bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Opioid Use and Survival Time in Patients With Unresectable Pancreatic Cancer
Authors: Oh Tak Kyu , Do Sang-Hwan , Yoon Yoo-Suk , Song In-Ae
Published: June 2018

Objectives

Patients with pancreatic cancer generally experience increasing pain as their disease progresses, making the titration of opioids difficult. This study aimed to determine a correlation between prescribed opioid doses and survival time in patients with unresectable pancreatic cancer.

Methods

This retrospective observational cohort study in a tertiary care institution reviewed the medical records of patients diagnosed with unresectable pancreatic cancer and treated over a 10-year period.

Results

We screened 1152 patients with unresectable pancreatic cancer, and 566 were eligible for inclusion in this study. There was a statistically significant negative correlation between initial opioid dose and survival time from initial opioid dose (correlation coefficient, −0.184; P < 0.01) and survival time from initial pancreatic cancer diagnosis (correlation coefficient, −0.177; P < 0.01). In addition, there were 0.8% and 0.6% increases in initial opioid dosage (morphine equivalent daily dose) and rate of increasing opioid dose (morphine equivalent daily dose per month), respectively, associated with the risk of early death (≤180 days, P < 0.05).

Conclusions

Correlations between patient survival, initial opioid dose, final opioid dose, and the rate of increase of opioid dosage could provide useful information for clinicians treating unresectable pancreatic cancer patients.
Association Between Hepatitis B Infection and Pancreatic Cancer
Authors: Desai Rupak , Patel Upenkumar , Sharma Shobhit , Singh Sandeep , Doshi Shreyans , Shaheen Sana , Shamim Sofia , Korlapati Lakshmi Shirisha , Balan Shuba , Bray Christopher , Williams Renee , Shah Nihar
Published: June 2018

Objectives

The aim of this study was to assess the role of hepatitis B (HepB) infection in the causation of pancreatic cancer and the predictors of pancreatic cancer and mortality.

Methods

We identified pancreatic cancer patients 11 to 70 years of age from the 2013–2014 National Inpatient Sample. Pearson χ2 test and Student’s t-test were used for categorical and continuous variables, respectively. We assessed the association of HepB and pancreatic cancer and the independent mortality predictors by multivariate analyses.

Results

Of 69,210 pancreatic cancer patients, 175 patients with a history of HepB and 69,035 patients without a history of HepB were identified. Compared with the pancreatic cancer–non-HepB group, the pancreatic cancer–HepB group consisted more of younger (mean, 60.4 [standard deviation, 7.4] years vs 68.2 [standard deviation, 12.1] years), male, black, and Asian patients with low household income and nonelective admissions. The odds of developing pancreatic cancer among the HepB patients were significantly higher (adjusted odds ratio, 1.24; 95% confidence interval, 1.056–1.449; P = 0.008). Black race, age ≥ 65 years, and male sex demonstrated greater odds of mortality.

Conclusions

This study concluded up to a 24% increased likelihood of pancreatic cancer among the HepB patients. Blacks showed greater odds of pancreatic cancer and related mortality.
Mortality Risk Using a Pediatric Quick Sequential (Sepsis-Related) Organ Failure Assessment Varies With Vital Sign Thresholds*
Authors: Peters Cheryl , Murthy Srinivas , Brant Rollin , Kissoon Niranjan , Görges Matthias
Published: June 2018

Objectives:

We evaluated adapting the quick Sequential (Sepsis-Related) Organ Failure Assessment score (fast respiratory rate, altered mental status, low blood pressure) for pediatric use by selecting thresholds from three commonly used definitions: Pediatric Logistic Organ Dysfunction 2, Pediatric Advanced Life Support, and International Pediatric Sepsis Consensus Conference. We examined their respective performance in identifying children who had a discharge diagnosis of infection at high risk of mortality using PICU registry data, with additional focus on the influence of age on performance.

Design:

Analysis of retrospective data obtained from the Virtual Pediatric Systems PICU database. The performance in predicting observed mortality was assessed for the three candidate approaches using receiver operating characteristics analysis, including age group effects.

Setting:

The Virtual Pediatric Systems database contains data on diagnosis, clinical markers, and outcomes in prospectively collected clinical records from 130 participating PICUs in the United States and Canada.

Patients:

Children who had a discharge diagnosis of infection in a participating PICU between 2009 and 2014, for which all required data were available.

Interventions:

None.

Measurements and Main Results:

Data from 40,228 children revealed an overall mortality of 4.22%. Area under the receiver operating characteristics curve (95% CI) was 0.760 (0.749–0.771) for Pediatric Logistic Organ Dysfunction 2 with mechanical ventilation, 0.700 (0.689–0.712) for Pediatric Advanced Life Support, and 0.709 (0.696–0.721) for International Pediatric Sepsis Consensus Conference. When split by age group, the performance of Pediatric Logistic Organ Dysfunction 2 with mechanical ventilation was lowest in the youngest neonates (under 1 wk old), with an area under the receiver operating characteristics curve (95% CI) of 0.724 (0.656–0.791), and in the teenagers (13–18 yr), with an area under the receiver operating characteristics curve of 0.710 (0.682–0.738), yet it still outperformed Pediatric Advanced Life Support and International Pediatric Sepsis Consensus Conference in both groups.

Conclusions:

Among critically ill children who had a discharge diagnosis of infection in the PICU, quick Sequential (Sepsis-Related) Organ Failure Assessment score performs best when using the Pediatric Logistic Organ Dysfunction 2 age thresholds with mechanical ventilation, while all definitions performed worse at extremes of pediatric age. Thus, mortality risk varies with vital sign thresholds, and although Pediatric Logistic Organ Dysfunction 2 with mechanical ventilation performed marginally better, it is unlikely to be of use to clinicians. More work is needed to develop a robust and relevant pediatric sepsis risk score.
Quality and Safety in Health Care, Part XLII
Authors: Harolds Jay A.
Published: June 2018

Implantable cardioverter defibrillators for both primary and secondary prevention have been successful in decreasing sudden cardiac death. The Implantable Cardioverter Defibrillator Registry was established partly for reimbursement for primary prevention. However, the registry also has been helpful in better understanding the risks and appropriate selection of patients to receive these devices, serving as an impetus for quality improvement by giving outcome information to the contributing institutions regarding their performance relative to the national results, and increasing research. It is also expected to be helpful to compare results from different devices and provide information to the public.
Progression of Focal to Diffuse Thyroid Uptake Detected by 18F-FDG PET/CT
Authors: Thuillier Philippe , Crouzeix Geneviève , Descourt Renaud , Salaun Pierre-Yves , Abgral Ronan
Published: June 2018

A 49-year-old man was referred to our department for an assessment of a cerebral metastasis of unknown primary with 18F-FDG PET/CT. This imaging led to detection of a suspected pulmonary primary carcinoma, as well as an incidental left focal thyroid uptake. An ultrasonography, performed a month later, revealed a thyroiditis aspect. An anti-PD1 immunotherapy was also proposed 2 months later after confirmation of a lung adenocarcinoma. A second baseline FDG PET/CT surprisingly showed a diffuse thyroid uptake. A fine-needle aspiration biopsy of thyroid parenchyma finally revealed a diffuse involvement from lung adenocarcinoma (ie, primary lung metastasis to the thyroid gland).
Utility of 68Ga-PSMA-11 PET/CT in Imaging of Glioma—A Pilot Study
Authors: Sasikumar Arun , Kashyap Raghava , Joy Ajith , Charan Patro Kanhu , Bhattacharya Parthasarathy , Reddy Pilaka Venkata Krishna , Oommen Karuna Elza , Pillai Maroor Raghavan Ambikalmajan
Published: June 2018

Background

Imaging of gliomas remains challenging. The aim of the study was to assess the feasibility of using 68Ga-PSMA-11 PET/CT for imaging gliomas.

Methods

Fifteen patients with glioma from 2 centers were included in the study. Ten patients were treated cases of glioblastoma with suspected recurrence. Two patients were sent for assessing the nature (primary lesion/metastasis) of space-occupying lesion in the brain; 3 patients were imaged immediately after surgery and before radiotherapy. Target-to-background ratios (TBR) for the brain lesions were calculated using contralateral cerebellar uptake as background.

Results

Among the 10 cases with suspected recurrence, scan was positive in 9, subsequent surgery was done, and histopathology proved it to be true recurrence. In the scan-negative case on follow-up, no evidence of disease could be made clinically or radiologically. Among the other cases the presence or absence of disease could be unequivocally identified on the 68Ga-PSMA-11 brain scan and correlated with the histopathology or other imaging. Apart from the visual assessment quantitative assessment of the lesions with TBR also showed a significantly high TBR value for those with true disease compared with those with no disease.

Conclusions

In the evaluation of gliomas, 68Ga-PSMA-11 PET/CT brain imaging is a potentially useful imaging tool. The use of 68Ga-PSMA-11 brain PET/CT in evaluation of recurrent glioma seems promising. Absence of physiological uptake of 68Ga-PSMA-11 in the normal brain parenchyma results in high TBR values and consequently better visualization of glioma lesions.
18F-Fluciclovine Uptake by an Incidentally Detected Hepatocellular Carcinoma in a Case of Biochemically Recurrent Prostate Cancer
Authors: Sannananja Bhagya , Shah Hardik Uresh , Behnia Fatemeh
Published: June 2018

Prostate cancer is one of the most common cancers affecting men worldwide with a high recurrence rate following therapy. 18F-fluciclovine, is a US Food and Drug Administration–approved radiopharmaceutical for PET imaging in biochemically recurrent prostate cancer. It targets increased amino acid transporters in the cell membrane of cancer cells. We report a case of incidentally detected hepatocellular carcinoma showing 18F-fluciclovine uptake in a 71-year-old man with biochemically recurrent prostate cancer.
Detection of Metastatic Meningioma to the Liver Using 68Ga-DOTA-Octreotate PET/CT
Authors: Villanueva-Meyer Javier E. , Magill Stephen T. , Lee Julieann C. , Umetsu Sarah E. , Flavell Robert R.
Published: June 2018

We present a case of metastatic meningioma detected on 68Ga-DOTA-octreotate PET. A 52-year-old woman presented with multiply recurrent multifocal meningioma. A staging 68Ga-DOTATATE PET/CT demonstrated focal radiotracer uptake within the known intracranial meningiomas. In addition, a DOTATATE-avid mass was found in the liver that was biopsied, confirming metastatic meningioma. This report suggests that 68Ga-DOTATATE PET/CT should be considered whenever screening meningioma patients for metastases.
Prostate-specific membrane antigen for prostate cancer theranostics: from imaging to targeted therapy
Authors: Arsenault Frédéric , Beauregard Jean-Mathieu , Pouliot Frédéric
Published: June 2018

Purpose of review

In recent years, major advances in molecular imaging of prostate cancers (PCa) were made with the development and clinical validation of highly accurate PET tracers to stage and restage the disease. Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in PCa, and its expression has led to the development of PSMA-binding radiopharmaceuticals for molecular imaging or radioligand therapy (RLT). We herein review the recent literature published on diagnostic and therapeutic (i.e. theranostic) PSMA tracers.

Recent findings

Development in small PSMA-targeted molecules labeled with gallium-68 and fluorine-18 show promising results for primary staging and detection of disease at biochemical recurrence using PET/computed tomography (PET/CT). Studies show a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and bone scan) or choline PET tracers, especially for restaging after prostate-specific antigen failure following loco-regional therapy. In addition, some PSMA tracers can be labeled with beta-minus and alpha particle emitters, yielding encouraging response rates and low toxicity, and potentially offering a new line of targeted therapy for metastatic castration-resistant PCa.

PSMA-targeted tracers have shown unprecedented accuracy to stage and restage PCa using PET/CT. Given their specific biodistribution toward PCa tissue, PSMA RLT now offers new therapeutic possibilities to target metastatic PCa. Prospective multicenter randomized studies investigating the clinical impact of PSMA–targeted molecules are urgently needed.
A nonsense mutation in Myelin Protein Zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function
Authors: Fratta Pietro , Ornaghi Francesca , Dati Gabriele , Zambroni Desirée , Saveri Paola , Belin Sophie , D’Adamo Patrizia , Shy Michael , Quattrini Angelo , Laura Feltri M. , Wrabetz Lawrence
Published: June 2018

Protein Zero (P0) is the major structural protein in peripheral myelin and mutations in the Myelin Protein Zero (Mpz) gene produce wide ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells (SC). We show that the loss of the C-terminal YAML motif is responsible for P0 mislocalisation, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wildtype P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.
Citizen science data enhance spatio-temporal extent and resolution of animal population studies
Authors: Sun Catherine C. , Fuller Angela K. , Hurst Jeremy E.
Published: June 2018

Informed management and conservation decisions for animal populations often require data at sufficient geographic, temporal, and demographic resolutions for precise and unbiased estimates of parameters including population size and demographic rates. Recently developed integrated population models estimate such parameters by unifying population presence-absence and demographic data, and we demonstrate how citizen science offers a cost-efficient mechanism to collect such data. We describe the early results of iSeeMammals, a citizen science project that collects opportunistic data on the black bear population in New York State by enlisting volunteers to collect data through observations, hikes, and trail cameras. In 10 months, iSeeMammals increased the spatio-temporal extent of data collection by approximately fourfold and reduced cost by 83% compared to systematic sampling. In combination with other datasets in integrated population model frameworks, large, spatiotemporally extensive datasets from citizen science projects like iSeeMammals can help improve inferences about population-level structure and dynamics.
Simulation of P2X-mediated calcium signaling in microglia
Authors: Chun Ben , Stewart Bradley D. , Vaughan Darin , Bachstetter Adam D. , Kekenes-Huskey Peter M.
Published: June 2018

Microglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adenosine triphosphate (ATP), transient increases in intracellular Ca2+driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis and potentially their release. While steps comprising the pathways bridging purinergic receptor activation with transcriptional responses have been probed in great detail, a quantitative model for how these steps collectively control cytokine production has not been established. Here we developed a minimal computational model that quantitatively links extracellular stimulation of two prominent ionotropic puriner-gic receptors, P2X4and P2X7, with the graded production of a gene product, namely the tumor necrosis factorα(TNFα) cytokine. In addition to Ca2+handling mechanisms common to eukaryotic cells, our model includes microglia-specific processes including ATP-dependent P2X4and P2X7activation, activation of NFAT transcription factors, and TNFαproduction. Parameters for this model were optimized to reproduce published data for these processes, where available. With this model, we determined the propensity for TNFαproduction in microglia, subject to a wide range of ATP exposure amplitudes, frequencies and durations that the cells could encounterin vivo.Furthermore, we have investigated the extent to which modulation of the signal transduction pathways influence TNFαproduction. Our key findings are that TNFαproduction via P2X4is maximized at low ATP when subject to high frequency ATP stimulation, whereas P2X7contributes most significantly at millimolar ATPranges. Given that Ca2+homeostasis in microglia is profoundly important to its function, this computational model provides a quantitative framework to explore hypotheses pertaining to microglial physiology.
Spatial Organization of Rho GTPase signaling by RhoGEF/RhoGAP proteins
Authors: Müller Paul M. , Rademacher Juliane , Bagshaw Richard D. , Alp Keziban M. , Giudice Girolamo , Heinrich Louise E. , Barth Carolin , Eccles Rebecca L. , Sanchez-Castro Marta , Brandenburg Lennart , Mbamalu Geraldine , Tucholska Monika , Spatt Lisa , Wortmann Celina , Czajkowski Maciej T. , Welke Robert-William , Zhang Sunqu , Nguyen Vivian , Rrustemi Trendelina , Trnka Philipp , Freitag Kiara , Larsen Brett , Popp Oliver , Mertins Philipp , Bakal Chris , Gingras Anne-Claude , Pertz Olivier , Roth Frederick P. , Colwill Karen , Pawson Tony , Petsalaki Evangelia , Rocks Oliver
Published: June 2018

Rho GTPases control cell morphogenesis and thus fundamental processes in all eukaryotes. They are regulated by 145 RhoGEF and RhoGAP multi-domain proteins in humans. How the Rho signaling system is organized to generate localized responses in cells and prevent their spreading is not understood. Here, we systematically characterized the substrate specificities, localization and interactome of the RhoGEFs/RhoGAPs and revealed their critical role in contextualizing and spatially delimiting Rho signaling. They localize to multiple compartments providing positional information, are extensively interconnected to jointly coordinate their signaling networks and are widely autoinhibited to remain sensitive to local activation. RhoGAPs exhibit lower substrate specificity than RhoGEFs and may contribute to preserving Rho activity gradients. Our approach led us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling a Cdc42/RhoA crosstalk. The spatial organization of Rho signaling thus differs from other small GTPases and expands the repertoire of mechanisms governing localized signaling activity.
Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer
Authors: Mattiuz Giorgio , Giorgio Salvatore Di , Tofani Lorenzo , Frandi Antonio , Donati Francesco , Brilli Matteo , Conticello Silvestro G
Published: June 2018

Alterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.
Deep SNP: An End-to-end Deep Neural Network with Attention-based Localization for Break-point Detection in SNP Array Genomic data
Authors: Eghbal-zadeh Hamid , Fischer Lukas , Popitsch Niko , Kromp Florian , Taschner-Mandl Sabine , Koutini Khaled , Gerber Teresa , Bozsaky Eva , Ambros Peter F. , Ambros Inge M. , Widmer Gerhard , Moser Bernhard A.
Published: June 2018

Diagnosis and risk stratification of cancer and many other diseases require the detection of genomic breakpoints as a prerequisite of calling copy number alterations (CNA). This, however, is still challenging and requires time-consuming manual curation. As deep-learning methods outperformed classical state-of-the-art algorithms in various domains and have also been successfully applied to life science problems including medicine and biology, we here propose Deep SNP, a novel Deep Neural Network to learn from genomic data. Specifically, we used a manually curated dataset from 12 genomic single nucleotide polymorphism array (SNPa) profiles as truth-set and aimed at predicting the presence or absence of genomic breakpoints, an indicator of structural chromosomal variations, in windows of 40,000 probes. We compare our results with well-known neural network models as well as Rawcopy though this tool is designed to predict breakpoints and in addition genomic segments with high sensitivity. We show, that Deep SNP is capable of successfully predicting the presence or absence of a breakpoint in large genomic windows and outperforms state-of-the-art neural network models. Qualitative examples suggest that integration of a localization unit may enable breakpoint detection and prediction of genomic segments, even if the breakpoint coordinates were not provided for network training. These results warrant further evaluation of DeepSNP for breakpoint localization and subsequent calling of genomic segments.
The washing machine as a reservoir for transmission of ESBL-producingKlebsiella oxytocain newborns
Authors: Schmithausen R.M. , Exner M. , Rösing C. , Savin M. , Hack S. , Bloomfield S.F. , Kaase M. , Gebel J. , Engelhart S. , Exner D.
Published: June 2018

During the period from April 2012 to May 2013, 13 newborns and one child in a paediatric hospital ward in Germany were found to be colonised with a distinct clinical clone of an (extended spectrum β-lactamase) (ESBL)-producingKlebsiella oxytoca. This clone was specific to this hospital and had not been previously isolated in Germany.

A source-tracking analysis was carried out to identify the source and transmission pathways of the ESBL-producingK. oxytocaclone. A systematic environmental survey of the ward and an audit of the procedures for cleaning and disinfecting surfaces, instruments, incubators, and washing machines was performed. Microbiological samples were obtained from environmental surfaces. Risk factors were analysed for epidemiological linkage.

Isolates of an ESBL-producingK. oxytocawere found in the detergent drawer and on the rubber door seal of a washing machine and in two sinks. These strains were typed by pulsed-field-gel-electrophoresis (PFGE) and compared with the isolates from the newborns and their clothing and found to be identical. The retrospective analysis demonstrated that only newborns who had worn clothes that had been washed in the washing machine were colonised with the identical clone. After the washing machine was taken out of use, no further cases were detected over the following 4-year period.

We conclude that washing machines are potential reservoirs and vectors for transmission ofEnterobacteriaceae, and likely other bacteria.

Importance

Washing machines should be further investigated as possible sites for horizontal gene transfer (ESBL-/carbapenemase-genes) and cross-contamination of clinically important Gram-negative strains. Particularly in the healthcare sector, the knowledge of possible (re-) contamination of laundry (patients clothes, staff uniforms) with multidrug-resistant Gram-negative bacteria could help to prevent and control nosocomial infections. To date, the potential of the washing machine as a source and vector of antibiotic-resistant gram-negative bacteria causing an outbreak in a clinical setting has not been investigated. This report shows that sampling of washing machines should be included in environmental audits associated with outbreak control management, and conditions for the laundering of baby 64 clothing should be reviewed.
Analysis and Correction of Inappropriate Image Duplication: The Molecular and Cellular Biology Experience
Authors: Bik Elisabeth M. , Fang Ferric C. , Kullas Amy L. , Davis Roger J. , Casadevall Arturo
Published: June 2018

The present study analyzed 960 papers published in Molecular and Cellular Biology (MCB) from 2009-2016 and found 59 (6.1%) to contain inappropriately duplicated images. The 59 instances of inappropriate image duplication led to 42 corrections, 5 retractions and 12 instances in which no action was taken. Our experience suggests that the majority of inappropriate image duplications result from errors during figure preparation that can be remedied by correction. Nevertheless, ~10% of papers with inappropriate image duplications in MCB were retracted. If this proportion is representative, then as many as 35,000 papers in the literature are candidates for retraction due to image duplication. The resolution of inappropriate image duplication concerns after publication required an average of 6 h of journal staff time per published paper. MCB instituted a pilot program to screen images of accepted papers prior to publication that identified 12 manuscripts (14.5% out of 83) with image concerns in two months. The screening and correction of papers before publication required an average of 30 min of staff time per problematic paper. Image screening can identify papers with problematic images prior to publication, reduces post-publication problems and requires significantly less staff time than the correction of problems after publication.
Modeling of DNA replication in rapidly growing bacteria with one and two replication origins
Authors: Retkute Renata , Hawkins Michelle , Rudolph Christian J. , Nieduszynski Conrad A.
Published: June 2018

In rapidly growing bacteria initiation of DNA replication occurs at intervals shorter than the time required for completing genome duplication, leading to overlapping rounds of replication. We propose a mathematical model of DNA replication defined by the periodicity of replication initiation. Our model predicts that a steeper gradient of the replication profile is to be expected in origin proximal regions due to the overlapping rounds of synthesis. By comparing our model with experimental data from a strain with an additional replication origin, we predict defined alterations to replication parameters: (i) a reduced fork velocity when there were twice as many forks as normal; (ii) a slower fork speed if forks move in a direction opposite to normal, in line with head-on replication-transcription collisions being a major obstacle for fork progression; (iii) slower cell doubling for a double origin strain compared to wild-type cells; and (iv) potentially an earlier initiation of replication at the ectopic origin than at the natural origin, which, however, does not a˙ect the overall time required to complete synthesis.
Modification and de novo design of non-ribosomal peptide synthetases (NRPS) using specific assembly points within condensation domains
Authors: Bozhüyük Kenan A. J. , Linck Annabell , Tietze Andreas , Wesche Frank , Nowak Sarah , Fleischhacker Florian , Bode Helge B.
Published: June 2018

Many important natural products are produced by non-ribosomal peptide synthetases (NRPSs) 1.These giant enzyme machines activate amino acids in an assembly line fashion in which a set of catalytically active domains is responsible for the section, activation, covalent binding and connection of a specific amino acid to the growing peptide chain 1,2. Since NRPS are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would give access to a diverse range of peptides available biotechnologically. Here we describe a new fusion point inside condensation (C) domains of NRPSs that enables the efficient production of peptides, even containing non-natural amino acids, in yields higher than 280 mg/L. The technology called eXchange Unit 2.0 (XU2.0) also allows the generation of targeted peptide libraries and therefore might be suitable for the future identification of bioactive peptide derivatives for pharmaceutical and other applications.
The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization
Authors: Herberg Sarah , Gert Krista R. , Schleiffer Alexander , Pauli Andrea
Published: June 2018

Fertilization is fundamental for sexual reproduction, yet its molecular mechanisms are poorly understood. Here, we identify an oocyte-expressed Ly6/uPAR protein, which we call Bouncer, as a crucial fertilization factor in zebrafish. We show that membrane-bound Bouncer mediates sperm-egg binding and is thus essential for sperm entry into the egg. Remarkably, Bouncer is not only required for sperm-egg interaction, but also sufficient to allow cross-species fertilization between zebrafish and medaka, two fish species that diverged over 150 million years ago. Our study thus identifies Bouncer as a key determinant of species-specific fertilization in fish. Bouncer’s closest homolog in tetrapods, SPACA4, is restricted to the male gonad in internally fertilizing vertebrates, suggesting that our findings in fish have relevance to human biology.
Drosophila small ovaryencodes a zinc-finger repressor required for ovarian differentiation
Authors: Benner Leif , Castro Elias A. , Whitworth Cale , Venken Koen J.T. , Yang Haiwang , Oliver Brian , Cook Kevin R. , Lerit Dorothy A.
Published: June 2018

Repression is essential for coordinated cell type-specific gene regulation and controlling the expression of transposons. In theDrosophilaovary, stem cell regeneration and differentiation requires controlled gene expression, with derepression leading to tissue degeneration and ovarian tumors. Likewise, the ovary is acutely sensitive to deleterious consequences of transposon derepression. Thesmall ovary(sov) locus was identified in a female sterile screen, and mutants show dramatic ovarian morphogenesis defects. We mapped the locus to the uncharacterized geneCG14438, which encodes a zinc-finger protein that colocalizes with the essential Heterochromatin Protein 1 (HP1a). We demonstrate that Sov functions to repress inappropriate cell signaling, silence transposons, and suppress position-effect variegation in the eye, suggesting a central role in heterochromatin stabilization.
TP53mutations promote immunogenic activity in breast cancer
Authors: Liu Zhixian , Jiang Zehang , Gao Yingsheng , Wang Lirui , Chen Cai , Wang Xiaosheng
Published: June 2018

Background

Although immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy.TP53mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a highTP53mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for theTP53-mutated BC subtype, we studied the associations betweenTP53mutations and immunogenic activity in BC.

Methods

We compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways betweenTP53-mutated andTP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity betweenTP53-mutated andTP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.

Results

We found that almost all analyzed immune gene-sets had significantly higher enrichment levels inTP53-mutated BCs compared toTP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed thatTP53mutations could promote BC immunogenicityviaregulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis inTP53-mutated BCs, but not necessarily inTP53-wildtype BCs.

Conclusions

TP53mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that theTP53mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.
ATR repression at telomeres by POT1a and POT1b: RPA exclusion and interference by CST
Authors: Kratz Katja , Lange Titia de
Published: June 2018

Telomeres carry a constitutive 3’ overhang that can bind RPA and activate ATR signaling. POT1a, a single-stranded (ss) DNA binding protein in mouse shelterin, has been proposed to repress ATR signaling by preventing RPA binding. Repression of ATR at telomeres requires the TPP1/TIN2 mediated tethering of POT1a to the the rest of the shelterin complex situated on the ds telomeric DNA. The simplest version of the tethered exclusion model for ATR repression suggests that the only critical features of POT1a are its connection to shelterin and its binding to ss telomeric DNA binding. In agreement with the model, we show that a shelterin-tethered RPA70 mutant, lacking the ATR recruitment domain, is effective in repressing ATR signaling at telomeres. However, arguing against the simple tethered exclusion model, the nearly identical POT1b subunit of shelterin is much less proficient in ATR repression than POT1a. We now show that POT1b has the intrinsic ability to fully repress ATR but is prevented from doing so when bound to the CST/Polα/primase complex. The data establish that shelterin represses ATR with a tethered ssDNA-binding domain that excludes RPA from the 3’ overhang and suggest that ATR repression does not require the interaction of POT1 with the 3’ end or G4 DNA.
Slow Normal Modes of Proteins are Accurately Reproduced across Different Platforms
Authors: Na Hyuntae , ben-Avraham Daniel , Tirion Monique M.
Published: June 2018

The Protein Data Bank (PDB) [1] contains the atomic structures of over 105biomolecules with better than 2.8Å resolution. The listing of the identities and coordinates of the atoms comprising each macromolecule permits an analysis of the slow-time vibrational response of these large systems to minor perturbations. 3D video animations of individual modes of oscillation demonstrate how regions interdigitate to create cohesive collective motions, providing a comprehensive framework for and familiarity with the overall 3D architecture. Furthermore, the isolation and representation of the softest, slowest deformation coordinates provide opportunities for the development of mechanical models of enzyme function. The eigenvector decomposition, therefore, must be accurate, reliable as well as rapid to be generally reported upon. We obtain the eigenmodes of a 1.2Å 34kDa PDB entry using either exclusively heavy atoms or partly or fully reduced atomic sets; Cartesian or internal coordinates; interatomic force fields derived either from a full Cartesian potential, a reduced atomic potential or a Gaussian distance-dependent potential; and independently developed software. These varied technologies are similar in that each maintains proper stereochemistry either by use of dihedral degrees of freedom which freezes bond lengths and bond angles, or by use of a full atomic potential that includes realistic bond length and angle restraints. We find that the shapes of the slowest eigenvectors are nearly identical, not merely similar.
Differences in the path to exit the ribosome across the three domains of life
Authors: Duc Khanh Dao , Batra Sanjit S. , Bhattacharya Nicholas , Cate Jamie H. D. , Song Yun S.
Published: June 2018

Recent advances in biological imaging have led to a surge of fine-resolution structures of the ribosome from diverse organisms. Comparing these structures, especially the exit tunnel, to characterize the key similarities and differences across species is essential for various important applications, such as designing antibiotic drugs and understanding the intricate details of translation dynamics. Here, we compile and compare 20 fine-resolution cryo-EM and X-ray crystallography structures of the ribosome recently obtained from all three domains of life (bacteria, archaea and eukarya). We first show that a hierarchical clustering of tunnel shapes closely reflects the species phylogeny. Then, by analyzing the ribosomal RNAs and proteins localized near the tunnel, we explain the observed geometric variations and show direct association between the conservations of the geometry, structure, and sequence. We find that the tunnel is more conserved in its upper part, from the polypeptide transferase center to the constriction site. In the lower part, tunnels are significantly narrower in eukaryotes than in bacteria, and we provide evidence for the existence of a second constriction site in eukaryotic tunnels. We also show that ribosomal RNA and protein sequences are more likely to be conserved closer to the tunnel, as is the presence of positively charged amino acids. Overall, our comparative analysis shows how the geometric and biophysical properties of the exit tunnel play an important role in ensuring proper transit of the nascent polypeptide chain, and may explain the differences observed in several co-translational processes across species.
Antiretroviral Adverse Drug Reactions Pharmacovigilance in Harare City, Zimbabwe, 2017
Authors: Mugauri Hamufare , Mugurungi Owen , Juru Tsitsi , Gombe Notion , Shambira Gerald , Tshimanga Mufuta
Published: June 2018

Introduction

Key to pharmacovigilance is spontaneously reporting all Adverse Drug Reactions (ADR) during post-market surveillance. This facilitates identification and evaluation of previously unreported ADR’s, acknowledging the trade-off between benefits and potential harm of medications. Only 41% ADR’s documented in Harare city clinical records for January to December 2016 were reported to Medicines Control Authority of Zimbabwe (MCAZ). We investigated reasons contributing to underreporting of ADR’s in Harare city.

Methods

A descriptive cross-sectional study and the updated Centers for Disease Control (CDC) guided surveillance evaluation was conducted. Two hospitals were purposively included. Seventeen health facilities and 52 health workers were randomly selected. Interviewer-administered questionnaires, key informant interviews and WHO pharmacovigilance checklists were used to collect data. Likert scales were applied to draw inferences and Epi info 7 used to generate frequencies and proportions.

Results

Of the 52 participants, 32 (61.5%) distinguished the ADR defining criteria. Twenty-nine (55.8%) knew system’s purpose whilst 28 (53.8%) knew the reporting process. Knowledge scored average on the 5-point-Likert scale. Thirty-eight (73.1%) participants identified ADR’s following client complaints and nine (1.3%) enquired clients’ medication response. Forty-six (88.5%) cited non-feedback from MCAZ for underreporting. Inadequate ADR identification skills were cited by 21 (40.4%) participants. Reporting forms were available in five (26.3%) facilities and reports were generated from hospitals only. Forty-two (90.6%) clinicians made therapeutic decisions from ADR’s. Averaged usefulness score was 4, on the 5-point-Likert scale. All 642 generated signals were committed to Vigiflow by MCAZ, reflecting a case detection rate of 4/ 100 000. Data quality was 0.75–1.0 (WHO) and all reports were causally assessed.

Conclusion

The pharmacovigilance system was useful, simple, and acceptable despite being unstable, not representative and not sensitive. It was threatened by suboptimal health worker knowledge, weak detection strategies and referral policy preventing ADR identification by person place and time. Revisiting local policy, advocacy, communication and health worker orientation might improve pharmacovigilance performance in Harare city.
Predicting local tissue mechanics using immunohistochemistry
Authors: Koser David E. , Moeendarbary Emad , Kuerten Stefanie , Franze Kristian
Published: June 2018

Local tissue stiffness provides an important signal to which cells respond in vivo. However, assessing tissue mechanics is currently challenging and requires sophisticated technology. We here developed a model quantitatively predicting nervous tissue stiffness heterogeneities at cellular resolution based on cell density, myelin and GFAP fluorescence intensities. These histological parameters were identified by a correlation analysis of atomic force microscopy-based elasticity maps of spinal cord sections and immunohistochemical stainings. Our model provides a simple tool to estimate local stiffness distributions in nervous tissue, and it can easily be expanded to other tissue types, thus paving the way for studies of the role of mechanical signals in development and pathology.
Single-crystal structure determination of two new ternary bismuthides: Rh6Mn5Bi18 and RhMnBi3
Authors: Kainzbauer Peter , Richter Klaus W. , Effenberger Herta Silvia , Marker Martin C. J. , Ipser Herbert
Published: June 2018

A study of the ternary Rh–Mn–Bi phase diagram revealed the existence of two new ternary bismuthides, viz. hexarhodium pentamanganese octadecabismuthide (Rh6Mn5Bi18) and rhodium manganese tribismuthide (RhMnBi3). Their crystal structures represent new structure types. Rh6Mn5Bi18, with a Wyckoff sequence a
f2 g2 i5, crystallizes in the tetragonal system (space group P42/mnm; Pearson symbol tP58), and RhMnBi3, with a Wyckoff sequence a c g i q, crystallizes in the orthorhombic system (Cmmm; oS20). In the Rh6Mn5Bi18 structure, the transition metal atoms are linked into ribbon-like structural units aligned along the [001] direction, whereas planar sheets are formed in RhMnBi3. In both crystal structures, the units formed by the transition metal atoms are enveloped by Bi atoms, which themselves form a loosely bound network. The linkage results in a layer structure for RhMnBi3, while in the case of Rh6Mn5Bi18, a three-dimensional network is formed; the latter, however, contains several areas where Bi...Bi distances suggest van der Waals interactions. Both phases under discussion have analogous structural motifs.
Solution of interval shallow water wave equations using homotopy perturbation method
Authors: Karunakar Perumandla , Chakraverty Snehashish
Published: June 2018

Purpose

This paper aims to present solutions of uncertain linear and non-linear shallow water wave equations. The uncertainty has been taken as interval and one-dimensional interval shallow water wave equations have been solved by homotopy perturbation method (HPM). In this study, basin depth and initial conditions have been taken as interval and the single parametric concept has been used to handle the interval uncertainty.

Design/methodology/approach

HPM has been used to solve interval shallow water wave equation with the help of single parametric concept.

Findings

Previously, few authors found solution of shallow water wave equations with crisp basin depth and initial conditions. But, in actual sense, the basin depth, as well as initial conditions, may not be found in crisp form. As such, here these are considered as uncertain in term of intervals. Hence, interval linear and non-linear shallow water wave equations are solved in this study using single parametric concept-based HPM.

Originality/value

As mentioned above, uncertainty is must in the above-titled problems due to the various parametrics involved in the governing differential equations. These uncertain parametric values may be considered as interval. To the best of the authors’ knowledge, no work has been reported on the solution of uncertain shallow water wave equations. But when the interval uncertainty is involved in the above differential equation, then direct methods are not available. Accordingly, single parametric concept-based HPM has been applied in this study to handle the said problems.
Centralisation of corporate governance framework for Islamic financial institutions
Authors: Abd Razak Abd Hakim
Published: June 2018

Purpose

The purpose of this paper is to supply basic insights into the principle ofshūrā(consultation) in Islamic banking, the idea of a centralised approach to the corporate governance of Islamic financial institutions (IFIs), the roles of a centralised Sharīʿah board as the highest authority on Sharīʿah issues and its distinguishing features from a de-centralised system and the advantages and disadvantages of the two governance systems.

Design/methodology/approach

In analyzing these, the paper adopts the critical legal studies approach and refers to the provisions of the Qurʾan and Sunnah,ijmāʿ(consensus) of Sharīʿah scholars and recent Islamic banking reports.

Findings

Despite the fact that the double-digit growth of the current US$2tn Islamic banking industry is a promising sign for its further expansion – expecting to cross the US$6.5tn mark by 2020 – there remains concern over the lack of standardization or rather the diversified approaches to the corporate governance of IFIs across key Islamic banking regions.

Practical implications

There has been much debate surrounding the issue of whether the Islamic banking industry requires a centralised Sharīʿah board at the state level to complement the Sharīʿah boards at the IFIs’ individual level in providing better supervision of the Sharīʿah-compliance of IFIs. The fact that the industry is already equipped with two prominent standard-setting agencies in the form of the AAOIFI, the IFSB does little to suggest that best governance practices – which centre around the themes of consistency, harmony and uniformity – are on the horizon, at least not whilst their issued standards and guidelines remain voluntary for IFIs.

Originality/value

All in all, it is aspired that this paper may assist the reader in evaluating the pros and cons of the whole concept of Sharīʿah board centralisation.