bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-assembly of highly efficient, broadband plasmonic absorbers for solar steam generation
Authors: Zhou Lin , Tan Yingling , Ji Dengxin , Zhu Bin , Zhang Pei , Xu Jun , Gan Qiaoqiang , Yu Zongfu , Zhu Jia
Published: April 2016

A self-assembling plasmonic absorber absorbs light efficiently across a wide range of wavelengths and could be used in nanophotonic devices.
Climate-driven polar motion: 2003–2015
Authors: Adhikari Surendra , Ivins Erik R.
Published: April 2016

Ice sheets and continental hydrology changes on decadal time scales are the dominant drivers of decadal scale polar motion.
A specialized flavone biosynthetic pathway has evolved in the medicinal plant,
Scutellaria baicalensis
Authors: Zhao Qing , Zhang Yang , Wang Gang , Hill Lionel , Weng Jing-Ke , Chen Xiao-Ya , Xue Hongwei , Martin Cathie
Published: April 2016

Scutellaria baicalensis
(Huang-Qin in Chinese medicine) produces bioactive 4′-deoxyflavones by a newly evolved metabolic pathway.
The presence of clathrates in comet 67P/Churyumov-Gerasimenko
Authors: Luspay-Kuti Adrienn , Mousis Olivier , Hässig Myrtha , Fuselier Stephen A. , Lunine Jonathan I. , Marty Bernard , Mandt Kathleen E. , Wurz Peter , Rubin Martin
Published: April 2016

In situ coma measurements of 67P suggest that volatiles in the nucleus are stored as clathrates and pure condensates.
Filling-enforced quantum band insulators in spin-orbit coupled crystals
Authors: Po Hoi Chun , Watanabe Haruki , Zaletel Michael P. , Vishwanath Ashvin
Published: April 2016

Quantum effects produce a band insulator with fewer electrons than permitted in any classical picture.
Electrolytes induce long-range orientational order and free energy changes in the H-bond network of bulk water
Authors: Chen Yixing , Okur Halil I. , Gomopoulos Nikolaos , Macias-Romero Carlos , Cremer Paul S. , Petersen Poul B. , Tocci Gabriele , Wilkins David M. , Liang Chungwen , Ceriotti Michele , Roke Sylvie
Published: April 2016

Ions induce changes in the H-bond network of water that extend by >20 nm, vary for H
2
O and D
2
O, and lead to surface tension anomalies.
Coordinated Regulation of Species-Specific Hydroxycinnamic Acid Degradation and Siderophore Biosynthesis Pathways in Agrobacterium fabrum
Authors: Baude Jessica , Vial Ludovic , Villard Camille , Campillo Tony , Lavire Céline , Nesme Xavier , Hommais Florence
Published: April 2016

The rhizosphere-inhabiting speciesAgrobacterium fabrum(genomospecies G8 of theAgrobacterium tumefaciensspecies complex) is known to degrade hydroxycinnamic acids (HCAs), especially ferulic acid andp-coumaric acid, via the novelA. fabrumHCA degradation pathway. Gene expression profiles ofA. fabrumstrain C58 were investigated in the presence of HCAs, using a C58 whole-genome oligoarray. Both ferulic acid andp-coumaric acid caused variations in the expression of more than 10% of the C58 genes. Genes of theA. fabrumHCA degradation pathway, together with the genes involved in iron acquisition, were among the most highly induced in the presence of HCAs. Two operons coding for the biosynthesis of a particular siderophore, as well as genes of theA. fabrumHCA degradation pathway, have been described as being specific to the species. We demonstrate here their coordinated expression, emphasizing the interdependence between the iron concentration in the growth medium and the rate at which ferulic acid is degraded by cells. The coordinated expression of these functions may be advantageous in HCA-rich but iron-starved environments in which microorganisms have to compete for both iron and carbon sources, such as in plant roots. The present results confirm that there is cooperation between theA. fabrum-specific genes, defining a particular ecological niche.

IMPORTANCEWe previously identified seven genomic regions inAgrobacterium fabrumthat were specifically present in all of the members of this species only. Here we demonstrated that two of these regions, encoding the hydroxycinnamic acid degradation pathway and the iron acquisition pathway, were regulated in a coordinated manner. The coexpression of these functions may be advantageous in hydroxycinnamic acid-rich but iron-starved environments in which microorganisms have to compete for both iron and carbon sources, such as in plant roots. These data support the view that bacterial genomic species emerged from a bacterial population by acquiring specific functions that allowed them to outcompete their closest relatives. In conclusion, bacterial species could be defined not only as genomic species but also as ecological species.
Restructuring of the Aquatic Bacterial Community by Hydric Dynamics Associated with Superstorm Sandy
Authors: Ulrich Nikea , Rosenberger Abigail , Brislawn Colin , Wright Justin , Kessler Collin , Toole David , Solomon Caroline , Strutt Steven , McClure Erin , Lamendella Regina
Published: April 2016

Bacterial community composition and longitudinal fluctuations were monitored in a riverine system during and after Superstorm Sandy to better characterize inter- and intracommunity responses associated with the disturbance associated with a 100-year storm event. High-throughput sequencing of the 16S rRNA gene was used to assess microbial community structure within water samples from Muddy Creek Run, a second-order stream in Huntingdon, PA, at 12 different time points during the storm event (29 October to 3 November 2012) and under seasonally matched baseline conditions. High-throughput sequencing of the 16S rRNA gene was used to track changes in bacterial community structure and divergence during and after Superstorm Sandy. Bacterial community dynamics were correlated to measured physicochemical parameters and fecal indicator bacteria (FIB) concentrations. Bioinformatics analyses of 2.1 million 16S rRNA gene sequences revealed a significant increase in bacterial diversity in samples taken during peak discharge of the storm. Beta-diversity analyses revealed longitudinal shifts in the bacterial community structure. Successional changes were observed, in which
Betaproteobacteria
and
Gammaproteobacteria
decreased in 16S rRNA gene relative abundance, while the relative abundance of members of the
Firmicutes
increased. Furthermore, 16S rRNA gene sequences matching pathogenic bacteria, including strains of
Legionella
,
Campylobacter
,
Arcobacter
, and
Helicobacter
, as well as bacteria of fecal origin (e.g.,
Bacteroides
), exhibited an increase in abundance after peak discharge of the storm. This study revealed a significant restructuring of in-stream bacterial community structure associated with hydric dynamics of a storm event.

IMPORTANCE
In order to better understand the microbial risks associated with freshwater environments during a storm event, a more comprehensive understanding of the variations in aquatic bacterial diversity is warranted. This study investigated the bacterial communities during and after Superstorm Sandy to provide fine time point resolution of dynamic changes in bacterial composition. This study adds to the current literature by revealing the variation in bacterial community structure during the course of a storm. This study employed high-throughput DNA sequencing, which generated a deep analysis of inter- and intracommunity responses during a significant storm event. This study has highlighted the utility of applying high-throughput sequencing for water quality monitoring purposes, as this approach enabled a more comprehensive investigation of the bacterial community structure. Altogether, these data suggest a drastic restructuring of the stream bacterial community during a storm event and highlight the potential of high-throughput sequencing approaches for assessing the microbiological quality of our environment.
Involvement of Vitamin B6Biosynthesis Pathways in the Insecticidal Activity of Photorhabdus luminescens
Authors: Sato Kazuki , Yoshiga Toyoshi , Hasegawa Koichi
Published: April 2016

Photorhabdus luminescensis a Gram-negative entomopathogenic bacterium which symbiotically associates with the entomopathogenic nematodeHeterorhabditis bacteriophora.P. luminescensis highly virulent to many insects and nonsymbiotic nematodes, includingCaenorhabditis elegans. To understand the virulence mechanisms ofP. luminescens, we obtained virulence-deficient and -attenuated mutants againstC. elegansthrough a transposon-mutagenized library. From the genetic screening, we identified thepdxBgene, encoding erythronate-4-phosphate dehydrogenase, as required forde novovitamin B6biosynthesis. Mutation inpdxBcaused growth deficiency ofP. luminescensin nutrient-poor medium, which was restored under nutrient-rich conditions or by supplementation with pyridoxal 5′-phosphate (PLP), an active form of vitamin B6. Supplementation with three other B6vitamers (pyridoxal, pyridoxine, and pyridoxamine) also restored the growth of thepdxBmutant, suggesting the existence of a salvage pathway for vitamin B6biosynthesis inP. luminescens. Moreover, supplementation with PLP restored the virulence-deficient phenotype againstC. elegans. Combining these results with the fact thatpdxBmutation also caused attenuation of insecticidal activity, we concluded that the production of appropriate amounts of vitamin B6is critical forP. luminescenspathogenicity.

IMPORTANCEThe Gram-negative entomopathogenic bacteriumPhotorhabdus luminescenssymbiotically associates with the entomopathogenic nematodeHeterorhabditis bacteriophora.P. luminescensis highly virulent to many insects and nonsymbiotic nematodes, includingCaenorhabditis elegans. We have obtained several virulence-deficient and -attenuatedP. luminescensmutants againstC. elegansthrough genetic screening. From the genetic analysis, we present the vitamin B6biosynthetic pathways inP. luminescensthat are important for its insecticidal activity. Mutation inpdxB, encoding erythronate-4-phosphate dehydrogenase and required for thede novovitamin B6biosynthesis pathway, caused virulence deficiency againstC. elegansand growth deficiency ofP. luminescensin nutrient-poor medium. Because such phenotypes were restored under nutrient-rich conditions or by supplementation with B6vitamers, we showed the presence of the two vitamin B6synthetic pathways (de novoand salvage) inP. luminescensand also showed that the ability to produce an appropriate amount of vitamin B6is critical forP. luminescenspathogenicity.
Mechanism of Attenuation of Uranyl Toxicity by Glutathione in Lactococcus lactis
Authors: Obeid Muhammad H. , Oertel Jana , Solioz Marc , Fahmy Karim
Published: April 2016

Both prokaryotic and eukaryotic organisms possess mechanisms for the detoxification of heavy metals, and these mechanisms are found among distantly related species. We investigated the role of intracellular glutathione (GSH), which, in a large number of taxa, plays a role in protection against the toxicity of common heavy metals. Anaerobically grown
Lactococcus lactis
containing an inducible GSH synthesis pathway was used as a model organism. Its physiological condition allowed study of putative GSH-dependent uranyl detoxification mechanisms without interference from additional reactive oxygen species. By microcalorimetric measurements of metabolic heat during cultivation, it was shown that intracellular GSH attenuates the toxicity of uranium at a concentration in the range of 10 to 150 μM. In this concentration range, no effect was observed with copper, which was used as a reference for redox metal toxicity. At higher copper concentrations, GSH aggravated metal toxicity. Isothermal titration calorimetry revealed the endothermic binding of U(VI) to the carboxyl group(s) of GSH rather than to the reducing thiol group involved in copper interactions. The data indicate that the primary detoxifying mechanism is the intracellular sequestration of carboxyl-coordinated U(VI) into an insoluble complex with GSH. The opposite effects on uranyl and on copper toxicity can be related to the difference in coordination chemistry of the respective metal-GSH complexes, which cause distinct growth phase-specific effects on enzyme-metal interactions.

IMPORTANCE
Understanding microbial metal resistance is of particular importance for bioremediation, where microorganisms are employed for the removal of heavy metals from the environment. This strategy is increasingly being considered for uranium. However, little is known about the molecular mechanisms of uranyl detoxification. Existing studies of different taxa show little systematics but hint at a role of glutathione (GSH). Previous work could not unequivocally demonstrate a GSH function in decreasing the presumed uranyl-induced oxidative stress, nor could a redox-independent detoxifying action of GSH be identified. Combining metabolic calorimetry with cell number-based assays and genetics analysis enables a novel and general approach to quantify toxicity and relate it to molecular mechanisms. The results show that GSH-expressing microorganisms appear advantageous for uranyl bioremediation.
Cationized Magnetoferritin Enables Rapid Labeling and Concentration of Gram-Positive and Gram-Negative Bacteria in Magnetic Cell Separation Columns
Authors: Correia Carreira S. , Spencer J. , Schwarzacher W. , Seddon A. M.
Published: April 2016

In order to identify pathogens rapidly and reliably, bacterial capture and concentration from large sample volumes into smaller ones are often required. Magnetic labeling and capture of bacteria using a magnetic field hold great promise for achieving this goal, but the current protocols have poor capture efficiency. Here, we present a rapid and highly efficient approach to magnetic labeling and capture of both Gram-negative (
Escherichia coli
) and Gram-positive (
Staphylococcus aureus
) bacteria using cationized magnetoferritin (cat-MF). Magnetic labeling was achieved within a 1-min incubation period with cat-MF, and 99.97% of the labeled bacteria were immobilized in commercially available magnetic cell separation (MACS) columns. Longer incubation times led to more efficient capture, with
S. aureus
being immobilized to a greater extent than
E. coli
. Finally, low numbers of magnetically labeled
E. coli
bacteria (<100 CFU per ml) were immobilized with 100% efficiency and concentrated 7-fold within 15 min. Therefore, our study provides a novel protocol for rapid and highly efficient magnetic labeling, capture, and concentration of both Gram-positive and Gram-negative bacteria.

IMPORTANCE
Antimicrobial resistance (AMR) is a significant global challenge. Rapid identification of pathogens will retard the spread of AMR by enabling targeted treatment with suitable agents and by reducing inappropriate antimicrobial use. Rapid detection methods based on microfluidic devices require that bacteria are concentrated from large volumes into much smaller ones. Concentration of bacteria is also important to detect low numbers of pathogens with confidence. Here, we demonstrate that magnetic separation columns capture small amounts of bacteria with 100% efficiency. Rapid magnetization was achieved by exposing bacteria to cationic magnetic nanoparticles, and magnetized bacteria were concentrated 7-fold inside the column. Thus, bacterial capture and concentration were achieved within 15 min. This approach could be extended to encompass the capture and concentration of specific pathogens, for example, by functionalizing magnetic nanoparticles with antibodies or small molecule probes.
The Role of Punctuated Evolution in the Pathogenicity of Influenza Viruses
Authors: McCullers Jonathan A.
Published: April 2016

Influenza is an acute respiratory disease caused by influenza viruses. Evolutionarily, all influenza viruses are zoonoses, arising in the animal reservoir and spilling over into the human population. Several times a century, one of these zoonotic events results in a new influenza virus lineage becoming established in humans and circulating for years or decades as an endemic strain. The worldwide pandemic that occurs shortly after the nascent virus becomes established can have a profound impact on morbidity and mortality. Because influenza viruses continually evolve and the illness they engender can vary considerably based on characteristics of the strain, the weather, other circulating or endemic pathogens, as well as the number of susceptible hosts, the impact of each season on human health is unpredictable. Over time, the general pattern is for pandemic strains to adapt and gradually take on characteristics of seasonal strains with lower virulence and a diminished synergism with bacterial pathogens. Study of this punctuated evolution yields a number of insights into the overall pathogenicity of influenza viruses.
Bacterial Prostatitis: Bacterial Virulence, Clinical Outcomes, and New Directions
Authors: Krieger John N. , Thumbikat Praveen
Published: April 2016

Four prostatitis syndromes are recognized clinically: acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic prostatitis. Because
Escherichia coli
represents the most common cause of bacterial prostatitis, we investigated the importance of bacterial virulence factors and antimicrobial resistance in
E. coli
strains causing prostatitis and the potential association of these characteristics with clinical outcomes. A structured literature review revealed that we have limited understanding of the virulence-associated characteristics of
E. coli
causing acute prostatitis. Therefore, we completed a comprehensive microbiological and molecular investigation of a unique strain collection isolated from healthy young men. We also considered new data from an animal model system suggesting certain
E. coli
might prove important in the etiology of chronic prostatitis/chronic pelvic pain syndrome. Our human data suggest that
E. coli
needs multiple pathogenicity-associated traits to overcome anatomic and immune responses in healthy young men without urological risk factors. The phylogenetic background and accumulation of an exceptional repertoire of extraintestinal pathogenic virulence-associated genes indicate that these
E. coli
strains belong to a highly virulent subset of uropathogenic variants. In contrast, antibiotic resistance confers little added advantage to
E. coli
strains in these healthy outpatients. Our animal model data also suggest that certain pathogenic
E. coli
may be important in the etiology of chronic prostatitis/chronic pelvic pain syndrome through mechanisms that are dependent on the host genetic background and the virulence of the bacterial strain.
Gram-Positive Uropathogens, Polymicrobial Urinary Tract Infection, and the Emerging Microbiota of the Urinary Tract
Authors: Kline Kimberly A. , Lewis Amanda L.
Published: April 2016

Gram-positive bacteria are a common cause of urinary-tract infection (UTI), particularly among individuals who are elderly, pregnant, or who have other risk factors for UTI. Here we review the epidemiology, virulence mechanisms, and host response to the most frequently isolated Gram-positive uropathogens:
Staphylococcus saprophyticus, Enterococcus faecalis
, and
Streptococcus agalactiae
. We also review several emerging, rare, misclassified, and otherwise underreported Gram-positive pathogens of the urinary tract including
Aerococcus
,
Corynebacterium, Actinobaculum,
and
Gardnerella
. The literature strongly suggests that urologic diseases involving Gram-positive bacteria may be easily overlooked due to limited culture-based assays typically utilized for urine in hospital microbiology laboratories. Some UTIs are polymicrobial in nature, often involving one or more Gram-positive bacteria. We herein review the risk factors and recent evidence for mechanisms of bacterial synergy in experimental models of polymicrobial UTI. Recent experimental data has demonstrated that, despite being cleared quickly from the bladder, some Gram-positive bacteria can impact pathogenic outcomes of co-infecting organisms. When taken together, the available evidence argues that Gram-positive bacteria are important uropathogens in their own right, but that some can be easily overlooked because they are missed by routine diagnostic methods. Finally, a growing body of evidence demonstrates that a surprising variety of fastidious Gram-positive bacteria may either reside in or be regularly exposed to the urinary tract and further suggests that their presence is widespread among women, as well as men. Experimental studies in this area are needed; however, there is a growing appreciation that the composition of bacteria found in the bladder could be a potentially important determinant in urologic disease, including susceptibility to UTI.
Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections
Authors: O’Brien Valerie P. , Hannan Thomas J. , Nielsen Hailyn V. , Hultgren Scott J.
Published: April 2016

Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance andClostridium difficilecolitis. UropathogenicE. coli(UPEC) cause the vast majority of UTI, but less common pathogens such asEnterococcus faecalisand other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity.
The Structure and Function of Type III Secretion Systems
Authors: Notti Ryan Q. , Stebbins C. Erec
Published: April 2016

Type III secretion systems (T3SSs) afford Gram-negative bacteria an intimate means of altering the biology of their eukaryotic hosts—the direct delivery of effector proteins from the bacterial cytoplasm to that of the eukaryote. This incredible biophysical feat is accomplished by nanosyringe “injectisomes,” which form a conduit across the three plasma membranes, peptidoglycan layer, and extracellular space that form a barrier to the direct delivery of proteins from bacterium to host. The focus of this chapter is T3SS function at the structural level; we will summarize the core findings that have shaped our understanding of the structure and function of these systems and highlight recent developments in the field. In turn, we describe the T3SS secretory apparatus, consider its engagement with secretion substrates, and discuss the posttranslational regulation of secretory function. Lastly, we close with a discussion of the future prospects for the interrogation of structure-function relationships in the T3SS.
Bacterial Evasion of Host Antimicrobial Peptide Defenses
Authors: Cole Jason N. , Nizet Victor
Published: April 2016

Antimicrobial peptides (AMPs), also known as host defense peptides, are small naturally occurring microbicidal molecules produced by the host innate immune response that function as a first line of defense to kill pathogenic microorganisms by inducing deleterious cell membrane damage. AMPs also possess signaling and chemoattractant activities and can modulate the innate immune response to enhance protective immunity or suppress inflammation. Human pathogens have evolved defense molecules and strategies to counter and survive the AMPs released by host immune cells such as neutrophils and macrophages. Here, we review the various mechanisms used by human bacterial pathogens to resist AMP-mediated killing, including surface charge modification, active efflux, alteration of membrane fluidity, inactivation by proteolytic digestion, and entrapment by surface proteins and polysaccharides. Enhanced understanding of AMP resistance at the molecular level may offer insight into the mechanisms of bacterial pathogenesis and augment the discovery of novel therapeutic targets and drug design for the treatment of recalcitrant multidrug-resistant bacterial infections.

Abbreviations: ABC, adenosine triphosphate-binding cassette; AMPs, antimicrobial peptides;
l
-Ara4N, 4-amino-4-deoxy-
l
-arabinose; GAC, group A carbohydrate; GAS, group A
Streptococcus
; GBS, group B
Streptococcus
; GlcNAc,
N
-acetylglucosamine; HBD 1-6, human β-defensin 1-6; HD 5-6, human α-defensin 5-6; HNP 1-4, human neutrophil peptide 1-4; LL-37, human cathelicidin; LOS, lipooligosaccharide; LPS, lipopolysaccharide; LTA, lipoteichoic acid; mCRAMP, murine cathelicidin-related antimicrobial peptide; MprF, membrane protein multipeptide resistance factor; NETs, neutrophil extracellular traps; pEtN, phosphoethanolamine; PG, phosphatidylglycerol; Sap, sensitive to antimicrobial peptides ABC importer; SK, staphylokinase; TA, teichoic acid; TLR, toll-like receptor; WT, wild-type.
Type VII Secretion: A Highly Versatile Secretion System
Authors: Ates Louis S. , Houben Edith N. G. , Bitter Wilbert
Published: April 2016

Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylumActinobacteria, and functional T7S-like systems have been identified inFirmicutes. Most of the T7S substrates can be divided into two families: the Esx proteins, which are found in bothFirmicutesandActinobacteria, and the PE and PPE proteins, which are more mycobacterium-specific. Members of both families have been shown to be secreted as folded heterodimers, suggesting that this is a conserved feature of T7S substrates. Most knowledge of the mechanism of T7S and the roles of T7S systems in virulence comes from studies of pathogenic mycobacteria. These bacteria can contain up to five T7S systems, called ESX-1 to ESX-5, each having its own role in bacterial physiology and virulence.

In this article, we discuss the general composition of T7S systems and the role of the individual components in secretion. These conserved components include two membrane proteins with (predicted) enzymatic activities: a predicted ATPase (EccC), likely to be required for energy provision of T7S, and a subtilisin-like protease (MycP) involved in processing of specific substrates. Additionally, we describe the role of a conserved intracellular chaperone in T7S substrate recognition, based on recently published crystal structures and molecular analysis. Finally, we discuss system-specific features of the different T7S systems in mycobacteria and their role in pathogenesis and provide an overview of the role of T7S in virulence of other pathogenic bacteria.
Bacterial Secretion Systems: An Overview
Authors: Green Erin R. , Mecsas Joan
Published: April 2016

Bacterial pathogens utilize a multitude of methods to invade mammalian hosts, damage tissue sites, and thwart the immune system from responding. One essential component of these strategies for many bacterial pathogens is the secretion of proteins across phospholipid membranes. Secreted proteins can play many roles in promoting bacterial virulence, from enhancing attachment to eukaryotic cells, to scavenging resources in an environmental niche, to directly intoxicating target cells and disrupting their functions. Many pathogens use dedicated protein secretion systems to secrete virulence factors from the cytosol of the bacteria into host cells or the host environment. In general, bacterial protein secretion apparatuses can be divided into classes, based on their structures, functions, and specificity. Some systems are conserved in all classes of bacteria and secrete a broad array of substrates, while others are only found in a small number of bacterial species and/or are specific to only one or a few proteins. In this chapter, we review the canonical features of several common bacterial protein secretion systems, as well as their roles in promoting the virulence of bacterial pathogens. Additionally, we address recent findings that indicate that the innate immune system of the host can detect and respond to the presence of protein secretion systems during mammalian infection.
Novel Targets of Antimicrobial Therapies
Authors: Maddocks Sarah E.
Published: April 2016

Antibiotics are undoubtedly a pillar of modern medicine; their discovery in 1929 revolutionized the fight against infectious disease, instigating a worldwide decline in infection-associated mortality. Throughout the 1930s, 1940s, and 1950s the golden age of antibiotic discovery was underway with numerous new classes of antibiotics identified and brought to market. By 1962 all of our currently known families of antibiotics had been discovered, and it was a widely held belief, that humanity had conquered infectious disease. Despite varying bacterial cellular targets, most antibiotics targeted exponentially multiplying bacteria by interfering with integral processes such as peptidoglycan synthesis or ribosomal activity. The very nature of this targeted approach has driven the emergence of antibiotic-resistant bacteria.

Methods of antibiotic identification relied solely on scientific observation, and while chemical analogues such as amoxicillin, derived from penicillin, continued to be developed, they retained the same mechanisms of action and hence the same bacterial targets. This article describes and discusses some of the emerging novel targets for antimicrobial treatments, highlighting pivotal research on which our ability to continue to successfully treat bacterial infection relies.
Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections
Authors: Cusumano Zachary T. , Klein Roger D. , Hultgren Scott J.
Published: April 2016

Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.
Prevalence of passive smoking in the community population aged 15 years and older in China: a systematic review and meta-analysis
Authors: Zeng Jing , Yang Shanshan , Wu Lei , Wang Jianhua , Wang Yiyan , Liu Miao , Zhang Di , Jiang Bin , He Yao
Published: April 2016

Objectives

To estimate the prevalence and distribution of passive smoking in the community population aged 15 years and older in China.

Design

A systematic review and meta-analysis of cross-sectional studies reporting the prevalence of passive smoking in China and a series of subgroup, trend and sensitivity analyses were conducted in this study.

Data source

The systematic review and meta-analysis, which included 46 studies with 381 580 non-smokers, estimated the prevalence and distribution of passive smoking in China. All studies were published between 1997 and 2015.

Results

The pooled prevalence of passive smoking was 48.7% (95% CI 44.8% to 52.5%) and was relatively stable from 1995 to 2013. The prevalence in the subgroups of gender, area, age and time varied from 35.1% (95% CI 31.8% to 38.3%) in the elderly (≥60 years) to 48.6% (95% CI 42.9% to 54.2%) in urban areas. The prevalence was lower in the elderly (≥60 years) than in those between 15 and 59 years of age (OR 1.61, 95% CI 1.44 to 1.81). The difference between females and males in urban and rural areas was not statistically significant (OR: 1.27, 95% CI 0.93 to 1.74 and OR: 1.14, 95% CI 0.82 to 1.58, respectively). In addition, a significantly increasing trend was found among males from 2002 to 2010. Heterogeneity was high in all pooled estimates (I2>98%, p<0.001).

Conclusions

The high and stable prevalence of passive smoking in China is raising increasing national concern regarding specific research and tobacco control programmes. Attention should be focused on young, middle-aged and male non-smokers regardless of region.
Cigarette smoking in a Middle Eastern country and its association with hospitalisation use: a nationwide cross-sectional study
Authors: Sibai Abla Mehio , Iskandarani Mohamad , Darzi Andrea , Nakkash Rima , Saleh Shadi , Fares Souha , Hwalla Nahla
Published: April 2016

Objectives

Little is known about the distribution of cigarette smoking by place and persons at the national level or its burden on healthcare expenditure in countries of the Middle East. We examine in this study the pattern of cigarette smoking by age, gender and geography and assess its association with hospitalisation use in Lebanon, a small middle-income country in the Middle East.

Design

Population-based cross-sectional study.

Setting

The study draws on data collected as part of the nationwide multistage cluster sample Nutrition and Non-Communicable Disease Risk Factor survey conducted in Lebanon in 2009.

Participants

A total of 2836 Lebanese adults 18 years and over.

Measures

Hospitalisation, the outcome variable, was measured using one item and recoded as a dichotomous variable. Cigarette smoking, the main exposure variable, was assessed by examining smoking status and pack-years, capturing intensity, frequency and duration of exposure.

Results

The overall prevalence rate of current smoking in this study was 34.7%, with significantly higher rates in males than females (42.9% and 27.5%, respectively). Close to two-thirds of the study population reported ever being hospitalised (62.8%). Compared to non-smokers, past and current smokers were significantly more likely to be hospitalised, after controlling for sociodemographic and health-related characteristics (OR=2.9, 95% CI 1.26 to 3.34, and OR=1.35, 95% CI 1.12 to 1.63, respectively). Hospitalisation use increased significantly in a dose–response manner with increasing pack-years.

Conclusions

When compared to regional and international estimates, the prevalence rates of smoking in Lebanon are considerably high, with percentages among women being among the highest in the region. Our findings of increased odds of hospitalisation among ever smokers, net of the effect of comorbidity, underscore the additional burden of smoking on the healthcare bill cost. Continued monitoring of smoking rates and disease surveillance frameworks are warranted in developing countries for policy development and evaluation.
Effects of different photoperiods on digestive enzyme activities in rainbow trout (Oncorhynchus mykiss) alevin and fry
Authors: Ramzanzadeh Fereshteh , Yeganeh Sakineh , JaniKhalili Khosro , Babaei Seyedeh Sedigheh
Published: April 2016

The aim of this study was to investigate the ontogeny of digestive enzymes and effects of photoperiod on pancreatic enzyme activity in rainbow trout (Oncorhynchus mykiss (Walbaum, 1792)) alevin and fry. After hatching, 3600 individuals of first-feeding alevin with a mean (±SD) mass of 119 ± 0.01 mg were reared in plastic tanks at four photoperiod levels (llight (L) : dark (D) cycle) for 6 weeks. Each replicate contained 300 alevin. Photoperiod treatments consisted of 14 h L : 10 h D, 10 h L : 14 h D, 4 h L : 20 h D, and 24 h L : 0 h D. During the rearing period, environmental variables including water temperature, oxygen, and pH were checked. Random sampling of alevin and fry was done at 0, 1, 3, 5, 8, 10, 15, 20, 25, 30, 39, and 44 days after the beginning of the first feeding (equal to 18, 19, 23, 25, 28, 30, 35, 40, 45, 50, 58, 63 days post hatching (dph)). The digestive enzyme activities in alevin and fry had a similar variation trend with age at all photoperiod levels. The specific activities of trypsin, chymotrypsin, and α-amylase at 24 h L : 0 h D were significantly higher than other treatments, but there was no significant difference in specific activity of lipase among treatments. The results demonstrated that growth, feeding efficiency, and digestive enzyme activity improved with longer exposure to photoperiod in rearing conditions.
Changes in Epidermal Growth Factor Receptor Gene Copy Number during Oral Carcinogenesis
Authors: Bates Timothy , Kennedy Matthew , Diajil Ameena , Goodson Michaela , Thomson Peter , Doran Emma , Farrimond Heather , Thavaraj Selvam , Sloan Philip , Kist Ralf , Robinson Max
Published: April 2016

Background: Oral squamous cell carcinoma (OSCC) is a global healthcare problem associated with poor clinical outcomes. Early detection is key to improving patient survival. OSCC may be preceded by clinically recognizable lesions, termed oral potentially malignant disorders (OPMD). As histologic assessment of OPMD does not accurately predict their clinical behavior, biomarkers are required to detect cases at risk of malignant transformation. Epidermal growth factor receptor gene copy number (EGFR GCN) is a validated biomarker in lung non–small cell carcinoma. We examined EGFR GCN in OPMD and OSCC to determine its potential as a biomarker in oral carcinogenesis.

Methods: EGFR GCN was examined by in situ hybridization (ISH) in biopsies from 78 patients with OPMD and 92 patients with early-stage (stages I and II) OSCC. EGFR ISH signals were scored by two pathologists and a category assigned by consensus. The data were correlated with patient demographics and clinical outcomes.

Results: OPMD with abnormal EGFR GCN were more likely to undergo malignant transformation than diploid cases. EGFR genomic gain was detected in a quarter of early-stage OSCC, but did not correlate with clinical outcomes.

Conclusion: These data suggest that abnormal EGFR GCN has clinical utility as a biomarker for the detection of OPMD destined to undergo malignant transformation. Prospective studies are required to verify this finding. It remains to be determined if EGFR GCN could be used to select patients for EGFR-targeted therapies.

Impact: Abnormal EGFR GCN is a potential biomarker for identifying OPMD that are at risk of malignant transformation. Cancer Epidemiol Biomarkers Prev; 25(6); 927–35. ©2016 AACR.
Effects of a Structured Exercise Program on Physical Activity and Fitness in Colon Cancer Survivors: One Year Feasibility Results from the CHALLENGE Trial
Authors: Courneya Kerry S. , Vardy Janette L. , O'Callaghan Christopher J. , Friedenreich Christine M. , Campbell Kristin L. , Prapavessis Harry , Crawford Jennifer J. , O'Brien Patti , Dhillon Haryana M. , Jonker Derek J. , Chua Neil S. , Lupichuk Sasha , Sanatani Michael S. , Gill Sharlene , Meyer Ralph M. , Begbie Stephen , Bonaventura Tony , Burge Matthew E. , Turner Jane , Tu Dongsheng , Booth Christopher M.
Published: April 2016

Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes; however, the optimal methods for achieving behavior change in large-scale pragmatic trials are unknown. Here, we report the 1-year feasibility results for exercise behavior change in the Canadian Cancer Trials Group CO.21 (CHALLENGE) Trial.

Methods: Between 2009 and 2014, 273 high-risk stage II and III colon cancer survivors from 42 centers in Canada and Australia were randomized to a structured exercise program (SEP; n = 136) or health education materials (HEM; n = 137). The primary feasibility outcome in a prespecified interim analysis was a difference between randomized groups of ≥5 metabolic equivalent task (MET)-hours/week in self-reported recreational physical activity (PA) after at least 250 participants reached the 1-year follow-up. Secondary outcomes included health-related fitness.

Results: The SEP group reported an increase in recreational PA of 15.6 MET-hours/week compared with 5.1 MET-hours/week in the HEM group [mean difference = +10.5; 95% confidence interval (CI) = +3.1–+17.9; P = 0.002]. The SEP group also improved relative to the HEM group in predicted VO2max (P = 0.068), 6-minute walk (P < 0.001), 30-second chair stand (P < 0.001), 8-foot up-and-go (P = 0.004), and sit-and-reach (P = 0.08).

Conclusions: The behavior change intervention in the CHALLENGE Trial produced a substantial increase in self-reported recreational PA that met the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colon cancer outcomes in observational studies.

Impact: The CHALLENGE Trial is poised to determine the causal effects of PA on colon cancer outcomes. Cancer Epidemiol Biomarkers Prev; 25(6); 969–77. ©2016 AACR.
Exosomes in Human Breast Milk Promote EMT
Authors: Qin Wenyi , Tsukasaki Yoshikazu , Dasgupta Santanu , Mukhopadhyay Nitai , Ikebe Mitsuo , Sauter Edward R.
Published: April 2016

Purpose: Pregnancy increases breast cancer risk for all women for at least 5 years after parturition. During weaning and involution, the breast microenvironment becomes tumor promotional. Exosomes provide cell–cell communication during physiologic processes such as lactation, but also in breast cancer. We determined whether molecules in milk exosomes from healthy lactating women modulate the development and progression of breast cancer.

Experimental Design: Thirteen nursing women provided three (transitional, mature, and wean) milk samples. Exosomes were extracted and MCF7 and MCF10A breast cells labeled. The expression of six proteins linked to breast cancer was measured. On the basis of the findings, TGFβ2 concentration in exosome samples was measured, breast cells incubated with the exosomes and effect (epithelial–mesenchymal transition, EMT) on EMT-related proteins [E-cadherin, α-smooth muscle actin (α-SMA), filamentous (F)-actin and vimentin] measured.

Results: Human milk exosomes entered benign and malignant breast cells. The greatest change in wean milk protein was in TGFβ2 (P = 0.01). Exosomes with a high (but not low) level of TGFβ2 led to EMT in both cancer and benign cells, based on (i) change in cell morphology, actin cytoskeleton, and loss of cell–cell junction structure and (ii) increased α-SMA and vimentin and decreased E-cadherin.

Conclusions: TGFβ2 is significantly upregulated in breast milk exosomes during weaning/early involution. Breast milk exosomes containing high levels of TGFβ2 induce changes in both benign and malignant breast epithelial cells, consistent with the development and progression of breast cancer, suggesting a role for high TGFβ2-expressing breast milk exosomes in influencing breast cancer risk. Clin Cancer Res; 22(17); 4517–24. ©2016 AACR.
A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort
Authors: Terry Kathryn L. , Schock Helena , Fortner Renée T. , Hüsing Anika , Fichorova Raina N. , Yamamoto Hidemi S. , Vitonis Allison F. , Johnson Theron , Overvad Kim , Tjønneland Anne , Boutron-Ruault Marie-Christine , Mesrine Sylvie , Severi Gianluca , Dossus Laure , Rinaldi Sabina , Boeing Heiner , Benetou Vassiliki , Lagiou Pagona , Trichopoulou Antonia , Krogh Vittorio , Kuhn Elisabetta , Panico Salvatore , Bueno-de-Mesquita H. Bas , Onland-Moret N. Charlotte , Peeters Petra H. , Gram Inger Torhild , Weiderpass Elisabete , Duell Eric J. , Sanchez Maria-Jose , Ardanaz Eva , Etxezarreta Nerea , Navarro Carmen , Idahl Annika , Lundin Eva , Jirström Karin , Manjer Jonas , Wareham Nicholas J. , Khaw Kay-Tee , Byrne Karl Smith , Travis Ruth C. , Gunter Marc J. , Merritt Melissa A. , Riboli Elio , Cramer Daniel W. , Kaaks Rudolf
Published: April 2016

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study.

Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis.

Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker.

Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664–75. ©2016 AACR.

See related commentary by Skates, p. 4542