bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of a Disinfectant Wipe Intervention on Fomite-to-Finger Microbial Transfer
Authors: Lopez Gerardo U. , Kitajima Masaaki , Havas Aaron , Gerba Charles P. , Reynolds Kelly A.
Published: March 2014

Inanimate surfaces, or fomites, can serve as routes of transmission of enteric and respiratory pathogens. No previous studies have evaluated the impact of surface disinfection on the level of pathogen transfer from fomites to fingers. Thus, the present study investigated the change in microbial transfer from contaminated fomites to fingers following disinfecting wipe use.
Escherichia coli
(10
8
to 10
9
CFU/ml),
Staphylococcus aureus
(10
9
CFU/ml),
Bacillus thuringiensis
spores (10
7
to 10
8
CFU/ml), and poliovirus 1 (10
8
PFU/ml) were seeded on ceramic tile, laminate, and granite in 10-μl drops and allowed to dry for 30 min at a relative humidity of 15 to 32%. The seeded fomites were treated with a disinfectant wipe and allowed to dry for an additional 10 min. Fomite-to-finger transfer trials were conducted to measure concentrations of transferred microorganisms on the fingers after the disinfectant wipe intervention. The mean log
10
reduction of the test microorganisms on fomites by the disinfectant wipe treatment varied from 1.9 to 5.0, depending on the microorganism and the fomite. Microbial transfer from disinfectant-wipe-treated fomites was lower (up to <0.1% on average) than from nontreated surfaces (up to 36.3% on average, reported in our previous study) for all types of microorganisms and fomites. This is the first study quantifying microbial transfer from contaminated fomites to fingers after the use of disinfectant wipe intervention. The data generated in the present study can be used in quantitative microbial risk assessment models to predict the effect of disinfectant wipes in reducing microbial exposure.
Sonorensin: an Antimicrobial Peptide, Belonging to the Heterocycloanthracin Subfamily of Bacteriocins, from a New Marine Isolate, Bacillus sonorensis MT93
Authors: Chopra Lipsy , Singh Gurdeep , Choudhary Vikas , Sahoo Debendra K.
Published: March 2014

Marine environments are the greatest fronts of biodiversity, representing a resource of unexploited or unknown microorganisms and new substances having potential applications. Among microbial products, antimicrobial peptides (AMPs) have received great attention recently due to their applications as food preservatives and therapeutic agents. A new marine soil isolate producing an AMP was identified as
Bacillus sonorensis
based on 16S rRNA gene sequence analysis. It produced an AMP that showed a broad spectrum of activity against both Gram-positive and Gram-negative bacteria. The peptide, named sonorensin, was purified to homogeneity using a combination of chromatographic techniques. The intact molecular mass of the purified peptide, 6,274 Da, as revealed by matrix-assisted laser desorption ionization–time of flight (MALDI-TOF), was in agreement with Tricine-SDS-PAGE analysis. A PCR array of primers was used to identify AMP structural genes, which allowed the successful amplification of the related genes from strain MT93. The putative open reading frame of sonorensin was amplified, cloned into the pET-32a(+) vector, expressed as a thioredoxin (Trx) fusion protein in
Escherichia coli
, and then purified. Sequence alignment analysis revealed that the bacteriocin being reported could belong to new subfamily of bacteriocins, heterocycloanthracin. The peptide indicated its potential as a biocontrol agent or food antimicrobial agent, due to its antimicrobial activity against bacteria such as
Listeria monocytogenes
and
Staphylococcus aureus
. This is the first report of the production, purification, and characterization of wild-type and recombinant bacteriocin by
B. sonorensis
and the first bacteriocin of the heterocycloanthracin subfamily to be characterized.
Genetic Validation of Trypanosoma brucei Glutathione Synthetase as an Essential Enzyme
Authors: Pratt Chelsea , Nguyen Suong , Phillips Margaret A.
Published: March 2014

Human African trypanosomiasis (HAT) is a debilitating and fatal vector-borne disease. Polyamine biosynthesis is the target of one of the key drugs (eflornithine) used for the treatment of late-stage disease, suggesting that the pathway might be exploited for the identification of additional drug targets. The polyamine spermidine is required in trypanosomatid parasites for formation of a unique redox cofactor termed trypanothione, which is formed from the conjugation of glutathione to spermidine. Here we characterize recombinant
Trypanosoma brucei
glutathione synthetase (
Tb
GS) and show that depletion of
Tb
GS in blood-form parasites using a regulated knockout strategy leads to loss of trypanothione and to cell death as quantified by fluorescence-activated cell sorter (FACS) analysis. These data suggest that >97% depletion of
Tb
GS is required before trypanothione is depleted and cell growth arrest is observed. Exogenous glutathione was able to partially compensate for the loss of
Tb
GS, suggesting that parasites are able to transport intact glutathione. Finally, reduced expression of
Tb
GS leads to increased levels of upstream glutathione biosynthetic enzymes and decreased expression of polyamine biosynthetic enzymes, providing evidence that the cells cross regulate the two branches of the trypanothione biosynthetic pathway to maintain spermidine and trypanothione homeostasis.
A Role for the Rap GTPase YlRsr1 in Cellular Morphogenesis and the Involvement of YlRsr1 and the Ras GTPase YlRas2 in Bud Site Selection in the Dimorphic Yeast Yarrowia lipolytica
Authors: Li Yun-Qing , Li Min , Zhao Xiao-Feng , Gao Xiang-Dong
Published: March 2014

Yarrowia lipolytica
is a dimorphic yeast species that can grow in the ovoid yeast form or in the elongated pseudohyphal or hyphal form depending on the growth conditions. Here, we show that the Rap GTPase Rsr1 of
Y. lipolytica
(YlRsr1) plays an important role in cellular morphogenesis in this microorganism. Cells deleted for Yl
RSR1
exhibited impaired polarized growth during yeast-form growth. Pseudohyphal and hyphal development were also abnormal. YlRsr1 is also important for cell growth, since the deletion of Yl
RSR1
in cells lacking the Ras GTPase YlRas2 caused lethality.
Y. lipolytica
cells bud in a bipolar pattern in which the cells produce the new buds at the two poles. YlRsr1 plays a prominent role in this bud site selection process. YlRsr1's function in bud site selection absolutely requires the cycling of YlRsr1 between the GTP- and GDP-bound states but its function in cellular morphogenesis does not, suggesting that the two processes are differentially regulated. Interestingly, the Ras GTPase YlRas2 is also involved in the control of bud site selection, as Yl
ras2
Δ cells were severely impaired in bipolar bud site selection. The GTP/GDP cycling and the plasma membrane localization of YlRas2 are important for YlRas2's function in bud site selection. However, they are not essential for this process, suggesting that the mechanism by which YlRas2 acts is different from that of YlRsr1. Our results suggest that YlRsr1 is regulated by the GTPase-activating protein (GAP) YlBud2 and partially by YlCdc25, the potential guanine nucleotide exchange factor (GEF) for YlRas2.
Amylocyclicin, a Novel Circular Bacteriocin Produced by Bacillus amyloliquefaciens FZB42
Authors: Scholz Romy , Vater Joachim , Budiharjo Anto , Wang Zhiyuan , He Yueqiu , Dietel Kristin , Schwecke Torsten , Herfort Stefanie , Lasch Peter , Borriss Rainer
Published: March 2014

Bacillus amyloliquefaciens
FZB42 is a Gram-positive plant growth-promoting bacterium with an impressive capacity to synthesize nonribosomal secondary metabolites with antimicrobial activity. Here we report on a novel circular bacteriocin which is ribosomally synthesized by FZB42. The compound displayed high antibacterial activity against closely related Gram-positive bacteria. Transposon mutagenesis and subsequent site-specific mutagenesis combined with matrix-assisted laser desorption ionization–time of flight mass spectroscopy revealed that a cluster of six genes covering 4,490 bp was responsible for the production, modification, and export of and immunity to an antibacterial compound, here designated amylocyclicin, with a molecular mass of 6,381 Da. Peptide sequencing of the fragments obtained after tryptic digestion of the purified peptide revealed posttranslational cleavage of an N-terminal extension and head-to-tail circularization of the novel bacteriocin. Homology to other putative circular bacteriocins in related bacteria let us assume that this type of peptide is widespread among the
Bacillus/Paenibacillus
taxon.
Iron-Regulated Protein HupB of Mycobacterium tuberculosis Positively Regulates Siderophore Biosynthesis and Is Essential for Growth in Macrophages
Authors: Pandey Satya Deo , Choudhury Mitali , Yousuf Suhail , Wheeler Paul R. , Gordon Stephen V. , Ranjan Akash , Sritharan Manjula
Published: March 2014

Mycobacterium tuberculosis
expresses the 28-kDa protein HupB (Rv2986c) and the Fe
3+
-specific high-affinity siderophores mycobactin and carboxymycobactin upon iron limitation. The objective of this study was to understand the functional role of HupB in iron acquisition. A
hupB
mutant strain of
M. tuberculosis
, subjected to growth in low-iron medium (0.02 μg Fe ml
−1
), showed a marked reduction of both siderophores with low transcript levels of the
mbt
genes encoding the MB biosynthetic machinery. Complementation of the mutant strain with
hupB
restored siderophore production to levels comparable to that of the wild type. We demonstrated the binding of HupB to the
mbtB
promoter by both electrophoretic mobility shift assays and DNA footprinting. The latter revealed the HupB binding site to be a 10-bp AT-rich region. While negative regulation of the
mbt
machinery by IdeR is known, this is the first report of positive regulation of the
mbt
operon by HupB. Interestingly, the mutant strain failed to survive inside macrophages, suggesting that HupB plays an important role
in vivo
.
Identification of a Novel Aminopropyltransferase Involved in the Synthesis of Branched-Chain Polyamines in Hyperthermophiles
Authors: Okada Kazuma , Hidese Ryota , Fukuda Wakao , Niitsu Masaru , Takao Koichi , Horai Yuhei , Umezawa Naoki , Higuchi Tsunehiko , Oshima Tairo , Yoshikawa Yuko , Imanaka Tadayuki , Fujiwara Shinsuke
Published: March 2014

Longer- and/or branched-chain polyamines are unique polycations found in thermophiles.N4-aminopropylspermine is considered a major polyamine inThermococcus kodakarensis. To determine whether a quaternary branched penta-amine,N4-bis(aminopropyl)spermidine, an isomer ofN4-aminopropylspermine, was also present, acid-extracted cytoplasmic polyamines were analyzed by high-pressure liquid chromatography, gas chromatography (HPLC), and gas chromatography-mass spectrometry.N4-bis(aminopropyl)spermidine was an abundant cytoplasmic polyamine in this species. To identify the enzyme that catalyzesN4-bis(aminopropyl)spermidine synthesis, the active fraction was concentrated from the cytoplasm and analyzed by linear ion trap–time of flight mass spectrometry with an electrospray ionization instrument after analysis by the MASCOT database. TK0545, TK0548, TK0967, and TK1691 were identified as candidate enzymes, and the corresponding genes were individually cloned and expressed inEscherichia coli. Recombinant forms were purified, and theirN4-bis(aminopropyl)spermidine synthesis activity was measured. Of the four candidates, TK1691 (BpsA) was found to synthesizeN4-bis(aminopropyl)spermidine from spermidine viaN4-aminopropylspermidine. Compared to the wild type, thebpsA-disrupted strain DBP1 grew at 85°C with a slightly longer lag phase but was unable to grow at 93°C. HPLC analysis showed that bothN4-aminopropylspermidine andN4-bis(aminopropyl)spermidine were absent from the DBP1 strain grown at 85°C, demonstrating that the branched-chain polyamine synthesized by BpsA is important for cell growth at 93°C. Sequence comparison to orthologs from various microorganisms indicated that BpsA differed from other known aminopropyltransferases that produce spermidine and spermine. BpsA orthologs were found only in thermophiles, both in archaea and bacteria, but were absent from mesophiles. These findings indicate that BpsA is a novel aminopropyltransferase essential for the synthesis of branched-chain polyamines, enabling thermophiles to grow in high-temperature environments.
Acupuncture and Standard Emergency Department Care for Pain And/Or Nausea and Its Impact on Emergency Care Delivery: A Feasibility Study
Authors: Zhang Anthony L , Parker Shefton J , Smit De Villiers , Taylor David McD , Xue Charlie C L
Published: March 2014

Objective

To evaluate the feasibility of delivering acupuncture in an emergency department (ED) to patients presenting with pain and/or nausea.

Methods

A feasibility study (with historical controls) undertaken at the Northern Hospital ED in Melbourne, Australia, involving people presenting to ED triage with pain (VAS 0–10) and/or nausea (Morrow Index 1–6) between January and August 2010 (n=400). The acupuncture group comprised 200 patients who received usual medical care and acupuncture; the usual care group comprised 200 patients with retrospective data closely matched from ED electronic health records.

Results

Refusal rate was 31%, with ‘symptoms under control owing to medical treatment before acupuncture’ the most prevalent reason for refusal (n=36); 52.5% of participants responded ‘definitely yes’ for their willingness to repeat acupuncture, and a further 31.8% responded ‘probably yes’. Over half (57%) reported a satisfaction score of 10 for acupuncture treatment. Musculoskeletal conditions were the most common conditions treated n=117 (58.5%), followed by abdominal or flank pain n=49 (24.5%). Adverse events were rare (2%) and mild. Pain and nausea scores reduced from a mean±SD of 7.01±2.02 before acupuncture to 4.72±2.62 after acupuncture and from 2.6±2.19 to 1.42±1.86, respectively.

Conclusions

Acupuncture in the ED appears safe and acceptable for patients with pain and/or nausea. Results suggest combined care may provide effective pain and nausea relief in ED patients. Further high-quality, sufficiently powered randomised studies evaluating the cost-effectiveness and efficacy of the add-on effect of acupuncture are recommended.
Integration of HIV and maternal healthcare in a high HIV-prevalence setting: analysis of client flow data over time in Swaziland
Authors: Birdthistle Isolde J , Mayhew Susannah H , Kikuvi Joshua , Zhou Weiwei , Church Kathryn , Warren Charlotte E , Nkambule Rejoice , Fenty Justin ,   on behalf of the Integra Initiative
Published: March 2014

Objective

Maternal and child health (MCH) care may provide an entry point for HIV services in high HIV-prevalence settings. Our objective was to assess integration of HIV with MCH services in public sector facilities in Swaziland.

Design

In 2009, 2010 and 2012, client flow assessments (CFAs) were conducted over 5 days in the MCH units of eight government facilities, purposively selected as intervention or comparison sites.

Participants

8263 MCH visits with female clients were tracked: 3261 in 2009, 2086 in 2010 and 2916 in 2012.

Intervention

Activities and resources to strengthen integration of HIV services into postnatal care (PNC), 2009–2010.

Main outcome measures

The proportion of all visits in which an HIV/sexually transmitted infection (STI) testing, counselling or treatment was received together with an MCH service; the proportion of all visits in which a client receives HIV counselling.

Results

Across facilities, the proportion of visits in which HIV/STI and MCH services were received varied considerably, for example, from 9% to 49% in 2009. HIV/STI services were integrated most frequently with child health (CH), antenatal care (ANC) and family planning (FP)—the most common reasons for women's attendance—and least often with PNC and cervical screening (CS). There was no meaningful difference in integration over time by design group and considerable heterogeneity across facilities. Receipt of integrated services increased in one intervention and two comparison facilities, where HIV counselling also rose, and fell in one intervention and two comparison facilities.

Conclusions

Provision of HIV/STI services with MCH care occurred at all facilities, yet relatively few women receive integrated services. Increases in integration were driven by increases in HIV counselling, while sharp declines in some facilities indicate that integration is difficult to sustain. Opportunities for intensifying HIV integration lie with ANC, CH and FP, while HIV-PNC integration will remain limited until more women attend PNC.

Trial registration number

Current Controlled TrialsNCT01694862.
Systematic review of percutaneous closure versus medical therapy in patients with cryptogenic stroke and patent foramen ovale
Authors: Spencer Frederick A , Lopes Luciane C , Kennedy Sean A , Guyatt Gordon
Published: March 2014

Objectives

To provide a comprehensive comparison of patent foramen ovale (PFO) closure versus medical therapy in patients with cryptogenic stroke or transient ischaemic attack (TIA) and demonstrated PFO.

Design

Systematic review with complete case meta-analysis and sensitivity analyses. Data sources included MEDLINE and EMBASE from 1980 up to May 2013. All randomised controlled trials (RCTs) comparing treatment with percutaneous catheter-based closure of PFO to anticoagulant or antiplatelet therapy in patients with cryptogenic stroke or TIA and echocardiographically confirmed PFO or atrial septal defect (ASD) were eligible.

Participants

1967 participants with prior stroke or TIA and echocardiographically confirmed PFO or ASD.

Primary outcome measures

The primary outcome of interest was recurrence of ischaemic stroke. We utilised data from complete cases only for the primary endpoint and combined data from trials to estimate the pooled risk ratio (RR) and associated 95% CIs calculated using random effects models.

Results

We identified 284 potentially eligible articles of which three RCTs including 2303 patients proved eligible and 1967 patients had complete data. Of the 1026 patients randomised to PFO closure and followed to study conclusion 22 experienced non-fatal ischaemic strokes, as did 34 of 941 patients randomised to medical therapy (risk ratio (RR) 0.61, 95% CI 0.34 to 1.07; heterogeneity: p=0.34, I2=8%, confidence in estimates low due to risk of bias and imprecision). Analyses for ischaemic stroke restricted to ‘per-protocol’ patients or patients with concomitant atrial septal aneurysm did not substantially change the observed RRs. Complication rates associated with either PFO closure or medical therapy were low.

Conclusions

Pooled data from three RCTs provides insufficient support that PFO closure is preferable to medical therapy for secondary prevention of cryptogenic stroke in patients with PFO.
Acute Exacerbation and Respiratory InfectionS in COPD (AERIS): protocol for a prospective, observational cohort study
Authors: Bourne Simon , Cohet Catherine , Kim Viktoriya , Barton Anna , Tuck Andy , Aris Emmanuel , Mesia-Vela Sonia , Devaster Jeanne-Marie , Ballou W Ripley , Clarke Stuart , Wilkinson Tom
Published: March 2014

Introduction

The aetiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) remains incompletely understood and strategies for treatment and prevention have not altered significantly for many years. Improved understanding of the role of respiratory pathogens in acute exacerbations of COPD (AECOPD) is required and the use of molecular microbiological techniques may lead to insights into host–pathogen interactions and the development of more targeted therapeutic approaches.

Methods and analyses

Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) is a longitudinal epidemiological study to assess how changes in the COPD airway microbiome contribute to the incidence and severity of AECOPD. Patients with COPD aged 40–85 are followed monthly for 2 years, and reviewed within 72 h of onset of symptoms of AECOPD. Exacerbations are detected using daily electronic diary cards. Blood, sputum, nasopharyngeal and urine samples are collected at prespecified timepoints. Molecular diagnostic and typing techniques are used to describe the dynamics of airway infection during AECOPD and stable disease, and associations with clinical outcome. This study aims to refine the case definition of AECOPD to reflect the possible microbiological aetiology. AERIS will assess the impact of AECOPD on health-related quality of life and healthcare resource utilisation, and the possible interactions between nutritional status, infection and immune responses.

Ethics and dissemination

AERIS is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and has been approved by the institutional ethics and review board. All participants must provide written informed consent. The results obtained will be disseminated at international medical conferences and in peer-reviewed publications.

Discussion

Few other studies have addressed the complexity of the microbiological and systemic components of COPD or employed real-time electronic tracking of symptoms to identify AECOPD and potential aetiological triggers.

Results

Results of AERIS will increase our understanding of the contribution of pathogens to AECOPD, potentially leading to new targeted therapeutic and preventative interventions.

Trial registration number

ClinicalTrials.govNCT01360398.
Protocol for the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) retrospective study of coronary catheterisation and percutaneous coronary intervention
Authors: Li Jing , Dharmarajan Kumar , Li Xi , Lin Zhenqiu , Normand Sharon-Lise T , Krumholz Harlan M , Jiang Lixin ,   for the China PEACE Collaborative Group
Published: March 2014

Introduction

During the past decade, the volume of percutaneous coronary intervention (PCI) in China has risen by more than 20-fold. Yet little is known about patterns of care and outcomes across hospitals, regions and time during this period of rising cardiovascular disease and dynamic change in the Chinese healthcare system.

Methods and analysis

Using the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) research network, the Retrospective Study of Coronary Catheterisation and Percutaneous Coronary Intervention (China PEACE-Retrospective CathPCI Study) will examine a nationally representative sample of 11 900 patients who underwent coronary catheterisation or PCI at 55 Chinese hospitals during 2001, 2006 and 2011. We selected patients and study sites using a two-stage cluster sampling design with simple random sampling stratified within economical-geographical strata. A central coordinating centre will monitor data quality at the stages of case ascertainment, medical record abstraction and data management. We will examine patient characteristics, diagnostic testing patterns, procedural treatments and in-hospital outcomes, including death, complications of treatment and costs of hospitalisation. We will additionally characterise variation in treatments and outcomes by patient characteristics, hospital, region and study year.

Ethics and dissemination

The China PEACE collaboration is designed to translate research into improved care for patients. The study protocol was approved by the central ethics committee at the China National Center for Cardiovascular Diseases (NCCD) and collaborating hospitals. Findings will be shared with participating hospitals, policymakers and the academic community to promote quality monitoring, quality improvement and the efficient allocation and use of coronary catheterisation and PCI in China.

Registration details

http://www.clinicaltrials.gov(NCT01624896).
Contribution of hospital mortality variations to socioeconomic disparities in in-hospital mortality
Authors: Kim Yoon , Oh Juhwan , Jha Ashish
Published: March 2014

Background

While disparities in hospital care outcomes based on ethnicity or socioeconomic status have been documented in some nations, it is unclear to what extent this phenomenon occurs in high-income countries like Korea with relatively low income inequality.

Methods

We examined in-hospital mortality rates for wealthy and poor patients in South Korea for five common medical conditions. We measured in-hospital mortality rates and examined within-hospital differences (wealthy and poor patients receive different care at the same institution) as well as between-hospital differences (wealthy and poor patients receiving care at different institutions) across socioeconomic status. We built multivariable models that adjusted for risk and further adjusted our analyses for hospital characteristics including a hospital's overall mortality ranking.

Results

There were 127 438 patients with one of the five conditions examined nested in 66 Korean hospitals. We found moderate differences in mortality rates between wealthy and poor patients across four of the five conditions. These mortality differences were largely attributable to differences in mortality rates for wealthy patients compared with those for poor patients within the same hospital (within-hospital variation) while a relatively small portion of these disparities were attributable to mortality difference between hospitals where wealthy and poor patients seek care (between-hospital variation). For example, we estimate that improving care for poor patients in the same hospital can eliminate 86% of the disparities for acute myocardial infarction outcomes, while ensuring equal access to low mortality hospitals would reduce only 16% of the disparities in outcomes.

Conclusions

This study suggests that to reduce socioeconomic disparities in hospital mortality, interventions that target within-hospital effects may be more effective than interventions targeting between hospital effects.
WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma
Authors: Rauscher Julian , Beschorner Rudi , Gierke Midea , Bisdas Sotirios , Braun Christian , Ebner Florian H , Schittenhelm Jens
Published: March 2014

Aims

The zinc finger transcription factor WT1 is expressed in astrocytic neoplasms and therefore is a potential target of immunotherapy in brain tumours. Our aim was to further elucidate the role of WT1 as a diagnostic and prognostic marker in neuropathology, particularly as to the differentiation of astrocytoma from oligodendroglioma as well as to the dependency of WT1 expression on clinically relevant parameters.

Methods

829 evaluable brain tumour samples were investigated by WT1 immunohistochemistry on full tissue routine slides, consisting of 442 glioblastomas, 303 astrocytomas, 41 oligodendrogliomas and 43 oligoastrocytomas. In addition public WT1 gene expression data of 351 gliomas were analysed.

Results

Our data show that WT1 expression in diffuse astrocytic tumours increases with WHO tumour grade and is associated with older age, absence of IDH1 mutation but not related to O(6)- methyl guanine methyl transferase (MGMT) promoter methylation status. Univariable, but not multivariable survival analysis indicates that WT1 expression is associated with worse outcome in patients with diffuse astrocytoma but not glioblastoma.

Conclusions

The significant WT1 expression differences between diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas, which are also present in the Repository for Molecular Brain Neoplasia Data, National Cancer Institute (REMBRANDT, 2005, http://rembrandt.nci.nih.gov) gene database set, provide a rationale for use of WT1 as part of a routine immunohistochemistry panel.
Immunohistochemical analysis of molecular drivers in melanoma identifies p16 as an independent prognostic biomarker
Authors: Lade-Keller Johanne , Riber-Hansen Rikke , Guldberg Per , Schmidt Henrik , Hamilton-Dutoit Stephen Jacques , Steiniche Torben
Published: March 2014

Aims

To perform immunohistochemical (IHC) analysis of molecular drivers related to the development and maintenance of melanoma and to assess their value as diagnostic and prognostic melanoma biomarkers in routine clinical practice.

Methods

Tissue microarrays constructed from a cohort of primary melanomas (n=355), benign naevi (n=37) and melanoma metastases (n=14) were evaluated for IHC expression of c-KIT, BRAFV600E, MITF, p16, p53 and PTEN, as well as for pERK, a surrogate marker for mitogen-activated protein kinase pathway activation. The results were correlated with clinicopathological parameters and clinical outcome.

Results

Absent p16 expression and reduced MITF expression were both associated with the adverse prognostic markers ulceration (p=0.009 and p<0.0001, respectively), advanced tumour stage (p<0.0001 and p=0.001, respectively) and higher Breslow thickness (both p<0.0001), as well as with an adverse overall relapse-free survival (p<0.0001 and p=0.003, respectively). Absence of p16 expression predicted overall relapse-free (p=0.02) and distant metastasis-free (p=0.04) survival, independently of Breslow thickness, ulceration and tumour stage.

Conclusions

IHC determined p16 expression is an independent prognostic biomarker of potential value in routine melanoma diagnostic practice.
Screening for latent tuberculosis and gastrointestinal parasite infections in Gurkha recruits: research driving policy change
Authors: O'Shea Matthew K , Fletcher T E , Tupper D , Ross D , Wilson D
Published: March 2014

Nepalese Gurkha soldiers are recruited from a country endemic for a number of infectious diseases, including tuberculosis and gastrointestinal parasites. This article describes a prospective cohort study which investigated screening strategies for these infections among Gurkha recruits arriving in the UK to begin basic training. Several recommendations were made as a result of the study which were supported for early implementation and subsequently fully adopted. Military screening and treatment policies have been directly influenced by this research which also has translational application to similar migrant civilian populations.
Reaction products of diorganotin(IV) oxides, R2SnO, with nitric acid. Part 1: R = methyl, ethyl, and isopropyl
Authors: Reuter Hans , Reichelt Martin
Published: March 2014

The reaction of diorganotin(IV) oxides, R2SnO with R = Me, Et, and i-Pr, with nitric acid in different stoichiometric ratios resulted in the formation of different products depending on the organic groups. The diorganotin(IV) nitrate hydroxides Me2Sn(NO3)(OH) (1a) Et2Sn(NO3)(OH), α-1b, β-1b, i-Pr2Sn(NO3)(OH) (1c), the diisopropyltin(IV) dinitrate dihydrate, i-Pr2Sn(NO3)2·2H2O (2c) and the diisopropyltin(IV) nitrate oxalate dihydrate, [i-Pr2Sn(NO3)]2Ox·2H2O (3) as side-product. On examination of the solubility of the primary reaction products in different solvents, the two additional compounds Me2Sn(NO3)(OH)·DMSO (4) and 2i-Pr2Sn(NO3)2·3DMSO = [i-Pr2Sn(NO3)(dmso)3] [i-Pr2Sn(NO3)3] (5) have been isolated. All compounds have been structurally characterized by single crystal X-ray diffraction with special respect to dimensionality (1a, α-1b, 1c = dimeric molecules hydrogen bonded to one-dimensional chains; β-1b = two-dimensional coordination polymer; 2c = monomeric; 3 = monomeric, tin atoms linked via a double side-on chelating oxalate ion; 4 = dimeric, 5 = monomeric anion/cation), tin coordination (trigonal-bipyramidal = 1a, α-1b, 1c; six-fold = β-1b; seven-fold = 3, 4, 5-cation; eight-fold = 2c, 5-anion) and nitrate bonding modes (monodentate = 1a, α-1b, 1c; unsymmetrical bidentate = 3, symmetrical bidentate = 3, 4, 5-cation, 5-anion; syn-anti bridging = β-1b), the latter one being analysed using both, Sn–O and N–O distances.
Hysteresis curves for some periodic and aperiodic perturbations in gases
Authors: Perelomova Anna
Published: March 2014

Evolution of sound in a medium whose properties irreversibly vary in the course of wave propagation, is studied. For example, a gas that is a particular case of a Newtonian fluid is considered. Hysteresis curves, pictorial representations of irreversible attenuation of the sound energy, in the plane of thermodynamic states are plotted. The irreversible losses in internal energy are proportional to the total attenuation and depend on the intensity and shape of sound waveform. Curves and loops for some periodic (including the sawtooth wave) and aperiodic impulse sounds are discussed and compared.
Factors influencing mortality of Lesser Scaup (Aythya affinis) ducklings during a West Nile virus outbreak
Authors: Gurney K.E.B. , Clark R.G. , Curry P.S.
Published: March 2014

Temporal variation in exposure and (or) susceptibility to disease-causing agents may result in changing disease risks for offspring of seasonally reproducing organisms. Although increases in disease risk and disease-related mortality have been observed during the course of the breeding cycle in some systems, the extent to which this is a generalized ecological pattern remains uncertain. We obtained data during an outbreak of West Nile virus (WNV) associated mortality in 50 semicaptive Lesser Scaup (Aythya affinis (Eyton, 1838)) ducklings and used known-fate survival models to assess whether daily survival rate (DSR) was related to age, hatch date, immunogenic challenge, vector abundance, and risk of WNV infection. Ducklings produced late in the breeding cycle had lower survival probabilities, relative to earlier conspecifics, but the best predictor of DSR was relative risk, suggesting that reduced survival of late-hatched individuals may have been related to increasing exposure to WNV-infected vectors.
EBS behaviour immediately after repository closure in a clay host rock: HE-E experiment (Mont Terri URL)
Authors: Gaus I. , Wieczorek K. , Schuster K. , Garitte B. , Senger R. , Vasconcelos R. , Mayor J. C.
Published: March 2014

The evolution of the clay-based engineered barrier system (EBS) of geological repositories for radioactive waste has been the subject of many research programmes during the last decade. The early post-closure thermal behaviour is elucidated by the HE-E experiment, a 1:2 scale heating experiment (at the Mont Terri Rock Laboratory), which was implemented in the first semester of 2011, with the initiation of the heating phase in June 2011. A maximum temperature of 140 °C was reached in June 2012. After 15 months of heating, the temperature evolution in the EBS and the Opalinus Clay reflects the design calculations, and thermally induced porewater overpressures are being measured at a few metres’ distance in the Opalinus Clay. Seismic methods proved to be a sensitive tool for the continuous characterization of changes of EBS and Opalinus Clay properties. Design modelling and predictive modelling based on the as-built parameter dataset with established coupled codes (TOUGH, CODE_BRIGHT; using various geometries) are described. The results indicate that the models are generally in agreement with the observations and capable of capturing the evolution of the experiment.
Lipids and Extracellular Materials
Authors: Dowhan William
Published: March 2014

This article introduces the Lipids and Extracellular Materials theme of the Annual Review of Biochemistry, Volume 83.
Regulating the Chromatin Landscape: Structural and Mechanistic Perspectives
Authors: Bartholomew Blaine
Published: March 2014

A large family of chromatin remodelers that noncovalently modify chromatin is crucial in cell development and differentiation. They are often the targets of cancer, neurological disorders, and other human diseases. These complexes alter nucleosome positioning, higher-order chromatin structure, and nuclear organization. They also assemble chromatin, exchange out histone variants, and disassemble chromatin at defined locations. We review aspects of the structural organization of these complexes, the functional properties of their protein domains, and variation between complexes. We also address the mechanistic details of these complexes in mobilizing nucleosomes and altering chromatin structure. A better understanding of these issues will be vital for further analyses of subunits of these chromatin remodelers, which are being identified as targets in human diseases by NGS (next-generation sequencing).
Topological Regulation of Lipid Balance in Cells
Authors: Drin Guillaume
Published: March 2014

Lipids are unevenly distributed within and between cell membranes, thus defining organelle identity. Such distribution relies on local metabolic branches and mechanisms that move lipids. These processes are regulated by feedback mechanisms that decipher topographical information in organelle membranes and then regulate lipid levels or flows. In the endoplasmic reticulum, the major lipid source, transcriptional regulators and enzymes sense changes in membrane features to modulate lipid production. At the Golgi apparatus, lipid-synthesizing, lipid-flippase, and lipid-transport proteins (LTPs) collaborate to control lipid balance and distribution within the membrane to guarantee remodeling processes crucial for vesicular trafficking. Open questions exist regarding LTPs, which are thought to be lipid sensors that regulate lipid synthesis or carriers that transfer lipids between organelles across long distances or in contact sites. A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient.
Demystifying Heparan Sulfate–Protein Interactions
Authors: Xu Ding , Esko Jeffrey D.
Published: March 2014

Numerous proteins, including cytokines and chemokines, enzymes and enzyme inhibitors, extracellular matrix proteins, and membrane receptors, bind heparin. Although they are traditionally classified as heparin-binding proteins, under normal physiological conditions these proteins actually interact with the heparan sulfate chains of one or more membrane or extracellular proteoglycans. Thus, they are more appropriately classified as heparan sulfate–binding proteins (HSBPs). This review provides an overview of the various modes of interaction between heparan sulfate and HSBPs, emphasizing biochemical and structural insights that improve our understanding of the many biological functions of heparan sulfate.
Genome Engineering with Targetable Nucleases
Authors: Carroll Dana
Published: March 2014

Current technology enables the production of highly specific genome modifications with excellent efficiency and specificity. Key to this capability are targetable DNA cleavage reagents and cellular DNA repair pathways. The break made by these reagents can produce localized sequence changes through inaccurate nonhomologous end joining (NHEJ), often leading to gene inactivation. Alternatively, user-provided DNA can be used as a template for repair by homologous recombination (HR), leading to the introduction of desired sequence changes. This review describes three classes of targetable cleavage reagents: zinc-finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs), and CRISPR/Cas RNA-guided nucleases (RGNs). As a group, these reagents have been successfully used to modify genomic sequences in a wide variety of cells and organisms, including humans. This review discusses the properties, advantages, and limitations of each system, as well as the specific considerations required for their use in different biological systems.
Human RecQ Helicases in DNA Repair, Recombination, and Replication
Authors: Croteau Deborah L. , Popuri Venkateswarlu , Opresko Patricia L. , Bohr Vilhelm A.
Published: March 2014

RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.
Hierarchy of RNA Functional Dynamics
Authors: Mustoe Anthony M. , Brooks Charles L. , Al-Hashimi Hashim M.
Published: March 2014

RNA dynamics play a fundamental role in many cellular functions. However, there is no general framework to describe these complex processes, which typically consist of many structural maneuvers that occur over timescales ranging from picoseconds to seconds. Here, we classify RNA dynamics into distinct modes representing transitions between basins on a hierarchical free-energy landscape. These transitions include large-scale secondary-structural transitions at >0.1-s timescales, base-pair/tertiary dynamics at microsecond-to-millisecond timescales, stacking dynamics at timescales ranging from nanoseconds to microseconds, and other “jittering” motions at timescales ranging from picoseconds to nanoseconds. We review various modes within these three different tiers, the different mechanisms by which they are used to regulate function, and how they can be coupled together to achieve greater functional complexity.
Small Proteins Can No Longer Be Ignored
Authors: Storz Gisela , Wolf Yuri I. , Ramamurthi Kumaran S.
Published: March 2014

Small proteins, here defined as proteins of 50 amino acids or fewer in the absence of processing, have traditionally been overlooked due to challenges in their annotation and biochemical detection. In the past several years, however, increasing numbers of small proteins have been identified either through the realization that mutations in intergenic regions are actually within unannotated small protein genes or through the discovery that some small, regulatory RNAs encode small proteins. These insights, together with comparative sequence analysis, indicate that tens if not hundreds of small proteins are synthesized in a given organism. This review summarizes what has been learned about the functions of several of these bacterial small proteins, most of which act at the membrane, illustrating the astonishing range of processes in which these small proteins act and suggesting several general conclusions. Important questions for future studies of these overlooked proteins are also discussed.
Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions
Authors: Oldfield Christopher J. , Dunker A. Keith
Published: March 2014

Intrinsically disordered proteins (IDPs) and IDP regions fail to form a stable structure, yet they exhibit biological activities. Their mobile flexibility and structural instability are encoded by their amino acid sequences. They recognize proteins, nucleic acids, and other types of partners; they accelerate interactions and chemical reactions between bound partners; and they help accommodate posttranslational modifications, alternative splicing, protein fusions, and insertions or deletions. Overall, IDP-associated biological activities complement those of structured proteins. Recently, there has been an explosion of studies on IDP regions and their functions, yet the discovery and investigation of these proteins have a long, mostly ignored history. Along with recent discoveries, we present several early examples and the mechanisms by which IDPs contribute to function, which we hope will encourage comprehensive discussion of IDPs and IDP regions in biochemistry textbooks. Finally, we propose future directions for IDP research.
Progress Toward Synthetic Cells
Authors: Blain J. Craig , Szostak Jack W.
Published: March 2014

The complexity of even the simplest known life forms makes efforts to synthesize living cells from inanimate components seem like a daunting task. However, recent progress toward the creation of synthetic cells, ranging from simple protocells to artificial cells approaching the complexity of bacteria, suggests that the synthesis of life is now a realistic goal. Protocell research, fueled by advances in the biophysics of primitive membranes and the chemistry of nucleic acid replication, is providing new insights into the origin of cellular life. Parallel efforts to construct more complex artificial cells, incorporating translational machinery and protein enzymes, are providing information about the requirements for protein-based life. We discuss recent advances and remaining challenges in the synthesis of artificial cells, the possibility of creating new forms of life distinct from existing biology, and the promise of this research for gaining a deeper understanding of the nature of living systems.
Population Balance Modeling: Current Status and Future Prospects
Authors: Ramkrishna Doraiswami , Singh Meenesh R.
Published: March 2014

Population balance modeling is undergoing phenomenal growth in its applications, and this growth is accompanied by multifarious reviews. This review aims to fortify the model's fundamental base, as well as point to a variety of new applications, including modeling of crystal morphology, cell growth and differentiation, gene regulatory processes, and transfer of drug resistance. This is accomplished by presenting the many faces of population balance equations that arise in the foregoing applications.
Earth Abides Arsenic Biotransformations
Authors: Zhu Yong-Guan , Yoshinaga Masafumi , Zhao Fang-Jie , Rosen Barry P.
Published: March 2014

Arsenic is the most prevalent environmental toxic element and causes health problems throughout the world. The toxicity, mobility, and fate of arsenic in the environment are largely determined by its speciation, and arsenic speciation changes are driven, at least to some extent, by biological processes. In this article, biotransformation of arsenic is reviewed from the perspective of the formation of Earth and the evolution of life, and the connection between arsenic geochemistry and biology is described. The article provides a comprehensive overview of molecular mechanisms of arsenic redox and methylation cycles as well as other arsenic biotransformations. It also discusses the implications of arsenic biotransformation in environmental remediation and food safety, with particular emphasis on groundwater arsenic contamination and arsenic accumulation in rice.
Himalayan Metamorphism and Its Tectonic Implications
Authors: Kohn Matthew J.
Published: March 2014

The Himalayan range exposes a spectacular assemblage of metamorphic rocks from the mid- and deep crust that have fostered numerous models of how the crust responds to continental collisions. Recent petrogenetically based petrologic and geochronologic studies elucidate processes with unprecedented resolution and critically test models that range from continuum processes to one-time events. The pronounced metamorphic inversion across the Main Central Thrust reflects continuum thrusting between ca. 15 and 20 Ma, whereas exposure of ultrahigh-pressure rocks in northwestern massifs and syntaxis granulites reflects singular early (≥45 Ma) and late (≤10 Ma) exhumation events. Multiple mechanisms including wedge collapse and flow of melt-weakened midcrust are debated to explain pressure-temperature trajectories, patterns of thinning, and thermal overprinting. A geochronologic revolution is under way in which spatially resolved compositions and ages of accessory minerals are combined in a petrogenetically valid context to recover specific temperature-time points and paths. Combined chemical and chronologic analysis of monazite is now well established and titanite is particularly promising, but recent zircon data raise questions about anatectic rocks and their use for investigating tectonism.