has been much less studied than each of them separately. Here, we use a computational model to draw a bridge between inhibitory control and voluntary action generation and thereby provide a novel account of seemingly paradoxical findings in the task switch literature. We investigated task switching in the mixed antisaccade task, in which participants are cued to saccade either in the same or in the opposite direction to a peripheral stimulus. Our model demonstrates that stopping a habitual action leads to increased inhibitory control that persists on the next trial. However, enhanced inhibition affects only the probability of generating habitual responses, and, contrary to previous accounts, cannot be characterized as proactive task interference. In addition, our model demonstrates that voluntary actions (but not habitual responses) are slower and more prompt to errors on switch trials compared to repeat trials. We conclude that precisely the interaction between these two effects explains a variety of contradictory findings reported in the literature.
Substrate binding allosterically relieves autoinhibition of the TRIB1 pseudokinase
Authors: Jamieson Sam A. , Ruan Zheng , Burgess Abigail E. , Curry Jack R. , McMillan Hamish D. , Brewster Jodi L. , Dunbier Anita K. , Axtman Alison D. , Kannan Natarajan , Mace Peter D.
Published: May 2018

One Sentence Summary

Substrate binding to Tribbles-homolog 1 (TRIB1) pseudokinase induces allosteric changes that allow formation of a complex with the COP1 ubiquitin ligase.

The Tribbles family of pseudokinases recruit substrates to the COP1 ubiquitin ligase for ubiquitination. CCAAT-enhancer binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid development. Here we show that the TRIB1 pseudokinase can recruit various C/EBP family members, with binding of C/EBPβ attenuated by phosphorylation. To explain the mechanism of substrate recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPα. TRIB1 undergoes a significant conformational change relative to its substrate-free structure, to bind C/EBPα in a pseudo-substrate-like manner. Crucially, substrate binding triggers allosteric changes that link substrate recruitment to COP1 binding, which is consistent with molecular dynamics and biochemical studies. These findings offer a view of pseudokinase regulation with striking parallels to bona fide kinase regulation— via the activation loop and αC-helix—and raise the possibility of small molecules targeting either the activation loop-in, or loop-out, conformations of Tribbles pseudokinases.
Assessment of bias errors caused by texture and sampling methods in diffraction-based steel phase measurements
Authors: Creuziger Adam , Calhoun Christopher A. , Poling Whitney A. , Gnäupel-Herold Thomas
Published: May 2018

Many advanced high-strength steels rely on a metastable austenite phase for improvements in strength and formability. To date, no method has demonstrated the ability to provide accurate austenite phase fraction measurements in textured steels. Several techniques have been proposed, such as averaging the intensity of several peaks and/or summation of intensity from several sample orientations. The series of numerical experiments performed in this work sought to quantify the effects of texture on the measurement of the austenite phase fraction, with an emphasis on techniques suitable for laboratory X-ray diffraction. Simulated diffraction profiles were created with the following variables: texture components for the ferrite and austenite phases, the sharpness of each of the texture components, the number of peaks used for averaging in the phase fraction calculation, and the sampling scheme used for sample orientation summation in the phase fraction calculation. The resulting phase fraction calculations showed that texture, the number of peak pairs and the sampling method have a drastic effect on phase fraction measurements, causing significant bias errors. Hexagonal grids produced minimal bias errors and demonstrated a robust method of measuring phase fractions in textured materials.
Report of the Executive Committee for 2016
Authors: Dacombe M. , Ashcroft A. T.
Published: May 2018

The report of the Executive Committee for 2016 is presented.
Corporate social responsibility and financial performance in Saudi Arabia
Authors: Al-Malkawi Husam-Aldin Nizar , Javaid Saima
Published: May 2018

Purpose

The purpose of this paper is to investigate the impact of corporate social responsibility (CSR) on corporate financial performance (CFP) using Zakat as a measure for CSR.

Design/methodology/approach

The study examines a sample of 107 non-financial firms listed on the Saudi Arabia stock market over a ten-year period from 2004 to 2013. The authors use the generalized method of moments framework developed by Arellano and Bover (1995) and Blundell and Bond (1998). In addition, for comparison purpose and as a robustness check, the present study uses other panel data techniques including fixed effects model, random effects model (and pooled ordinary least squares.

Findings

The results reveal that there is a strong positive relationship between CSR (Zakat) and CFP. This suggests that Zakat contribute positively to both firm’s profitability and value and can be considered as a win-win strategy to maximize returns and improve performance while considering the society as a whole. The results are robust to alternative econometric estimation methods.

Practical implications

The companies in Islamic economies can effectively and efficiently implement the basic Shari’a Law of paying Zakat, as a successful measure to implement CSR program, thus benefiting the society by narrowing the gap between the haves and have-nots, that, in turn, leads the company to achieve successfully its short-term as well as long-term goals and enhances the value of the firm in the market. Moreover, corporations are generally encouraged to adopt CSR because of its perceived benefits to both macro- and micro-performances.

Originality/value

To the best of the author’s knowledge, this is the first empirical study attempting to examine CSR-CFP relationship within Saudi context employing Zakat as a proxy for CSR. Additionally, the paper provides support for the stakeholder theory from an Islamic perspective.
Comparative study of the bactericidal effects of indocyanine green‐ and methyl aminolevulinate‐based photodynamic therapy on Propionibacterium acnes as a new treatment for acne
Authors: Choi Seung‐Hwan , Seo Jeong‐Wan , Kim Ki‐Ho
Published: May 2018

Acne vulgaris is one of the most common dermatological problems, and its therapeutic options include topical and systemic retinoids and antibiotics. However, increase in problems associated with acne treatment, such as side‐effects from conventional agents and bacterial resistance to antibiotics, has led to greater use of photodynamic therapy. The purpose of this study was to compare the bactericidal effects of indocyanine green‐ and methyl aminolevulinate‐based photodynamic therapy on Propionibacterium acnes. P. acnes were cultured under anaerobic conditions; then they were divided into three groups (control, treated with indocyanine green and treated with methyl aminolevulinate) and illuminated with different lights (630‐nm light‐emitting diode, 805‐nm diode laser and 830‐nm light‐emitting diode). The bactericidal effects were evaluated by comparing each group's colony‐forming units. The cultured P. acnes were killed with an 805‐nm diode laser and 830‐nm light‐emitting diode in the indocyanine green group. No bactericidal effects of methyl aminolevulinate‐based photodynamic therapy were identified. The clinical efficacy of indocyanine green‐based photodynamic therapy in 21 patients was retrospectively analyzed. The Korean Acne Grading System was used to evaluate treatment efficacy, which was significantly decreased after treatment. The difference in the efficacy of the 805‐nm diode laser and 830‐nm light‐emitting diode was not statistically significant. Although the methyl aminolevulinate‐based photodynamic therapy showed no bactericidal effect, the indocyanine green‐based photodynamic therapy has bactericidal effect and clinical efficacy.
Vertical seismic profiling using a daisy‐chained deployment of fibre‐optic cables in four wells simultaneously – Case study at the Ketzin carbon dioxide storage site
Authors: Götz Julia , Lüth Stefan , Henninges Jan , Reinsch Thomas
Published: May 2018

The geological storage of carbon dioxide is considered as one of the measures to reduce greenhouse gas emissions and to mitigate global warming. Operators of storage sites are required to demonstrate safe containment and stable behaviour of the storage complex that is achieved by geophysical and geochemical monitoring, combined with reservoir simulations. For site characterization, as well as for imaging the carbon dioxide plume in the reservoir complex and detecting potential leakage, surface and surface‐borehole time‐lapse seismic monitoring surveys are the most widespread and established tools. At the Ketzin pilot site for carbon dioxide storage, permanently installed fibre‐optic cables, initially deployed for distributed temperature sensing, were used as seismic receiver arrays, demonstrating their ability to provide high‐resolution images of the storage formation. A vertical seismic profiling experiment was acquired using 23 source point locations and the daisy‐chained deployment of a fibre‐optic cable in four wells as a receiver array. The data were used to generate a 3D vertical seismic profiling cube, complementing the large‐scale 3D surface seismic measurements by a high resolution image of the reservoir close to the injection well. Stacking long vibro‐sweeps at each source location resulted in vertical seismic profiling shot gathers characterized by a signal‐to‐noise ratio similar to gathers acquired using geophones. A detailed data analysis shows strong dependency of data quality on borehole conditions with significantly better signal‐to‐noise ratio in regions with good coupling conditions.
Esophageal squamous cell carcinomas in a Malaysian cohort show a lack of association with human papillomavirus
Authors: Cheah Phaik‐Leng , Koh Cing‐Chai , Khang Tsung Fei , Goh Khean‐Lee , Lau Peng‐Choong , Chin Kin‐Fah , Teoh Kean‐Hooi , Toh Yen‐Fa , Looi Lai‐Meng
Published: May 2018

OBJECTIVE

With an age‐standardized incidence rate of 2 per 100 000, esophageal cancer is not common among Malaysians, but they are nevertheless important due to its poor prognosis. The study is to clarify whether the human papillomavirus (HPV) is associated with esophageal cancer in Malaysians as there has been no report to date on this in Malaysians and other South East Asians.

METHODS

Altogether 67 esophageal squamous cell carcinomas histologically diagnosed between 1 January 2004 and 31 December 2014 at the Department of Pathology, University of Malaya Medical Center, Malaysia were considered for HPV analysis using two commercially available methods, polymerase chain reaction with flow‐through hybridization (21 HPV GenoArray Diagnostic Kit) and multiplex real‐time polymerase chain reaction (Anyplex II HPV28 Detection). The DNA amplifiability of the formalin‐fixed, paraffin‐embedded tumor was checked by amplification of a 268 bp segment of the human β‐globin gene (GH20/PC04) prior to HPV detection.

RESULTS

HPV detection was finally carried out in 51 patients. HPV16 was detected in the moderately differentiated, stage IV lower esophageal tumor of a 32‐year‐old Malaysian‐born Chinese woman by both methods. Except for a predilection for Indians, the clinical characteristics of esophageal squamous cell carcinomas in this Malaysian cohort were generally similar to those of other populations.

CONCLUSION

It appears that HPV is rare and an unlikely oncovirus in esophageal squamous cell carcinomas of Malaysians.
High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma
Authors: Li Lei , Liu Yong‐Dong , Zhan Yu‐Ting , Zhu Ying‐Hui , Li Yan , Xie Dan , Guan Xin‐Yuan
Published: May 2018

Background

Tumor‐associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue‐conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed.

Methods

LUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real‐time quantitative PCR.

Results

Higher levels of chemokines MCP1/CCL2 (21.11‐fold increase) and MIP‐1β/CCL4 (19.33‐fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real‐time PCR analyses showed higher co‐expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P < 0.0001). Immunofluorescent co‐staining showed a high percentage of CCL2+/CD68+ and CCL4+/CD68+ tumor‐associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan–Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P = 0.048) and progression‐free survival (PFS; P = 0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P = 6.7e−08) and PFS (P = 0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P = 0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P = 0.013).

Conclusion

Our study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients.
EGFR mutations in early‐stage and advanced‐stage lung adenocarcinoma: Analysis based on large‐scale data from China
Authors: Pi Can , Xu Chong‐Rui , Zhang Ming‐feng , Peng Xiao‐xiao , Wei Xue‐wu , Gao Xing , Yan Hong‐Hong , Zhou Qing
Published: May 2018

Background

EGFR‐tyrosine kinase inhibitors play an important role in the treatment of advanced non‐small cell lung cancer (NSCLC). EGFR mutations in advanced NSCLC occur in approximately 35% of Asian patients and 60% of patients with adenocarcinoma. However, the frequency and type of EGFR mutations in early‐stage lung adenocarcinoma remain unclear.

Methods

We retrospectively collected data on patients diagnosed with lung adenocarcinoma tested for EGFR mutation. Early stage was defined as pathological stage IA–IIIA after radical lung cancer surgery, and advanced stage was defined as clinical stage IIIB without the opportunity for curative treatment or stage IV according to the American Joint Committee on Cancer Staging Manual, 7th edition.

Results

A total of 1699 patients were enrolled in this study from May 2014 to May 2016; 750 were assigned to the early‐stage and 949 to the advanced‐stage group. Baseline characteristics of the two groups were balanced, except that there were more smokers in the advanced‐stage group (P < 0.001). The total EGFR mutation rate in the early‐stage group was similar to that in the advanced‐stage group (53.6% vs. 51.4%, respectively; P = 0.379). There was no significant difference in EGFR mutation type between the two groups. In subgroup analysis of smoking history, there was no difference in EGFR mutation frequency or type between the early‐stage and advanced‐stage groups.

Conclusion

Early‐stage and advanced‐stage groups exhibited the same EGFR mutation frequencies and types.
Parabens generate reactive oxygen species in human spermatozoa
Authors: Samarasinghe S. V. A. C. , Krishnan K. , Naidu R. , Megharaj M. , Miller K. , Fraser B. , Aitken R. J.
Published: May 2018

Parabens are used as antimicrobial preservative agent in many commercial products including cosmetics and pharmaceuticals. Weak oestrogenic and antiandrogenic activities have been attributed to parabens in in vitro and in vivo studies. In this study, human spermatozoa were exposed to different concentrations of an equimolar paraben mixture containing methyl, ethyl, propyl and butylparaben as well as to methylparaben alone at a concentration that is typical of commercially available vaginal lubricants. The induction of oxidative stress and DNA damage was then assessed at different time points. Our results demonstrate that the paraben mixture was capable of stimulating the generation of mitochondrial and cytosolic reactive oxygen species (ROS), inhibiting sperm motility and viability in a dose‐dependent manner. The ability of individual parabens to activate ROS generation and induce oxidative DNA damage was related to alkyl chain length. At the concentration used clinically, methylparaben inhibited sperm motility after both 2 and 5 h exposure (p < 0.05) and affected cell viability (p < 0.01) while augmenting ROS production and oxidative DNA damage. However, DNA fragmentation was not evident following methylparaben exposure. Based on these results, we conclude that, at the concentrations used in commercially available formulations, parabens may impair sperm motility, enhance the generation of mitochondrial ROS and stimulate the formation of oxidative DNA adducts. Taken together, these data underline the potential cytotoxic and genotoxic impact of such compounds in a clinical setting.
Neonatologists can impede or support parents’ participation in decision‐making during medical rounds in neonatal intensive care units
Authors: Axelin Anna , Outinen Jyri , Lainema Kirsi , Lehtonen Liisa , Franck Linda S.
Published: May 2018

Aim

We explored the dynamics of neonatologist–parent communication and decision‐making during medical rounds in a level three neonatal intensive care unit.

Methods

This was a qualitative study, with an ethnographic approach, that was conducted at Turku University Hospital, Finland, from 2013 to 2014. We recruited eight mothers and seven couples, their 11 singletons and four sets of twins and two neonatologists and observed and video recorded 15 medical rounds. The infants were born at 23 + 5 to 40 + 1 weeks, and the parents were aged 24–47. The neonatologists and parents were interviewed separately after the rounds.

Results

Four patterns of interaction emerged. The collaborative pattern was most consistent, with the ideal of shared decision‐making, as the parents’ preferences were genuinely and visibly integrated into the treatment decisions. In the neonatologist‐led interactional pattern, the decision‐making process was only somewhat inclusive of the parents’ observations and preferences. The remaining two patterns, emergency and disconnected, were characterised by a paternalistic decision‐making model where the parents’ observations and preferences had minimal to no influence on the communication or decision‐making.

Conclusion

The neonatologists played a central role in facilitating parental participation and their interaction during medical rounds were characterised by the level of parent participation in decision‐making.
Placentophagy among women planning community births in the United States: Frequency, rationale, and associated neonatal outcomes
Authors: Benyshek Daniel C. , Cheyney Melissa , Brown Jennifer , Bovbjerg Marit L.
Published: May 2018

Background

Limited systematic research on maternal placentophagy is available to maternity care providers whose clients/patients may be considering this increasingly popular practice. Our purpose was to characterize the practice of placentophagy and its attendant neonatal outcomes among a large sample of women in the United States.

Methods

We used a medical records–based data set (n = 23 242) containing pregnancy, birth, and postpartum information for women who planned community births. We used logistic regression to determine demographic and clinical predictors of placentophagy. Finally, we compared neonatal outcomes (hospitalization, neonatal intensive unit admission, or neonatal death in the first 6 weeks) between placenta consumers and nonconsumers, and participants who consumed placenta raw vs cooked.

Results

Nearly one‐third (30.8%) of women consumed their placenta. Consumers were more likely to have reported pregravid anxiety or depression compared with nonconsumers. Most (85.3%) placentophagic mothers consumed their placentas in encapsulated form, and nearly half (48.4%) consumed capsules containing dehydrated, uncooked placenta. Placentophagy was not associated with any adverse neonatal outcomes. Women with home births were more likely to engage in placentophagy than women with birth center births. The most common reason given (73.1%) for engaging in placentophagy was to prevent postpartum depression. [Corrections added on 16 May 2018, after first online publication: The percentage values in the Results sections were updated.]

Conclusions

The majority of women consumed their placentas in uncooked/encapsulated form and hoping to avoid postpartum depression, although no evidence currently exists to support this strategy. Preparation technique (cooked vs uncooked) did not influence adverse neonatal outcomes. Maternity care providers should discuss the range of options available to prevent/treat postpartum depression, in addition to current evidence with respect to the safety of placentophagy.
A 1286‐year hydro‐climate reconstruction for the Balkan Peninsula
Authors: Klippel Lara , Krusic Paul J. , Brandes Robert , Hartl Claudia , Belmecheri Soumaya , Dienst Manuel , Esper Jan
Published: May 2018

We present a June–July drought reconstruction based on the standardized precipitation index (SPI) for the Balkan Peninsula over the period 730–2015 CE. The reconstruction is developed using a composite Pinus heldreichii tree‐ring width chronology, from a high‐elevation network of eight sites in the Pindus Mountains in northwest Greece, composed of living trees and relict wood. The dataset includes the ring width series of Europe's currently oldest known living tree, dendrochronologically dated to be more than 1075 years old. The spatial coverage of the reconstruction is improved by using an averaged gridded SPI data target derived from a response field that is located north of the study region. Justification for this approach includes the remoteness of instrumental data, the spatial variability of precipitation and synoptic scale circulation patterns. Over the past 1286 years, there have been 51 dry and 43 pluvial events. The driest year during the 1286‐year‐long period was 1660 and the wettest year was 1482. Comparison with shorter reconstructions and documentary evidence validates the new reconstruction, and provides additional insight into socioeconomic impacts and spatial patterns of extreme events. Fifty‐nine of 72 previously undescribed extremes occurred prior to the 17th century. The new reconstruction reveals long‐term changes in the number of extremes, including substantially fewer drought and pluvial events in the 20th century. Additional tests on the long‐term effects of age structure, replication and covariance changes support the heteroscedastic nature of the reconstructed hydro‐climatic extremes.
Pathogenic variants in theABCC6gene are associated with an increased risk for ischemic stroke
Authors: De Vilder Eva Y.G. , Cardoen Stefanie , Hosen Mohammad J. , Le Saux Olivier , De Zaeytijd Julie , Leroy Bart P. , De Reuck Jacques , Coucke Paul J. , De Paepe Anne , Hemelsoet Dimitri , Vanakker Olivier M.
Published: May 2018

Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated theABCC6gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenicABCC6variants, the higher cardiovascular risk in heterozygous carriers and the established role ofABCC6dysfunction in myocardial ischemia. We established segregation of a known pathogenicABCC6variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case‐control study in 424 ischemic stroke patients and 250 healthy controls, pathogenicABCC6variants were 4.9 times more frequent (P= 0.036; 95% CI 1.11–21.33) in the ischemic stroke patient cohort. To study cellular consequences ofABCC6deficiency in the brain, immunostaining of brain sections inAbcc6‐deficient mice and wild‐type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified inAbcc6−/− mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro‐ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenicABCC6variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygousABCC6variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfβ (Eng) signaling in the brain ofAbcc6−/− mice could lead to a pro‐ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of theABCC6gene in patients diagnosed with cryptogenic ischemic stroke.
Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells
Authors: Zuo Haoxiao , Han Bing , Poppinga Wilfred J , Ringnalda Lennard , Kistemaker Loes E M , Halayko Andrew J , Gosens Reinoud , Nikolaev Viacheslav O , Schmidt Martina
Published: May 2018

Background and Purpose

cAMP is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease, a lung disease primarily provoked by cigarette smoke (CS), the activation of cAMP‐dependent pathways, via inhibition of hydrolyzing PDEs, is a major therapeutic strategy. Mechanisms that disrupt cAMP signalling in airway cells, in particular regulation of endogenous PDEs, are poorly understood.

Experimental Approach

We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mice in vivo, ex vivo precision cut lung slices (PCLS) and in human cell models, in vitro, to track the effects of CS exposure.

Key Results

Under fenoterol stimulation, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein up‐regulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed down‐regulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre‐contracted airways.

Conclusion and Implications

Exposure to CS, in vitro or in vivo, up‐regulated expression and activity of both PDE3 and PDE4, which affected real‐time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS‐induced pulmonary pathophysiology.