bluuebunny/crossref_metadata_2025_split huggingface dataset:
SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection
Authors: McIntosh Anne , Meikle Lynsey M. , Ormsby Michael J. , McCormick Beth A. , Christie John M. , Brewer James M. , Roberts Mark , Wall Daniel M. 
Published: June 2017

ABSTRACTSalmonellainvasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or otherSalmonellapathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in anex vivointestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag forin vivotracking of individual effectors.
Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases
Authors: Parashar Kaustubh , Kopping Erik , Frank David , Sampath Vinaya , Thanassi David G. , Carpino Nick 
Published: June 2017

ABSTRACT

The
S
uppressor of
T
CR
s
ignaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated that
Sts
−/−
mice are profoundly resistant to systemic infection by
Candida albicans
, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response of
Sts
−/−
mice to infection by a Gram-negative bacterial pathogen.
Francisella tularensis
is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia.
Francisella
infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by the
l
ive
v
accine
s
train (LVS) of
F. tularensis
. Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs.
Sts
−/−
bone marrow-derived monocytes and neutrophils, infected with
F. tularensis
LVS
ex vivo
, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways.
Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays
Authors: Baarda Benjamin I. , Emerson Sarah , Proteau Philip J. , Sikora Aleksandra E. 
Published: June 2017

ABSTRACT

The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging drug-resistant pathogens, such as
Neisseria gonorrhoeae
. A proteomics-driven reverse vaccinology approach has delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates—NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344—in cell envelope homeostasis were probed using phenotype microarrays under 1,056 conditions and a Δ
bamE
mutant (Δ
ngo1780
) as a reference of perturbed outer membrane integrity. Optimal growth conditions for an
N. gonorrhoeae
phenotype microarray assay in defined liquid medium were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111, and NGO2054, with the last protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic-resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear to be the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism, such as
N. gonorrhoeae
.

IMPORTANCE
Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections, such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into
Neisseria gonorrhoeae
to probe the function of proteome-derived vaccine candidates in cell envelope homeostasis. Information gained from this screening can feed the vaccine candidate decision tree by providing insights into the roles these proteins play in membrane permeability, integrity, and overall
N. gonorrhoeae
physiology. The optimized screening protocol can be applied in investigations into the function of other hypothetical proteins of
N. gonorrhoeae
discovered in the expanding number of whole-genome sequences, in addition to revealing phenotypic differences between clinical and laboratory strains.
The DNA Repair Repertoire of Mycobacterium smegmatis FenA Includes the Incision of DNA 5′ Flaps and the Removal of 5′ Adenylylated Products of Aborted Nick Ligation
Authors: Uson Maria Loressa , Ghosh Shreya , Shuman Stewart 
Published: June 2017

ABSTRACT

We characterize
Mycobacterium smegmatis
FenA as a manganese-dependent 5′-flap endonuclease homologous to the 5′-exonuclease of DNA polymerase I. FenA incises a nicked 5′ flap between the first and second nucleotides of the duplex segment to yield a 1-nucleotide gapped DNA, which is then further resected in dinucleotide steps. Initial FenA cleavage at a Y-flap or nick occurs between the first and second nucleotides of the duplex. However, when the template 3′ single strand is eliminated to create a 5′-tailed duplex, FenA incision shifts to between the second and third nucleotides. A double-flap substrate with a mobile junction (mimicking limited strand displacement synthesis during gap repair) is preferentially incised as the 1-nucleotide 3′-flap isomer, with the scissile phosphodiester shifted by one nucleotide versus a static double flap. FenA efficiently removes the 5′ App(dN) terminus of an aborted nick ligation reaction intermediate, thereby highlighting FenA as an agent of repair of such lesions, which are formed under a variety of circumstances by bacterial NAD
+
-dependent DNA ligases and especially by mycobacterial DNA ligases D and C.

IMPORTANCE
Structure-specific DNA endonucleases are implicated in bacterial DNA replication, repair, and recombination, yet there is scant knowledge of the roster and catalytic repertoire of such nucleases in
Mycobacteria
. This study identifies
M. smegmatis
FenA as a stand-alone endonuclease homologous to the 5′-exonuclease domain of mycobacterial DNA polymerase 1. FenA incises 5′ flaps, 5′ nicks, and 5′ App(dN) intermediates of aborted nick ligation. The isolated N-terminal domain of
M. smegmatis
Pol1 is also shown to be a flap endonuclease.
Are fire safe cigarettes actually fire safe? Evidence from changes in US state laws
Authors: Bonander Carl , Jakobsson Niklas , Nilson Finn 
Published: June 2017

ObjectiveTo estimate the effects of fire safe cigarette laws on fire mortality and cigarette-related fires in the USA.MethodsWe examined the gradual implementation of the laws to identify their average effects, using difference-in-differences analysis to account for common year effects, time-invariant state effects, state-specific trends and observable time-varying state-level covariates.ResultsWe found no statistically significant effects on all-cause fire mortality, residential fire mortality or cigarette-caused fire rates. The estimates for cigarette-caused fire deaths were significant under some specifications, but were not robust to the inclusion of state-specific trends or comparisons to effects on other cause-determined fires.ConclusionsGiven the mixed state of our results, we conclude that previous claims regarding the effects of fire safe cigarette laws may be premature.
Infection Exposure PromotesETV6-RUNX1Precursor B-cell Leukemia via Impaired H3K4 Demethylases
Authors: Rodríguez-Hernández Guillermo , Hauer Julia , Martín-Lorenzo Alberto , Schäfer Daniel , Bartenhagen Christoph , García-Ramírez Idoia , Auer Franziska , González-Herrero Inés , Ruiz-Roca Lucia , Gombert Michael , Okpanyi Vera , Fischer Ute , Chen Cai , Dugas Martin , Bhatia Sanil , Linka René Martin , Garcia-Suquia Marta , Rascón-Trincado María Victoria , Garcia-Sanchez Angel , Blanco Oscar , García-Cenador Maria Begoña , García-Criado Francisco Javier , Cobaleda César , Alonso-López Diego , De Las Rivas Javier , Müschen Markus , Vicente-Dueñas Carolina , Sánchez-García Isidro , Borkhardt Arndt 
Published: June 2017

AbstractETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365–77. ©2017 AACR.
Dose-Finding Methods: Moving Away from the 3 + 3 to Include Richer Outcomes
Authors: Paoletti Xavier , Drubay Damien , Collette Laurence 
Published: June 2017

Abstract
The most commonly used method for dose finding, the 3 + 3, has poor performance. New adaptive designs are more efficient. Nevertheless, they have reached a maximum performance level, and further improvement requires either larger sample sizes or outcomes measures richer than the simplistic severe toxicity measured at cycle 1. Clin Cancer Res; 23(15); 3977–9. ©2017 AACR.
See related article by Yan et al., p. 3994
Nubis et Nuclei: A Study on Noise and Precision
Authors: Ergenzinger Kerstin 
Published: June 2017

Abstract
This study sets out to explore the perception of noise, as well as the relation toward meaning or information that it might contain, in arts, science and daily life. It is realized as an installation based on a suspended cloud of nitinol drums that create a sonic environment evolving in time and space. Digital random noise drives the instruments. Roaming freely and listening, visitors become part of an ecology of noise. As visitors explore differing regions in time and space, what appears to be noise can shift to a “meaningful” signal. This process of discovering a clear signal in a noisy background holds strong analogies to the scientific search for a nuclear resonance performed in the nuClock project.
Effect of Boundary Layer Roll Vortices on the Development of an Axisymmetric Tropical Cyclone
Authors: Gao Kun , Ginis Isaac , Doyle James D. , Jin Yi 
Published: June 2017

AbstractIn this study, the authors numerically investigate the response of an axisymmetric tropical cyclone (TC) vortex to the vertical fluxes of momentum, heat, and moisture induced by roll vortices (rolls) in the boundary layer. To represent the vertical fluxes induced by rolls, a two-dimensional high-resolution Single-Grid Roll-Resolving Model (SRM) is embedded at multiple horizontal grid points in the mesoscale COAMPS for Tropical Cyclones (COAMPS-TC) model domain. Idealized experiments are conducted with the SRM embedded within 3 times the radius of maximum wind of an axisymmetric TC. The results indicate that the rolls induce changes in the boundary layer wind distribution and cause a moderate (approximately 15%) increase in the TC intensification rate by increasing the boundary layer convergence in the eyewall region and induce more active eyewall convection. The numerical experiments also suggest that the roll-induced tangential momentum flux is most important in contributing to the TC intensification process, and the rolls generated at different radii (within the range considered in this study) all have positive contributions. The results are not qualitatively impacted by the initial TC vortex or the setup of the vertical diffusivity in COAMPS-TC.
Clino-suenoite, a newly approved magnesium-iron-manganese amphibole from Valmalenco, Sondrio, Italy
Authors: Oberti Roberta , Boiocchi Massimo , Hawthorne Frank C. , Ciriotti Marco E. , Revheim Olav , Bracco Roberto 
Published: June 2017

ABSTRACTClino-suenoite, ideally □${\rm Mn}_{2}^{2 +} $Mg5Si8O22(OH)2 is a new amphibole of the magnesium-iron-manganese subgroup of the amphibole supergroup. The type specimen was found at the Lower Scerscen Glacier, Valmalenco, Sondrio, Italy, where it occurs in Mn-rich quartzite erratics containing braunite, rhodonite, spessartine, carbonates and various accessory minerals. The empirical formula derived from electron microprobe analysis and single-crystal structure refinement is: ANa0.04B(${\rm Mn}_{1.58}^{2 +} $Ca0.26Na0.16)Σ2.00C(Mg4.21${\rm Mn}_{0. 61}^{2 +} {\rm Fe}_{0.04}^{2 +} $Zn0.01Ni0.01${\rm Fe}_{0.08}^{3 +} $Al0.04)Σ5.00TSi8.00O22W[(OH1.94F0.06)]Σ=2.00. Clino-suenoite is biaxial (+), with α = 1.632(2), β = 1.644(2), γ = 1.664(2) and 2Vmeas. = 78(2)° and 2Vcalc. = 76.3°. The unit-cell parameters in the C2/m space group are a = 9.6128(11), b = 18.073(2), c = 5.3073(6) Å, β = 102.825(2)° and V = 899.1(2) Å3 with Z = 2. The strongest ten reflections in the powder X-ray diffraction pattern [d (in Å), I, (hkl)] are: 2.728, 100, (151); 2.513, 77, ($\bar 2$02); 3.079, 62, (310); 8.321, 60, (110); 3.421, 54, (131); 2.603, 42, (061); 2.175, 42, (261); 3.253, 41, (240); 2.969, 40, (221); 9.036, 40, (020).
The phenotype and function of preterm infant monocytes: implications for susceptibility to infection
Authors: de Jong Emma , Strunk Tobias , Burgner David , Lavoie Pascal M , Currie Andrew 
Published: June 2017

Abstract
The extreme vulnerability of preterm infants to invasive microbial infections has been attributed to “immature” innate immune defenses. Monocytes are important innate immune sentinel cells critical in the defense against infection in blood. They achieve this via diverse mechanisms that include pathogen recognition receptor- and inflammasome-mediated detection of microbes, migration into infected tissues, and differentiation into Mϕs and dendritic cells, initiation of the inflammatory cascade by free radicals and cytokine/chemokine production, pathogen clearance by phagocytosis and intracellular killing, and the removal of apoptotic cells. Relatively little is known about these cells in preterm infants, especially about how their phenotype adapts to changes in the microbial environment during the immediate postnatal period. Overall, preterm monocytes exhibit attenuated proinflammatory cytokine responses following stimulation by whole bacterial or specific microbial components in vitro. These attenuated cytokine responses cannot be explained by a lack of intracellular signaling events downstream of pattern recognition receptors. This hyporesponsiveness also contrasts with mature, term-like phagocytosis capabilities detectable even in the most premature infant. Finally, human data on the effects of fetal chorioamnionitis on monocyte biology are incomplete and inconsistent. In this review, we present an integrated view of human studies focused on monocyte functions in preterm infants. We discuss how a developmental immaturity of these cells may contribute to preterm infants’ susceptibility to infections.
New horizons: Forensic mental health services for older people
Authors: Natarajan Muthusamy , Mulvana Sophie 
Published: June 2017

SummaryAlthough the older adult population makes up only a small percentage of mentally disordered offenders, there is a clear need for forensic mental health services for older people. However, these services to date have developedad hocand with no coordination. In this article we discuss the evolution, current provision, future direction and therapeutic implications of such services. Although the epidemiology, criminology and clinical characteristics of older people are sufficiently different from those of younger people to warrant such service specificity, we suggest that the provision of care should be geared to services based on older people's multiple and complex needs, rather than on arbitrary age cut-offs.Learning Objectives• Be able to use an understanding of epidemiology, criminology and clinical characteristics of older people in the provision of forensic mental healthcare• Understand the forensic mental healthcare needs of older people• Be able to develop forensic mental health services for older people
Controversial treatments in psychiatry
Authors: Luty Jason 
Published: June 2017

SummaryPsychiatry uses some of the most controversial treatments in medicine. This may be partly because several are administered under coercion and opposed to the patient's expressed will, under the protection of the relevant mental health legislation. Electroconvulsive therapy (ECT) is perhaps the archetypal controversial treatment; although it is considered to be effective, the research supporting it is much less impressive than one would expect. The prescription of stimulant drugs for childhood attention-deficit hyperactivity disorder (ADHD) and substitution therapy (such as methadone maintenance) in addictions treatment remain topical and appear to be subject to political interference. ‘Treatment’ for homosexuality and psychosurgery were common in the past but are now rare. These issues are discussed to give insight into how once common controversial treatments can decline and become obsolete. However, seclusion and covert medication remain in practice and are highly scrutinised.Learning Objectives• Recognise that many controversial treatments, such as psychosurgery, have been superseded by psychotropic drugs used since the 1950s• Be aware of the limitations of evidence supporting controversial treatments, such as stimulants for childhood ADHD and ECT for depression in adults• Be aware that controversial treatments are highly emotive and may be viewed negatively by the public or politicians, despite evidence for their safety and effectiveness
Going beyond ‘good enough’ teaching in psychiatric training
Authors: Sarkar S. Neil , Young Allan H. 
Published: June 2017

SummaryPsychiatrists have a role in teaching all medical undergraduates and foundation year doctors generic skills to become good doctors, but they also have to appeal to and nurture the interests of future psychiatrists by maintaining core psychiatric skills/knowledge in their teaching. They must tackle poor recruitment to psychiatry and stigma against both the profession and its patients. Medical students and junior doctors tend to be strategic learners, motivated by passing assessments, and psychiatrists are often guilty of gearing their teaching only to this. This article explores the assessment process itself and ways to optimise it, and presents a case for going beyond teaching how to pass exams in order to address wider issues relating to psychiatry.Learning Objectives• Identify the extent of current problems of recruitment and stigma in psychiatry and recognise the role of psychiatrists in addressing these through teaching• Be aware of the impact and limitations of tailoring teaching to assessment only• Identify ways of improving your own practice, taking account of the literature and strategies suggested
Therapeutic risk-taking: A justifiable choice
Authors: Felton Anne , Wright Nicola , Stacey Gemma 
Published: June 2017

SummaryTaking risks is a fundamental part of the human experience that supports personal growth. Therapeutic risk-taking enables patients to make decisions about their level of safety and to pursue goals. Promoting therapeutic risk-taking can be complex. Professionals can experience tension striving for a balance between the interests of the individual and societal pressures to control risk. This article examines therapeutic risk-taking, recognising the challenges to supporting it in practice and debating how they may be overcome.Learning Objectives• Be able to explain what therapeutic risk-taking is and discuss its application to psychiatric practice• Understand the factors that challenge and enable therapeutic risk-taking in psychiatric practice• Describe the association between therapeutic risk-taking and recovery
Psychiatry in the Foundation Programme: An overview for supervisors
Authors: Perry Jennifer , Ryland Howard , Thoms Lesley , Boyle Ann 
Published: June 2017

SummaryHealth Education England's 2014 reportBroadening the Foundation Programmehas led to a rapid increase in the number of psychiatry placements for foundation doctors. This will have implications for existing psychiatrists in that they will start to teach, train and supervise foundation doctors. This article outlines how to develop high-quality foundation posts and how to support doctors in meeting the foundation curriculum competencies, which include experience of working in multidisciplinary teams and developing communication skills. The knowledge and skills gained in psychiatry placements will be valuable to all doctors, no matter what their future career intentions.Learning Objectives• Describe the recent changes to the Foundation Programme in psychiatry and how they will affect supervisors• Learn how high-quality placements for foundation doctors can be developed• Recognise how foundation doctors can be supported to achieve the generic and mental health-specific competencies of the foundation curriculum in psychiatry placements