bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Stringent Response Promotes Antibiotic Resistance Dissemination by Regulating Integron Integrase Expression in Biofilms
Authors: Strugeon Emilie , Tilloy Valentin , Ploy Marie-Cécile , Da Re Sandra 
Published: August 2016

ABSTRACT
Class 1 integrons are genetic systems that enable bacteria to capture and express gene cassettes. These integrons, when isolated in clinical contexts, most often carry antibiotic resistance gene cassettes. They play a major role in the dissemination of antibiotic resistance among Gram-negative bacteria. The key element of integrons is the integrase, which allows gene cassettes to be acquired and shuffled. Planktonic culture experiments have shown that integrase expression is regulated by the bacterial SOS response. In natural settings, however, bacteria generally live in biofilms, which are characterized by strong antibiotic resilience and by increased expression of stress-related genes. Here, we report that under biofilm conditions, the stringent response, which is induced upon starvation, (i) increases basal integrase and SOS regulon gene expression via induction of the SOS response and (ii) exerts biofilm-specific regulation of the integrase via the Lon protease. This indicates that biofilm environments favor integron-mediated acquisition of antibiotic resistance and other adaptive functions encoded by gene cassettes.

IMPORTANCE
Multidrug-resistant bacteria are becoming a worldwide health problem. Integrons are bacterial genetic platforms that allow the bacteria to capture and express gene cassettes. In clinical settings, integrons play a major role in the dissemination of antibiotic resistance gene cassettes among Gram-negative bacteria. Cassette capture is catalyzed by the integron integrase, whose expression is induced by DNA damage and controlled by the bacterial SOS response in laboratory planktonic cultures. In natural settings, bacteria usually grow in heterogeneous environments known as biofilms, which have very different conditions than planktonic cultures. Integrase regulation has not been investigated in biofilms. Our results showed that in addition to the SOS response, the stringent response (induced upon starvation) is specifically involved in the regulation of class 1 integron integrases in biofilms. This study shows that biofilms are favorable environments for integron-mediated acquisition/exchange of antibiotic resistance genes by bacteria and for the emergence of multidrug-resistant bacteria.
Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
Authors: Kmiec Dorota , Iyer Shilpa S. , Stürzel Christina M. , Sauter Daniel , Hahn Beatrice H. , Kirchhoff Frank 
Published: August 2016

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into thevpugenes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.IMPORTANCEUnderstanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4+T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.
Hydrogen Metabolism in Helicobacter pylori Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
Authors: Wang Ge , Romero-Gallo Judith , Benoit Stéphane L. , Piazuelo M. Blanca , Dominguez Ricardo L. , Morgan Douglas R. , Peek Richard M. , Maier Robert J. 
Published: August 2016

ABSTRACT

A known virulence factor of
Helicobacter pylori
that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δ
hyd
mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-
n
-heptyl-4-hydroxyquinoline-
N
-oxide (HQNO) was used to specifically inhibit the H
2
-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H
2
-generated transmembrane potential is a contributor to toxin translocation. The Δ
hyd
strain showed a decreased frequency of DNA transformation, suggesting that
H. pylori
hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δ
hyd
strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δ
hyd
strain. By examining the hydrogenase activities from well-defined clinical
H. pylori
isolates, we observed that strains isolated from cancer patients (
n
= 6) have a significantly higher hydrogenase (H
2
/O
2
) activity than the strains isolated from gastritis patients (
n
= 6), further supporting an association between
H. pylori
hydrogenase activity and gastric carcinogenesis in humans.

IMPORTANCE
Hydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen’s (
H. pylori
) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H
2
-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H
2
oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.
Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of Clostridium difficile
Authors: Darkoh Charles , Odo Chioma , DuPont Herbert L. 
Published: August 2016

ABSTRACT

Clostridium difficile
infection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients.
C. difficile
, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. Some
C. difficile
strains encode two Agr loci in their genomes, designated
agr1
and
agr2
. The
agr1
locus is present in all of the
C. difficile
strains sequenced to date, whereas the
agr2
locus is present in a few strains. The functional roles of
agr1
and
agr2
in
C. difficile
toxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of both
agr
loci and examined the mutants for toxin production and virulence. The results showed that the
agr1
mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-type
agr1
. Furthermore, the
agr1
mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease.

IMPORTANCE
Within the last decade, the number of cases of
C. difficile
infections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen,
C. difficile
overpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment of
C. difficile
infections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection,
C. difficile
produces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy for
C. difficile
infections.
Outer Membrane Vesicle Biosynthesis in
Salmonella
: Is There More to Gram-Negative Bacteria?
Authors: Reidl Joachim 
Published: August 2016

ABSTRACT

Recent research has focused on the biological role of outer membrane vesicles (OMVs), which are derived from the outer membranes (OMs) of Gram-negative bacteria, and their potential exploitation as therapeutics. OMVs have been characterized in many ways and functions. Until recently, research focused on hypothetical and empirical models that addressed the molecular mechanisms of OMV biogenesis, such as vesicles bulging from the OM in various ways. The recently reported study by Elhenawy et al. (mBio 7:e00940-16, 2016,
http://dx.doi.org/10.1128/mBio.00940-16
) provided further insights into OMV biogenesis of
Salmonella enterica
serovar Typhimurium. That study showed that deacylation of lipopolysaccharides (LPS) influences the level of OMV production and, furthermore, determines a sorting of high versus low acylated LPS in OMs and OMVs, respectively. Interestingly, deacylation may inversely correlate with other LPS modifications, suggesting some synergy toward optimized host resistance via best OM compositions for
S
. Typhimurium.
Cardiovascular diseases in Paralympic athletes
Authors: Pelliccia Antonio , Quattrini Filippo M , Squeo Maria Rosaria , Caselli Stefano , Culasso Franco , Link Mark S , Spataro Antonio , Bernardi Marco 
Published: August 2016

BackgroundSport participation (SP) of individuals with impairments has recently grown exponentially. Scarce scientific data, however, exist regarding cardiovascular (CV) risk associated with competitive SP.ObjectiveAssessing the prevalence of CV abnormalities and the risk for SP in Paralympic athletes (PA).MethodsPA (n=267; 76% men), aged 35±9 years, engaged in 18 sport disciplines, with a spectrum of lesions including: spinal cord injury (paraplegia and spina bifida) (n=116); amputation, poliomyelitis, cerebral palsy and other neuromuscular and/or skeletal disorders (Les autres) or visual impairment (n=151) entered the study. CV evaluation included history, PE, 12-lead and exercise ECG, echocardiography. Of these, 105 participated in ≥2 consecutive games, and had evaluations available over a 6±4 year follow-up.ResultsStructural CV abnormalities were identified in 33 athletes (12%), including arrhythmogenic cardiomyopathies in 3, aortic root dilation in 3, valvular diseases in 7 (mitral valve prolapse in 4, bicuspid aortic valve in 3) and systemic hypertension in 11 (4%). In addition, ventricular (polymorphic, couplets or non-sustained ventricular tachycardia) or supraventricular tachyarrhythmias (atrial flutter, paroxysmal atrial fibrillation or SVT) were identified in 9 others. Over a 6-year follow-up, 6 of the 105 athletes (6%) developed CV diseases, including dilated cardiomyopathy in 1 and systemic hypertension in 5.ConclusionsPA present an unexpected high prevalence of CV abnormalities (12%), including a non-trivial proportion of diseases at risk for sudden death (2%), such as arrhythmogenic cardiomyopathies and dilated aortic root. This observation suggests that tailored recommendations for preparticipation screening and safe SP in this special athletic population are timely and appropriate.
Can standardised clinical examination of athletes with acute groin injuries predict the presence and location of MRI findings?
Authors: Serner Andreas , Weir Adam , Tol Johannes L , Thorborg Kristian , Roemer Frank , Guermazi Ali , Hölmich Per 
Published: August 2016

BackgroundLittle is known about the value of clinical examination in relation to diagnostic imaging for acute groin injuries in athletes. Primary aim: to investigate whether clinical examination tests predict a positive or negative MRI result (MRI±). Secondary aim: to assess accuracy of clinical tests to localise injury in MRI+ cases.MethodsWe consecutively included 81 male athletes with acute groin injuries. Standardised clinical examination (palpation, resistance and stretch tests) and MRI were performed within 7 days of injury. Diagnostic statistics including positive and negative predictive values (PPV/NPV) were calculated.Results85 acute injuries were found on MRI in 64 (79%) athletes with 17 (21%) athletes having MRI− injuries. Palpation had the highest NPV (91–96%, (95% CI 69% to 99%)). 3 specific adductor examination tests (resisted outer range adduction, squeeze test with hip neutral and long lever, and passive adductor stretch) showed 80–81% (95% CI 63% to 91%) probability of an MRI+ adductor lesion when positive, all with high accuracy of a correct MRI location (PPV 93–97% (95% CI 76% to 100%)). Hip flexor tests showed poor ability to predict MRI+ lesions (PPV 34–63% (95% CI 20% to 84%)) and low accuracy (PPV 17–71% (95% CI 7% to 85%)).Conclusions21% of athletes had negative imaging and the absence of palpation pain was best at predicting an MRI− result. Specific adductor examination tests accurately predicted MRI+ adductor injuries. Hip flexor clinical tests were poor at predicating and localising MRI+ injuries in the hip flexors. Clinical examination appears sufficient to diagnose acute adductor injuries, whereas MRI could assist in accurately locating acute hip flexor injuries.
Association of socioeconomic status with psychiatric problems and violent behaviours in a nationally representative sample of Iranian children and adolescents: the CASPIAN-IV study
Authors: Heshmat Ramin , Qorbani Mostafa , Ghoreshi Behnaz , Djalalinia Shirin , Tabatabaie Omid Reza , Safiri Saeid , Noroozi Mehdi , Motlagh Mohammad-Esmaeil , Ahadi Zeinab , Asayesh Hamid , Kelishadi Roya 
Published: August 2016

ObjectivesThe aim of the present study was to evaluate the association between socioeconomic status (SES) and psychiatric problems and violent behaviours in a nationally representative sample of Iranian children and adolescents, based on nationwide surveillance programme data, 2011–2012.MethodsOverall, 14 880 students, aged 6–18 years, were selected using a multistage cluster sampling method from rural and urban areas of 30 provinces in Iran. SES was estimated based on a main summarised component, extracted from principle component analysis of family assets and parents' jobs and education. For statistical analysis, SES was classified as ‘low’, ‘middle’ and ‘high’. The WHO-Global School Based Student Health Survey (WHO-GSHS) questionnaire was used to assess psychiatric problems and violent behaviours.ResultsIn total, 13 486 students (participation rate 90.6%) completed the study: 50.8% were boys and 75.6% were urban residents, with a mean age of 12.47±3.36 years. In the multivariate model, the ORs of depression, anxiety, feeling worthless, anger, insomnia, confusion and physical fights were lower in students with high SES compared with those with low SES (p<0.05) but physical fights was lower in the high SES group than in the low SES group (p<0.05). No significant relationship was documented between SES and other variables, including getting worried, history of bullying and being victimised.ConclusionsChildren and adolescents with low SES were at higher risk for psychiatric problems and violent behaviours. Mental health policies and public interventional strategies should be considered at the public level, notably for low SES families.
Systematic review of approaches to using patient experience data for quality improvement in healthcare settings
Authors: Gleeson Helen , Calderon Ana , Swami Viren , Deighton Jessica , Wolpert Miranda , Edbrooke-Childs Julian 
Published: August 2016

ObjectivesExplore how patient-reported experience measures (PREMs) are collected, communicated and used to inform quality improvement (QI) across healthcare settings.DesignSystematic review.SettingVarious primary and secondary care settings, including general practice, and acute and chronic care hospitals.ParticipantsA full range of patient populations from (children through to the elderly) and staff (from healthcare practitioners to senior managers).MethodsScientific databases were searched (CINAHL, PsycINFO, MEDLINE and Cochrane Libraries) as was grey literature. Qualitative and quantitative studies describing collection of PREM data and subsequent QI actions in any healthcare setting were included. Risk of bias was assessed using established criteria. Of 5312 initial hits, 32 full texts were screened, and 11 were included.ResultsPatient experience data were most commonly collected through surveys and used to identify small areas of incremental change to services that do not require a change to clinician behaviour (eg, changes to admission processes and producing educational materials). While staff in most studies reported having made effective improvements, authors struggled to identify what those changes were or the impact they had.ConclusionsFindings suggest there is no single best way to collect or use PREM data for QI, but they do suggest some key points to consider when planning such an approach. For instance, formal training is recommended, as a lack of expertise in QI and confidence in interpreting patient experience data effectively may continue to be a barrier to a successful shift towards a more patient-centred healthcare service. In the context of QI, more attention is required on how patient experience data will be used to inform changes to practice and, in turn, measure any impact these changes may have on patient experience.
Intimate partner violence experienced by HIV-infected pregnant women in South Africa: a cross-sectional study
Authors: Bernstein Molly , Phillips Tamsin , Zerbe Allison , McIntyre James A , Brittain Kirsty , Petro Greg , Abrams Elaine J , Myer Landon 
Published: August 2016

ObjectivesIntimate partner violence (IPV) during pregnancy may be common in settings where HIV is prevalent but there are few data on IPV in populations of HIV-infected pregnant women in Southern Africa. We examined the prevalence and correlates of IPV among HIV-infected pregnant women.SettingA primary care antenatal clinic in Cape Town, South Africa.Participants623 consecutive HIV-infected pregnant women initiating lifelong antiretroviral therapy.MeasuresIPV, depression, substance use and psychological distress were assessed using the 13-item WHO Violence Against Women questionnaire, the Edinburgh Postnatal Depression Scale (EPDS), Alcohol and Drug Use Disorders Identification Tests (AUDIT/DUDIT) and the Kessler 10 (K-10) scale, respectively.ResultsThe median age in the sample was 28 years, 97% of women reported being in a relationship, and 70% of women reported not discussing and/or agreeing on pregnancy intentions before conception. 21% of women (n=132) reported experiencing ≥1 act of IPV in the past 12 months, including emotional (15%), physical (15%) and sexual violence (2%). Of those reporting any IPV (n=132), 48% reported experiencing 2 or more types. Emotional and physical violence was most prevalent among women aged 18–24 years, while sexual violence was most commonly reported among women aged 25–29 years. Reported IPV was less likely among married women, and women who experienced IPV were more likely to score above threshold for substance use, depression and psychological distress. In addition, women who reported not discussing and/or not agreeing on pregnancy intentions with their partner prior to conception were significantly more likely to experience violence.ConclusionsHIV-infected pregnant women in the study reported experiencing multiple forms of IPV. While the impact of IPV on maternal and child health outcomes in the context of HIV infection requires further research attention, IPV screening and support services should be considered within the package of routine care for HIV-infected pregnant women.Trial registration numberNCT01933477.