bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Echinocandin Resistance in Candida tropicalis following Short-Term Exposure to Caspofungin for Empiric Therapy
Authors: Khan Ziauddin , Ahmad Suhail , Mokaddas Eiman , Meis Jacques F. , Joseph Leena , Abdullah Aneesa , Vayalil Sandhya 
Published: February 2018

ABSTRACT

Isolation of two echinocandin-resistant
Candida tropicalis
strains from endotracheal secretions of a patient following short-term exposure to caspofungin is described. Both strains exhibited resistance to echinocandins by Etest and reference broth microdilution, showing a homozygous S645P mutation within the hot spot 1 (HS-1) region of
FKS1
and belonging to a unique multilocus sequence type. Other
C. tropicalis
isolates collected from patients in the same intensive care unit within a 60-day period were susceptible to echinocandins and contained wild-type
FKS1
sequences.
In Vivo
Transfer and Microevolution of Avian Native IncA/C
2
bla
NDM-1
-Carrying Plasmid pRH-1238 during a Broiler Chicken Infection Study
Authors: Hadziabdic Sead , Fischer Jennie , Malorny Burkhard , Borowiak Maria , Guerra Beatriz , Kaesbohrer Annemarie , Gonzalez-Zorn Bruno , Szabo Istvan 
Published: February 2018

ABSTRACT

The emergence and spread of carbapenemase-producing
Enterobacteriaceae
(CPE) in wildlife and livestock animals pose an important safety concern for public health. With our
in vivo
broiler chicken infection study, we investigated the transfer and experimental microevolution of the
bla
NDM-1
-carrying IncA/C
2
plasmid (pRH-1238) introduced by avian native
Salmonella enterica
subsp.
enterica
serovar Corvallis without inducing antibiotic selection pressure. We evaluated the dependency of the time point of inoculation on donor (
S
. Corvallis [12-SA01738]) and plasmid-free
Salmonella
recipient [
d
-tartrate-fermenting (
d
-Ta
+
)
S
. Paratyphi B (13-SA01617), referred to here as
S
. Paratyphi B (
d
-Ta
+
)] excretion by quantifying their excretion dynamics. Using plasmid profiling by S1 nuclease-restricted pulsed-field gel electrophoresis, we gained insight into the variability of the native plasmid content among
S
. Corvallis reisolates as well as plasmid acquisition in
S
. Paratyphi B (
d
-Ta
+
) and the enterobacterial gut microflora. Whole-genome sequencing enabled us to gain an in-depth insight into the microevolution of plasmid pRH-1238 in
S
. Corvallis and enterobacterial recipient isolates. Our study revealed that the fecal excretion of avian native carbapenemase-producing
S
. Corvallis is significantly higher than that of
S
. Paratyphi (
d
-Ta
+
) and is not hampered by
S
. Paratyphi (
d
-Ta
+
). Acquisition of pRH-1238 in other
Enterobacteriaceae
and several events of plasmid pRH-1238 transfer to different
Escherichia coli
sequence types and
Klebsiella pneumoniae
demonstrated an interspecies broad host range. Regardless of the microevolutionary structural deletions in pRH-1238, the single carbapenem resistance marker
bla
NDM-1
was maintained on pRH-1238 throughout the trial. Furthermore, we showed the importance of the gut
E. coli
population as a vector of pRH-1238. In a potential scenario of the introduction of NDM-1-producing
S
. Corvallis into a broiler flock, the pRH-1238 plasmid could persist and spread to a broad host range even in the absence of antibiotic pressure.
In VitroMeasles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells
Authors: Laksono Brigitta M. , Grosserichter-Wagener Christina , de Vries Rory D. , Langeveld Simone A. G. , Brem Maarten D. , van Dongen Jacques J. M. , Katsikis Peter D. , Koopmans Marion P. G. , van Zelm Menno C. , de Swart Rik L. 
Published: February 2018

ABSTRACTMeasles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils toin vitroMV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (TH) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that TH1TH17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen-experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression.IMPORTANCEMeasles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cellsin vivo. However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness toin vitroMV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance.
CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function
Authors: Washington Shannan D. , Musarrat Farhana , Ertel Monica K. , Backes Gregory L. , Neumann Donna M. 
Published: February 2018

ABSTRACT
There are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV-1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner.

IMPORTANCE
The role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three-dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV-1.
Expanding Primary Metabolism Helps Generate the Metabolic Robustness To Facilitate Antibiotic Biosynthesis in
Streptomyces
Authors: Schniete Jana K. , Cruz-Morales Pablo , Selem-Mojica Nelly , Fernández-Martínez Lorena T. , Hunter Iain S. , Barona-Gómez Francisco , Hoskisson Paul A. 
Published: February 2018

ABSTRACT

The expansion of the genetic repertoire of an organism by gene duplication or horizontal gene transfer (HGT) can aid adaptation.
Streptomyces
bacteria are prolific producers of bioactive specialized metabolites that have adaptive functions in nature and have found extensive utility in human medicine. While the biosynthesis of these specialized metabolites is directed by dedicated biosynthetic gene clusters, little attention has been focused on how these organisms have evolved robustness in their genomes to facilitate the metabolic plasticity required to provide chemical precursors for biosynthesis during the complex metabolic transitions from vegetative growth to specialized metabolite production and sporulation. Here, we examine genetic redundancy in actinobacteria and show that specialized metabolite-producing bacterial families exhibit gene family expansion in primary metabolism. Focusing on a gene duplication event, we show that the two pyruvate kinases in the genome of
Streptomyces coelicolor
arose by an ancient duplication event and that each has evolved altered enzymatic kinetics, with Pyk1 having a 20-fold-higher
k
cat
than Pyk2 (4,703 s
−1
compared to 215 s
−1
, respectively), and yet both are constitutively expressed. The pyruvate kinase mutants were also found to be compromised in terms of fitness compared to wild-type
Streptomyces
. These data suggest that expanding gene families can help maintain cell functionality during metabolic perturbation such as nutrient limitation and/or specialized metabolite production.

IMPORTANCE
The rise of antimicrobial-resistant infections has prompted a resurgence in interest in understanding the production of specialized metabolites, such as antibiotics, by
Streptomyces
. The presence of multiple genes encoding the same enzymatic function is an aspect of
Streptomyces
biology that has received little attention; however, understanding how the metabolic expansion influences these organisms can help enhance production of clinically useful molecules. Here, we show that expanding the number of pyruvate kinases enables metabolic adaptation, increases strain fitness, and represents an excellent target for metabolic engineering of industrial specialized metabolite-producing bacteria and the activation of cryptic specialized metabolites.
CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection
Authors: Lee Jennifer S. , Raja Priya , Pan Dongli , Pesola Jean M. , Coen Donald M. , Knipe David M. 
Published: February 2018

ABSTRACT

Herpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC-binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (
CTRL2
) within the latency-associated transcript (
LAT
) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over the
LAT
promoter and intron. We therefore propose that CTCF binding at the
CTRL2
sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons. The mechanism by which HSV-1 transitions from the lytic to latent infection program is largely unknown; however, HSV-1 is able to coopt cellular silencing mechanisms to facilitate the suppression of lytic gene expression. Here, we demonstrate that the cellular CCCTC-binding factor (CTCF)-binding site within the latency associated transcript (
LAT
) region is critical for the maintenance of a specific local chromatin structure. Additionally, loss of CTCF binding has detrimental effects on the ability to reactivate from latent infection. These results argue that CTCF plays a critical role in epigenetic regulation of viral gene expression to establish and/or maintain a form of latent infection that can reactivate efficiently.
Exploring the Antimicrobial Action of Quaternary Amines against
Acinetobacter baumannii
Authors: Knauf Gregory A. , Cunningham Ashley L. , Kazi Misha I. , Riddington Ian M. , Crofts Alexander A. , Cattoir Vincent , Trent M. Stephen , Davies Bryan W. 
Published: February 2018

ABSTRACT

Quaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. While they are known for their membrane-damaging properties, QAC action has been suggested to extend beyond the surface to intracellular targets. Here we characterize the range of action of the QAC biocide benzalkonium chloride (BZK) against the bacterial pathogen
Acinetobacter baumannii
. At high concentrations, BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. Resistance to BZK is found to develop through ribosomal protein mutations that protect
A. baumannii
against BZK-induced protein aggregation. The multifunctional impact of BZK led us to discover that alternative QAC structures, with low human toxicity, retain potent action against multidrug-resistant
A. baumannii
,
Staphylococcus aureus
, and
Clostridium difficile
and present opportunities for their development as antibiotics.

IMPORTANCE
Quaternary amine compounds (QACs) are widely used to prevent the spread of bacterial pathogens, but our understanding of their mode of action is incomplete. Here we describe disruption of bacterial proteostasis as an unrecognized action of QAC antimicrobial action and uncover the potential of diverse QAC structures to act as multitarget antibiotics.
Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study
Authors: Kinnear Deborah , Morrison Jill , Allan Linda , Henderson Angela , Smiley Elita , Cooper Sally-Ann 
Published: February 2018

ObjectivesTo investigate the prevalence of multimorbidity in adults with intellectual disabilities with and without Down syndrome.DesignLarge, population-based cross-sectional study.SettingThe geographical area of one Health Board, Scotland.ParticipantsAll adults (aged 16+ years) known to general practitioners to have intellectual disabilities and adults receiving services provided or paid by intellectual disabilities health or social work services. 1023/1562 potential participants took part (65.5%); 562 (54.9%) men and 461 (45.1%) women, aged 43.9 years (16–83 years). 186 had Down syndrome and 837 did not.Main outcome measuresThe prevalence of International Statistical Classification of Diseases, 10th revision, physical health conditions and multimorbidity detected at a comprehensive health assessment.ResultsThe mean number of physical health conditions/participant was 11.04, and 98.7% had multimorbidity. The most prevalent conditions are painful and/or disabling and, in some cases, life threatening. The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders. The pattern of multimorbidity differs from that seen in the general population and is spread across the entire adult life course. The extent of multimorbidity in the adults with Down syndrome was similar to that of the adults without Down syndrome, while the prevalence of individual conditions differed.ConclusionsThis robustly designed study with a large population found an extremely high prevalence of multimorbidity in adults with intellectual disabilities across the entire adult life course. This increases complexity of medical management that secondary healthcare services and medical education are not yet geared towards, as these tend to focus on single conditions. This is in addition to complexity due to limitations in communication and understanding. As the physical conditions within their multimorbidity also differ from that seen in the older general population, urgent attention is needed to develop the care pathways and guidelines that are required to inform and so improve their healthcare.
Graphene–magnesium nanocomposite: An advanced material for aerospace application
Authors: Das D. K. , Sarkar Jit 
Published: February 2018

This work focuses on the analytical study of mechanical and thermal properties of a nanocomposite that can be obtained by reinforcing graphene in magnesium. The estimated mechanical and thermal properties of graphene–magnesium nanocomposite are much higher than magnesium and other existing alloys used in aerospace materials. We also altered the weight percentage of graphene in the composite and observed mechanical and thermal properties of the composite increase with increase in concentration of graphene reinforcement. The Young’s modulus and thermal conductivity of graphene–magnesium nanocomposite are found to be [Formula: see text][Formula: see text]165 GPa and [Formula: see text][Formula: see text]175 W/mK, respectively. Nanocomposite material with desired properties for targeted applications can also be designed by our analytical modeling technique. This graphene–magnesium nanocomposite can be used for designing improved aerospace structure systems with enhanced properties.
Formations defined by Doerk–Hawkes operation
Authors: Guo W. , Vorob’ev S. N. 
Published: February 2018

For a nonempty formation [Formula: see text], let [Formula: see text] be the least formation containing [Formula: see text] such that [Formula: see text] for all groups [Formula: see text] and [Formula: see text]. If [Formula: see text], then [Formula: see text] is said to be a DH-formation. A function [Formula: see text]: [Formula: see text] is called a formation function and [Formula: see text] is called the support of [Formula: see text]. If [Formula: see text] and [Formula: see text], where [Formula: see text], then [Formula: see text] is said to be a local formation defined by [Formula: see text]. If [Formula: see text] for all [Formula: see text], then [Formula: see text] is called a DH-function. In this paper, we prove that every local formation can be defined by a DH-function [Formula: see text] and each value of the DH-function [Formula: see text] is a DH-formation. Besides, we also give the necessary and sufficient condition under which a local Fitting class [Formula: see text] is a DH-formation.
CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes
Authors: Jung Younghun , Cackowski Frank C. , Yumoto Kenji , Decker Ann M. , Wang Jingcheng , Kim Jin Koo , Lee Eunsohl , Wang Yugang , Chung Jae-Seung , Gursky Amy M. , Krebsbach Paul H. , Pienta Kenneth J. , Morgan Todd M. , Taichman Russell S. 
Published: February 2018

Abstract
There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo. Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.
Significance: Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026–39. ©2018 AACR.
Moral Perception and the Reliability Challenge
Authors: Faraci David 
Published: February 2018

Given a traditional intuitionist moral epistemology, it is notoriously difficult for moral realists to explain the reliability of our moral beliefs. This has led some to go looking for an alternative to intuitionism. Perception is an obvious contender. I previously argued that this is a dead end, that all moral perception is dependent on a priori moral knowledge. This suggests that perceptualism merely moves the bump in the rug where the reliability challenge is concerned. Preston Werner responds that my account rests on an overly intellectualized model of perception. In this paper, I argue that though Werner may well be correct, my arguments, properly extended, still suggest that perceptualism leaves realists in no better position than intuitionism when it comes to the reliability challenge.
Satellite Investigation of the M2 Internal Tide in the Tasman Sea
Authors: Zhao Zhongxiang , Alford Matthew H. , Simmons Harper L. , Brazhnikov Dmitry , Pinkel Rob 
Published: February 2018

AbstractThe M2 internal tide in the Tasman Sea is investigated using sea surface height measurements made by multiple altimeter missions from 1992 to 2012. Internal tidal waves are extracted by two-dimensional plane wave fits in 180 km by 180 km windows. The results show that the Macquarie Ridge radiates three internal tidal beams into the Tasman Sea. The northern and southern beams propagate respectively into the East Australian Current and the Antarctic Circumpolar Current and become undetectable to satellite altimetry. The central beam propagates across the Tasman Sea, impinges on the Tasmanian continental slope, and partially reflects. The observed propagation speeds agree well with theoretical values determined from climatological ocean stratification. Both the northern and central beams refract about 15° toward the equator because of the beta effect. Following a concave submarine ridge in the source region, the central beam first converges around 45.5°S, 155.5°E and then diverges beyond the focal region. The satellite results reveal two reflected internal tidal beams off the Tasmanian slope, consistent with previous numerical simulations and glider measurements. The total energy flux from the Macquarie Ridge into the Tasman Sea is about 2.2 GW, of which about half is contributed by the central beam. The central beam loses little energy in its first 1000-km propagation, for which the likely reasons include flat bottom topography and weak mesoscale eddies.