bluuebunny/crossref_metadata_2025 huggingface dataset:
The Rim Pathway Mediates Antifungal Tolerance in Candida albicans through Newly Identified Rim101 Transcriptional Targets, Including Hsp90 and Ipt1
Authors: Garnaud Cécile , García-Oliver Encar , Wang Yan , Maubon Danièle , Bailly Sébastien , Despinasse Quentin , Champleboux Morgane , Govin Jérôme , Cornet Muriel
Published: January 2018

Invasive candidiasis (IC) is a major cause of morbidity and mortality despite antifungal treatment. Azoles and echinocandins are used as first-line therapies for IC. However, their efficacy is limited by yeast tolerance and the emergence of acquired resistance. Tolerance is a reversible stage created due to the yeast's capacity to counter antifungal drug exposure, leading to persistent growth. For
Candida albicans
, multiple stress signaling pathways have been shown to contribute to this adaptation. Among them, the pH-responsive Rim pathway, through its transcription factor Rim101p, was shown to mediate azole and echinocandin tolerance. The Rim pathway is fungus specific, is conserved among the members of the fungal kingdom, and plays a key role in pathogenesis and virulence. The present study aimed at confirming the role of Rim101p and investigating the implication of the other Rim proteins in antifungal tolerance in
C. albicans
, as well as the mechanisms underlying it. Time-kill curve experiments and colony formation tests showed that genetic inhibition of all the Rim factors enhances echinocandin and azole antifungal activity. Through RNA sequencing analysis of a
rim101
−/−
mutant, a strain constitutively overexpressing
RIM101
, and control strains, we discovered novel Rim-dependent genes involved in tolerance, including
HSP90
, encoding a major molecular chaperone, and
IPT1
, involved in sphingolipid biosynthesis. Rim mutants were also hypersensitive to pharmacological inhibition of Hsp90. Taken together, these data suggest that Rim101 acts upstream of Hsp90 and that targeting the Rim pathway in combination with existing antifungal drugs may represent a promising antifungal strategy to indirectly but specifically target Hsp90 in yeasts.
Mutant Prevention Concentration and Mutant Selection Window of Micafungin and Anidulafungin in Clinical Candida glabrata Isolates
Authors: Bordallo-Cardona María Ángeles , Marcos-Zambrano Laura Judith , Sánchez-Carrillo Carlos , de la Pedrosa Elia Gómez G. , Cantón Rafael , Bouza Emilio , Escribano Pilar , Guinea Jesús
Published: January 2018

We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat
Candida glabrata
. We also determine the mutation frequency. We studied 20 echinocandin-susceptible, fluconazole-intermediate, and
FKS
wild-type
C. glabrata
isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/liter were selected for antifungal susceptibility testing. The
FKS
genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, MSW, and mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence (
Galleria mellonella
model) of the resulting individual
FKS
mutant colonies were studied. For micafungin and anidulafungin, we found similar results for the MPC (0.06 to 2 mg/liter and 0.25 to 2 mg/liter, respectively), MSW (0.015 to 2 mg/liter for both echinocandins), and mutation frequency (3.7 × 10
−8
and 2.8 × 10
−8
, respectively). A total of 12 isolates were able to grow at 1 mg/liter on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however,
FKS2
mutations (ΔF658, S663P, W715L, and E655A) were observed only in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual
FKS2
mutant colonies. Echinocandin concentrations lower than 2 mg/liter can lead to selection of resistance mutations in
C. glabrata
isolates
in vitro
.
Transcriptional Responses of Pseudomonas aeruginosa to Potable Water and Freshwater
Authors: English Erika L. , Schutz Kristin C. , Willsey Graham G. , Wargo Matthew J.
Published: January 2018

Many
Pseudomonas aeruginosa
infections are derived from residential, recreational, or surface water sources; thus, these environments represent an important preinfection niche. To better understand
P. aeruginosa
biology in these environments, we quantified transcriptional changes by microarray after exposure to diluted LB, diluted R2B, potable tap water, and freshwater from a eutrophic pond. Quantitative reverse transcription-PCR (qRT-PCR) confirmed the conservation of these responses in other water sources, and competition experiments were used to test the importance of three implicated metabolic pathways. The global transcriptional responses in potable water and freshwater showed strong induction of genes involved in metabolism of the head groups and acyl tails of phospholipids, as well as nucleotide metabolism, with commensurate decreased transcript expression of genes encoding their synthetic pathways. These data suggest that phospholipids and nucleotides are part of the nutritional milieu of these two environments. A unique response in municipal-delivered potable water was to the metals in the piping system, particularly copper. To identify potential nutrient sources used by
P. aeruginosa
in these environments, we used competition assays between the wild-type and deletion mutant strains in three pathways induced under these conditions. For phospholipid head-group metabolism, ethanolamine utilization (
eutB
) was important for competition in potable water, while choline oxidation (
betBA
) was important for competition in freshwater. Nucleotide utilization, particularly pyrimidine metabolism (
dht
), showed a trend toward importance in freshwater but was not statistically significant. These findings provide new insights into the
P. aeruginosa
response to potable water and freshwater and led to the identification of potentially important nutrient sources in these environments.

IMPORTANCE
Much of our knowledge about
Pseudomonas aeruginosa
comes from the infection niche, and much less is known about its lifestyle in the environment.
P. aeruginosa
is an adaptable bacterium capable of growing in many environments but is particularly common in potable water systems and freshwater. We used the transcriptional responses of
P. aeruginosa
to these environments to identify important nutrient sources specific to either of these two environments. Additionally, these environments could provide experimental situations to understand gene function for the large number of transcripts with unknown functions induced under these conditions.
A Cytoplasmic Antiholin Is Embedded In Frame with the Holin in a Lactobacillus fermentum Bacteriophage
Authors: Guo Tingting , Xin Yongping , Zhang Chenchen , Kong Jian
Published: January 2018

In double-stranded DNA bacteriophages, infection cycles are ended by host cell lysis through the action of phage-encoded endolysins and holins. The precise timing of lysis is regulated by the holin inhibitors, named antiholins. Sequence analysis has revealed that holins with a single transmembrane domain (TMD) are prevalent in
Lactobacillus
bacteriophages. A temperate bacteriophage of
Lactobacillus fermentum
, ϕPYB5, has a two-component lysis cassette containing endolysin Lyb5 and holin Hyb5. The
hyb5
gene is 465 bp long, encoding 154 amino acid residues with an N-terminal TMD and a large cytoplasmic C-terminal domain. However, the N terminus contains no dual-start motif, suggesting that Hyb5 oligomerization could be inhibited by a specific antiholin. Two internal open reading frames in
hyb5
,
hyb5
157–465
and
hyb5
209–328
, were identified as genes encoding putative antiholins for Hyb5 and were coexpressed in
trans
with
lyb5-hyb5
in
Escherichia coli
. Surprisingly, host cell lysis was delayed by Hyb5
157–465
but accelerated by abolishment of the translation initiation site of this protein, indicating that Hyb5
157–465
acts as an antiholin to holin Hyb5. Moreover, deletion of 45 amino acid residues at the C terminus of Hyb5 resulted in early cell lysis, even in the presence of Hyb5
157–465
, implying that the interaction between Hyb5
157–465
and Hyb5 occurs at the C terminus of the holin.
In vivo
and
in vitro
, Hyb5
157–465
and Hyb5 were detected in the cytoplasmic and membrane fractions, respectively, and pulldown assays confirmed direct interaction between Hyb5
157–465
and Hyb5. All the results suggest that Hyb5
157–465
is an antiholin of Hyb5 that is involved in lysis timing.

IMPORTANCE
Phage-encoded holins are considered to be the “molecular clock” of phage infection cycles. The interaction between a holin and its inhibitor antiholin precisely regulates the timing of lysis of the host cells. As a prominent biological group in dairy processes, phages of lactic acid bacteria (LAB) have been extensively genome sequenced. However, little is known about the antiholins of LAB phage holins and the holin-antiholin interactions. In this work, we identified an in-frame antiholin against the class III holin of
Lactobacillus fermentum
phage ϕPYB5, Hyb5, and demonstrated its interaction with the cognate holin, which occurred in the bacterial cytoplasm.
Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection
Authors: Steiner Donald J. , Furuya Yoichi , Metzger Dennis W.
Published: January 2018

Opsonizing antibody is a critical component of the host protective immune response against many respiratory pathogens. However, the role of antibodies in protection against pulmonary infection with highly virulentFrancisella tularensisstrain SchuS4 is unclear, and the mechanism that allowsF. tularensisto evade antibody-mediated bacterial clearance is not fully understood. We have now found that depletion of alveolar macrophages reveals an otherwise cryptic protective effect of opsonizing antibody. While antibody opsonization alone failed to confer any survival benefit against SchuS4 lung infection, significant protection was observed when mice were depleted of alveolar macrophages prior to infection. Blood immune signature analyses and bacterial burden measurements indicated that the treatment regimen blocked establishment of productive, systemic infection. In addition, protection was found to be dependent upon neutrophils. The results show for the first time a protective effect of opsonizing antibodies against highly virulentF. tularensisSchuS4 pulmonary infection through depletion of alveolar macrophages, the primary bacterial reservoir, and prevention of systemic dissemination. These findings have important implications for the potential use of therapeutic antibodies against intracellular pathogens that may escape clearance by residing within mucosal macrophages.
Multicenter Evaluation of the Accelerate PhenoTest BC Kit for Rapid Identification and Phenotypic Antimicrobial Susceptibility Testing Using Morphokinetic Cellular Analysis
Authors: Pancholi Preeti , Carroll Karen C. , Buchan Blake W. , Chan Raymond C. , Dhiman Neelam , Ford Bradley , Granato Paul A. , Harrington Amanda T. , Hernandez Diana R. , Humphries Romney M. , Jindra Matthew R. , Ledeboer Nathan A. , Miller Shelley A. , Mochon A. Brian , Morgan Margie A. , Patel Robin , Schreckenberger Paul C. , Stamper Paul D. , Simner Patricia J. , Tucci Nancy E. , Zimmerman Cynthia , Wolk Donna M.
Published: January 2018

We describe results from a multicenter study evaluating the Accelerate Pheno system, a first of its kind diagnostic system that rapidly identifies common bloodstream pathogens from positive blood cultures within 90 min and determines bacterial phenotypic antimicrobial susceptibility testing (AST) results within ∼7 h. A combination of fresh clinical and seeded blood cultures were tested, and results from the Accelerate Pheno system were compared to Vitek 2 results for identification (ID) and broth microdilution or disk diffusion for AST. The Accelerate Pheno system accurately identified 14 common bacterial pathogens and two
Candida
spp. with sensitivities ranging from 94.6 to 100%. Of fresh positive blood cultures, 89% received a monomicrobial call with a positive predictive value of 97.3%. Six common Gram-positive cocci were evaluated for ID. Five were tested against eight antibiotics, two resistance phenotypes (methicillin-resistant
Staphylococcus aureus
and
Staphylococcus
spp. [MRSA/MRS]), and inducible clindamycin resistance (MLSb). From the 4,142 AST results, the overall essential agreement (EA) and categorical agreement (CA) were 97.6% and 97.9%, respectively. Overall very major error (VME), major error (ME), and minor error (mE) rates were 1.0%, 0.7%, and 1.3%, respectively. Eight species of Gram-negative rods were evaluated against 15 antibiotics. From the 6,331 AST results, overall EA and CA were 95.4% and 94.3%, respectively. Overall VME, ME, and mE rates were 0.5%, 0.9%, and 4.8%, respectively. The Accelerate Pheno system has the unique ability to identify and provide phenotypic MIC and categorical AST results in a few hours directly from positive blood culture bottles and support accurate antimicrobial adjustment.
Comparison of Four Serological Methods and Two Reverse Transcription-PCR Assays for Diagnosis and Surveillance of Zika Virus Infection
Authors: Balmaseda Angel , Zambrana José Victor , Collado Damaris , García Nadezna , Saborío Saira , Elizondo Douglas , Mercado Juan Carlos , Gonzalez Karla , Cerpas Cristhiam , Nuñez Andrea , Corti Davide , Waggoner Jesse J. , Kuan Guillermina , Burger-Calderon Raquel , Harris Eva
Published: January 2018

Zika virus (ZIKV) is a mosquito-borne flavivirus that is responsible for recent explosive epidemics in the Americas. Notably, ZIKV infection during pregnancy has been found to cause congenital birth defects, including microcephaly, and ZIKV has been associated with Guillain-Barré syndrome in adults. Diagnosis and surveillance of Zika in the Americas have been challenging due to similar clinical manifestations and extensive antibody cross-reactivity with endemic flaviviral diseases, such as dengue. We evaluated four serological and two reverse transcription-PCR (RT-PCR) methods in acute-phase (mean day, 1.8), early-convalescent-phase (mean day, 16.7), and late-convalescent-phase (mean, ~7 months) samples from the same individuals in a long-term pediatric cohort study in Nicaragua. Well-characterized samples from 301 cases of Zika, dengue, or non-Zika, nondengue febrile illnesses were tested. Compared to a composite reference, an in-house IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) and the NIAID-Biodefense and Emerging Infections (BEI) MAC-ELISA measuring IgM yielded sensitivities of 94.5% and 70.1% and specificities of 85.6% and 82.8%, respectively. The NS1 blockade-of-binding ELISA measuring anti-ZIKV NS1 antibody levels yielded sensitivities of 85.0% and 96.5% and specificities of 91.4% and 92.6% at early and late convalescence, respectively. An inhibition ELISA detecting total anti-ZIKV antibodies had sensitivity and specificity values of 68.3% and 58.3% for diagnosis and 94.0% and 98.6% for measuring annual infection incidence. Finally, the ZCD and Trioplex real-time RT-PCR assays detecting Zika, chikungunya, and dengue viruses both yielded a sensitivity of 96.1% and specificity of 100%. Together, these assays resolve the urgent need for diagnostic and surveillance tools for countries affected by Zika virus infections.
HLA Class I Downregulation by HIV-1 Variants from Subtype C Transmission Pairs
Authors: Ende Zachary , Deymier Martin J. , Claiborne Daniel T. , Prince Jessica L. , Mónaco Daniela C. , Kilembe William , Allen Susan A. , Hunter Eric
Published: January 2018

HIV-1 downregulates human leukocyte antigen A (HLA-A) and HLA-B from the surface of infected cells primarily to evade CD8 T cell recognition. HLA-C was thought to remain on the cell surface and bind inhibitory killer immunoglobulin-like receptors, preventing natural killer (NK) cell-mediated suppression. However, a recent study found HIV-1 primary viruses have the capacity to downregulate HLA-C. The goal of this study was to assess the heterogeneity of HLA-A, HLA-B, and HLA-C downregulation among full-length primary viruses from six chronically infected and six newly infected individuals from transmission pairs and to determine whether transmitted/founder variants exhibit common HLA class I downregulation characteristics. We measured HLA-A, HLA-B, HLA-C, and total HLA class I downregulation by flow cytometry of primary CD4 T cells infected with 40 infectious molecular clones. Primary viruses mediated a range of HLA class I downregulation capacities (1.3- to 6.1-fold) which could differ significantly between transmission pairs. Downregulation of HLA-C surface expression on infected cells correlated with susceptibility to
in vitro
NK cell suppression of virus release. Despite this, transmitted/founder variants did not share a downregulation signature and instead were more similar to the quasispecies of matched donor partners. These data indicate that a range of viral abilities to downregulate HLA-A, HLA-B, and HLA-C exist within and between individuals that can have functional consequences on immune recognition.

IMPORTANCE
Subtype C HIV-1 is the predominant subtype involved in heterosexual transmission in sub-Saharan Africa. Authentic subtype C viruses that contain natural sequence variations throughout the genome often are not used in experimental systems due to technical constraints and sample availability. In this study, authentic full-length subtype C viruses, including transmitted/founder viruses, were examined for the ability to disrupt surface expression of HLA class I molecules, which are central to both adaptive and innate immune responses to viral infections. We found that the HLA class I downregulation capacity of primary viruses varied, and HLA-C downregulation capacity impacted viral suppression by natural killer cells. Transmitted viruses were not distinct in the capacity for HLA class I downregulation or natural killer cell evasion. These results enrich our understanding of the phenotypic variation existing among natural HIV-1 viruses and how that might impact the ability of the immune system to recognize infected cells in acute and chronic infection.
The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K (gK) Is Required for gB Binding to Akt, Release of Intracellular Calcium, and Fusion of the Viral Envelope with Plasma Membranes
Authors: Musarrat Farhana , Jambunathan Nithya , Rider Paul J. F. , Chouljenko V. N. , Kousoulas K. G.
Published: January 2018

Previously, we have shown that the amino terminus of glycoprotein K (gK) binds to the amino terminus of gB and that deletion of the amino-terminal 38 amino acids of gK prevents herpes simplex virus 1 (HSV-1) infection of mouse trigeminal ganglia after ocular infection and virus entry into neuronal axons. Recently, it has been shown that gB binds to Akt during virus entry and induces Akt phosphorylation and intracellular calcium release. Proximity ligation and two-way immunoprecipitation assays using monoclonal antibodies against gB and Akt-1 phosphorylated at S473 [Akt-1(S473)] confirmed that HSV-1(McKrae) gB interacted with Akt-1(S473) during virus entry into human neuroblastoma (SK-N-SH) cells and induced the release of intracellular calcium. In contrast, the gB specified by HSV-1(McKrae) gKΔ31-68, lacking the amino-terminal 38 amino acids of gK, failed to interact with Akt-1(S473) and induce intracellular calcium release. The Akt inhibitor miltefosine inhibited the entry of McKrae but not the gKΔ31-68 mutant into SK-N-SH cells. Importantly, the entry of the gKΔ31-68 mutant but not McKrae into SK-N-SH cells treated with the endocytosis inhibitors pitstop-2 and dynasore hydrate was significantly inhibited, indicating that McKrae gKΔ31-68 entered via endocytosis. These results suggest that the amino terminus of gK functions to regulate the fusion of the viral envelope with cellular plasma membranes.

IMPORTANCE
HSV-1 glycoprotein B (gB) functions in the fusion of the viral envelope with cellular membranes during virus entry. Herein, we show that a deletion in the amino terminus of glycoprotein K (gK) inhibits gB binding to Akt-1(S473), the release of intracellular calcium, and virus entry via fusion of the viral envelope with cellular plasma membranes.
Germ Line IgM Is Sufficient, but Not Required, for Antibody-Mediated Alphavirus Clearance from the Central Nervous System
Authors: Nilaratanakul Voraphoj , Chen Jie , Tran Oanh , Baxter Victoria K. , Troisi Elizabeth M. , Yeh Jane X. , Griffin Diane E.
Published: January 2018

Sindbis virus (SINV) infection of neurons in the brain and spinal cord in mice provides a model system for investigating recovery from encephalomyelitis and antibody-mediated clearance of virus from the central nervous system (CNS). To determine the roles of IgM and IgG in recovery, we compared the responses of immunoglobulin-deficient activation-induced adenosine deaminase-deficient (AID−/−), secretory IgM-deficient (sIgM−/−), and AID−/−sIgM−/−double-knockout (DKO) mice with those of wild-type (WT) C57BL/6 mice for disease, clearance of infectious virus and viral RNA from brain and spinal cord, antibody responses, and B cell infiltration into the CNS. Because AID is essential for immunoglobulin class switch recombination and somatic hypermutation, AID−/−mice produce only germ line IgM, while sIgM−/−mice secrete IgG but no IgM and DKO mice produce no secreted immunoglobulin. After intracerebral infection with the TE strain of SINV, most mice recovered. Development of neurologic disease occurred slightly later in sIgM−/−mice, but disease severity, weight loss, and survival were similar between the groups. AID−/−mice produced high levels of SINV-specific IgM, while sIgM−/−mice produced no IgM and high levels of IgG2a compared to WT mice. All mice cleared infectious virus from the spinal cord, but DKO mice failed to clear infectious virus from brain and had higher levels of viral RNA in the CNS late after infection. The numbers of infected cells and the amount of cell death in brain were comparable. We conclude that antibody is required and that either germ line IgM or IgG is sufficient for clearance of virus from the CNS.

IMPORTANCEMosquito-borne alphaviruses that infect neurons can cause fatal encephalomyelitis. Recovery requires a mechanism for the immune system to clear virus from infected neurons without harming the infected cells. Antiviral antibody has previously been shown to be a noncytolytic means for alphavirus clearance. Antibody-secreting cells enter the nervous system after infection and produce antiviral IgM before IgG. Clinical studies of human viral encephalomyelitis suggest that prompt production of IgM is associated with recovery, but it was not known whether IgM is effective for clearance. Our studies used mice deficient in production of IgM, IgG, or both to characterize the antibody necessary for alphavirus clearance. All mice developed similar signs of neurologic disease and recovered from infection. Antibody was necessary for virus clearance from the brain, and either early germ line IgM or IgG was sufficient. These studies support the clinical observation that prompt production of antiviral antibody is a determinant of outcome.
In Nature, There Is Only Diversity
Authors: McLaren Michael R. , Callahan Benjamin J.
Published: January 2018

Microbial ecology has been transformed by the advent of high-throughput marker gene and metagenomic sequencing methods. These tools provide expansive descriptions of microbial communities, but the descriptions are framed in terms of molecular objects, such as 97% ribosomal operational taxonomic units (OTUs), rather than biological objects, such as species. A recent study by A. B. Chase and colleagues (mBio 8:e01809-17, 2017,
https://doi.org/10.1128/mBio.01809-17
) explores the so-called microdiversity within the
Curtobacterium
OTU, the most abundant OTU in a leaf litter community. Perhaps unsurprisingly, they find that some important ecologic traits, such as drought response, are coherent within the OTU, but that others vary significantly. Here we discuss their findings in relation to the more general issue of how molecular tools can be effectively used to study microbial ecology. We specifically note the need for investigators to choose the right molecular methods for their biological problem, as nature does not respect the limitations and conventions associated with our methods.
Mitochondrial Voltage-Dependent Anion Channel Protein Por1 Positively Regulates the Nuclear Localization of Saccharomyces cerevisiae AMP-Activated Protein Kinase
Authors: Shevade Aishwarya , Strogolova Vera , Orlova Marianna , Yeo Chay Teng , Kuchin Sergei
Published: January 2018

AMP-activated protein kinases (AMPKs) sense energy limitation and regulate transcription and metabolism in eukaryotes from yeast to humans. In mammals, AMPK responds to increased AMP-to-ATP or ADP-to-ATP ratios and is implicated in diabetes, heart disease, and cancer. Mitochondria produce ATP and are generally thought to downregulate AMPK. Indeed, some antidiabetic drugs activate AMPK by affecting mitochondrial respiration. ATP release from mitochondria is mediated by evolutionarily conserved proteins known as voltage-dependent anion channels (VDACs). One would therefore expect VDACs to serve as negative regulators of AMPK. However, our experiments in yeast reveal the existence of an opposite relationship. We previously showed that
Saccharomyces cerevisiae
VDACs Por1 and Por2 positively regulate AMPK/Snf1 catalytic activation. Here, we show that Por1 also plays an important role in promoting AMPK/Snf1 nuclear localization. Our counterintuitive findings could inform research in areas ranging from diabetes to cancer to fungal pathogenesis.
The Small RNA ncS35 Regulates Growth in Burkholderia cenocepacia J2315
Authors: Kiekens Sanne , Sass Andrea , Van Nieuwerburgh Filip , Deforce Dieter , Coenye Tom
Published: January 2018

Small RNAs play an important role in the survival of bacteria in diverse environments. We explored the physiological role of ncS35, a small RNA expressed in
B. cenocepacia
J2315, an opportunistic pathogen in cystic fibrosis patients. In cystic fibrosis patients, infections can lead to “cepacia syndrome,” a rapidly progressing and often fatal pneumonia. Infections with
Burkholderia
spp. are difficult to threat with antibiotics because of their high intrinsic resistance and ability to form biofilms. We show that ncS35 attenuates the growth and reduces the metabolic rate of
B. cenocepacia
and influences biofilm structure. This demonstrates that as-yet-uncharacterized small RNAs with regulatory function can influence physiological traits of
B. cenocepacia
that are relevant for infection.
Improving Virus Taxonomy by Recontextualizing Sequence-Based Classification with Biologically Relevant Data: the Case of the
Alphacoronavirus 1
Species
Authors: Whittaker Gary R. , André Nicole M. , Millet Jean Kaoru
Published: January 2018

Our work focuses on improving the classification of the
Alphacoronavirus
genus. The
Alphacoronavirus 1
species groups viruses of veterinary importance that infect distinct mammalian hosts and includes canine and feline coronaviruses and transmissible gastroenteritis virus. It is the prototype species of the
Alphacoronavirus
genus; however, it encompasses biologically distinct viruses. To better characterize this prototypical species, we performed phylogenetic analyses based on the sequences of the spike protein, one of the main determinants of tropism and pathogenesis, and reveal the existence of two subgroups or clades that fit with previously established serotype demarcations. We propose a new clade designation to better classify
Alphacoronavirus 1
members.
Differential Ability of Pandemic and Seasonal H1N1 Influenza A Viruses To Alter the Function of Human Neutrophils
Authors: Malachowa Natalia , Freedman Brett , Sturdevant Daniel E. , Kobayashi Scott D. , Nair Vinod , Feldmann Friederike , Starr Tregei , Steele-Mortimer Olivia , Kash John C. , Taubenberger Jeffery K. , Feldmann Heinz , DeLeo Frank R.
Published: January 2018

A long-standing notion is that IAV inhibits normal neutrophil function and thereby predisposes individuals to secondary bacterial infections. Here we report that seasonal H1N1 IAV primes human neutrophils for enhanced killing ofStaphylococcus aureus. Moreover, we provide a comprehensive view of the changes in neutrophil gene expression during interaction with seasonal or pandemic IAV and report how these changes relate to functions such as bactericidal activity. This study expands our knowledge of IAV interactions with human neutrophils.
Geospatial analysis of Oklahoma (USA) earthquakes (2011–2016): Quantifying the limits of regional-scale earthquake mitigation measures
Authors: Pollyea Ryan M. , Mohammadi Neda , Taylor John E. , Chapman Martin C.
Published: January 2018

The annual earthquake rate in Oklahoma (United States) has increased dramatically in recent years, owing in large part to the rapid proliferation of salt-water disposal (SWD) wells associated with unconventional oil and gas recovery. This study presents a geospatial analysis of earthquake occurrence and SWD volume within a 68,420 km2 area in north-central Oklahoma between 2011 and 2016. Results indicate that (1) the annual geographic centroid of Arbuckle Group SWD well locations predicts the geographic centroid for M3.0+ earthquake occurrence within an ∼1σ radius of gyration when the well centroid is geometrically weighted by SWD volume; (2) between 2014 and 2016 Arbuckle SWD volume and earthquake occurrence are spatially cross-correlated to a length scale of 125 km; and (3) earthquake mitigation strategies implemented in late 2015 and 2016 are preferentially affecting the joint variability of SWD volume and small-magnitude earthquakes. These results suggest that current earthquake mitigation may require further volume reductions and/or greater areal extent to increase effectiveness.
Do less populous countries receive more development assistance for health per capita? Longitudinal evidence for 143 countries, 1990–2014
Authors: Martinsen Lene , Ottersen Trygve , Dieleman Joseph L , Hessel Philipp , Kinge Jonas Minet , Skirbekk Vegard
Published: January 2018

Background

Per capita allocation of overall development assistance has been shown to be biased towards countries with lower population size, meaning funders tend to provide proportionally less development assistance to countries with large populations. Individuals that happen to be part of large populations therefore tend to receive less assistance. However, no study has investigated whether this is also true regarding development assistance for health. We examined whether this so-called ‘small-country bias’ exists in the health aid sector.

Methods

We analysed the effect of a country’s population size on the receipt of development assistance for health per capita (in 2015 US$) among 143 countries over the period 1990–2014. Explanatory variables shown to be associated with receipt of development assistance for health were included: gross domestic product per capita, burden of disease, under-5 mortality rate, maternal mortality ratio, vaccination coverage (diphtheria, tetanus and pertussis) and fertility rate. We used the within-between regression analysis, popularised by Mundluck, as well as a number of robustness tests, including ordinary least squares, random-effects and fixed-effects regressions.

Results

Our results suggest there exists significant negative effect of population size on the amount of development assistance for health per capita countries received. According to the within-between estimator, a 1% larger population size is associated with a 0.4% lower per capita development assistance for health between countries (−0.37, 95% CI −0.45 to –0.28), and 2.3% lower per capita development assistance for health within countries (−2.29, 95% CI −3.86 to –0.72).

Conclusions

Our findings support the hypothesis that small-country bias exists within international health aid, as has been previously documented for aid in general. In a rapidly changing landscape of global health and development, the inclusion of population size in allocation decisions should be challenged on the basis of equitable access to healthcare and health aid effectiveness.
Inequalities in access to cardiac rehabilitation after an acute coronary syndrome: the EPiHeart cohort
Authors: Viana Marta , Borges Andreia , Araújo Carla , Rocha Afonso , Ribeiro Ana I , Laszczyńska Olga , Dias Paula , Maciel Maria J , Moreira Ilídio , Lunet Nuno , Azevedo Ana
Published: January 2018

Objectives

To estimate cardiac rehabilitation (CR) referral and participation rates among patients with acute coronary syndrome (ACS) and to identify their determinants, in two Portuguese regions.

Design

Prospective cohort study.

Setting

Patients consecutively admitted to the cardiology department of two hospitals, one in the district of Porto and one in the north-east region (NER) of Portugal, were enrolled in the EPIHeart cohort and then followed up for 6 months.

Participants

Between August 2013 and December 2014, 939 patients were included in the cohort, and 853 were re-evaluated at 6-month follow-up.

Outcome measures

Referral rate was defined as the proportion of eligible patients who were referred to a CR programme, whereas participation rate was defined as the proportion of eligible patients who completed a CR programme, as was recommended by their physicians.

Results

Patients referred were 32.3% and 10.7% of those eligible in Porto and NER, respectively. In both regions, referral to CR decreased with age and with longer travel times to CR centres and increased with education or social class. At follow-up, 128 patients from Porto (26.2% of those eligible and 81.0% of those referred) and 26 from NER (7.1% of those eligible and 66.7% of those referred) reported actually participating in a CR programme. In Porto, the main barriers to participation were the long time until a programme was available and lack of perceived benefit. Patients in NER identified distance to CR and costs as the main barriers.

Conclusions

CR remains clearly underused in Portugal, with major inequalities in access between regions. Achieving equitable and greater use of CR requires a multilevel approach addressing barriers related to healthcare system, providers and patients in order to improve provision, referral and participation.
Engaging families in the management of adolescent self-harm
Authors: Aggarwal Shilpa , Patton George
Published: January 2018

Adolescent self-harm is an emerging public health challenge. It is associated with later psychiatric and substance use disorders, unemployment and suicide. Family interventions have been effective in a range of adolescent mental health problems and for that reason were reviewed for their effectiveness in the management of adolescent self-harm. The search identified 10 randomised and 2 non-randomised controlled trial conducted in the high-income countries. For the most part the evidence is of low quality. The interventions were classified as brief single session, intermediate-level and intensive family interventions depending on the intensity and duration of treatment. Brief interventions did not reduce adolescent self-harm. Intermediate interventions such as the Resourceful Adolescent Parent Programme, Safe Alternatives for Teens and Youth Programme and attachment-based family treatment were effective in reducing suicidal behaviour (effect size 0.72), suicide attempts (P=0.01) and suicidal ideations (effect size 0.95), respectively in the short-term with an absence of long-term follow-up data. Intensive adolescent interventions such as dialectical behaviour therapy and mentalisation-based therapy reduced suicidal ideation (effect size 0.89) and self-harm (56% vs 83%, P=0.01), respectively. The persistence of effects beyond the intervention end point is not known in many interventions. Early involvement of the family, an evaluation of the risks at the end of an acute crisis episode and a stepped-care model taking into account level of suicide risk and resources available to an adolescent and her/his family are likely to promote better outcomes in adolescents who self-harm.
Gene editing as a promising approach for respiratory diseases
Authors: Bai Yichun , Liu Yang , Su Zhenlei , Ma Yana , Ren Chonghua , Zhao Runzhen , Ji Hong-Long
Published: January 2018

Respiratory diseases, which are leading causes of mortality and morbidity in the world, are dysfunctions of the nasopharynx, the trachea, the bronchus, the lung and the pleural cavity. Symptoms of chronic respiratory diseases, such as cough, sneezing and difficulty breathing, may seriously affect the productivity, sleep quality and physical and mental well-being of patients, and patients with acute respiratory diseases may have difficulty breathing, anoxia and even life-threatening respiratory failure. Respiratory diseases are generally heterogeneous, with multifaceted causes including smoking, ageing, air pollution, infection and gene mutations. Clinically, a single pulmonary disease can exhibit more than one phenotype or coexist with multiple organ disorders. To correct abnormal function or repair injured respiratory tissues, one of the most promising techniques is to correct mutated genes by gene editing, as some gene mutations have been clearly demonstrated to be associated with genetic or heterogeneous respiratory diseases. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems are three innovative gene editing technologies developed recently. In this short review, we have summarised the structure and operating principles of the ZFNs, TALENs and CRISPR/Cas9 systems and their preclinical and clinical applications in respiratory diseases.
In vitro measurement of the permeability of endovascular coils deployed in cerebral aneurysms
Authors: Sadasivan Chander , Swartwout Erica , Kappel Ari D , Woo Henry H , Fiorella David J , Lieber Barry B
Published: January 2018

Background and purpose

Aneurysm recurrence is the primary limitation of endovascular coiling treatment for cerebral aneurysms. Coiling is currently quantified by a volumetric porosity measure called packing density (pd). Blood flow through a coil mass depends on the permeability of the coil mass, and not just its pd. The permeability of coil masses has not yet been quantified. Here we measure coil permeability with a traditional falling-head permeameter modified to incorporate idealized aneurysms.

Methods

Silicone replicas of idealized aneurysms were manufactured with three different aneurysm diameters (4, 5, and 8 mm). Four different coil types (Codman Trufill Orbit, Covidien Axium, Microvention Microplex 10, and Penumbra 400) were deployed into the aneurysms with a target pd of 35%. Coiled replicas were installed on a falling-head permeameter setup and the time taken for a column of fluid above the aneurysm to drop a certain height was recorded. Permeability of the samples was calculated based on a simple modification of the traditional permeameter equation to incorporate a spherical aneurysm.

Results

The targeted 35% pd was achieved for all samples (35%±1%, P=0.91). Coil permeabilities were significantly different from each other (P<0.001) at constant pd. Microplex 10 coils had the lowest permeability of all coil types. Data suggest a trend of increasing permeability with thicker coil wire diameter (not statistically significant).

Conclusions

A simple in vitro setup was developed to measure the permeabilities of coil masses based on traditional permeametry. Coil permeability should be considered when evaluating the hemodynamic efficacy of coiling instead of just packing density. Coils made of thicker wires may be more permeable, and thus less effective, than coils made from thinner wires. Whether aneurysm recurrence is affected by coil wire diameter or permeability needs to be confirmed with clinical trials.
Growth of tree diameter and stem taper as affected by reduced leaf area on selected branch whorls
Authors: Kidombo Shannon D. , Dean Thomas J.
Published: January 2018

Leaf area on branches is linked to the stem through hydraulic and physiological functions. We investigated whether this relationship extends to growth responses by examining coordinated growth between leaf area on selected branches in the crown and growth in form and taper of the main stem. The growth impact of leaf area carried on individual branch whorls on the stem profile and internodes was tested using a series of defoliation and shade treatments. The data were analyzed using a linear mixed-effects model relating relative diameter to the relative height of the measured internodes. Defoliation and shade treatments on selected branches significantly affected the stem profile compared with untreated trees. The effect of reduced leaf area due to defoliation and shading of branch whorls was localized to internodes immediately below or above treated whorls. The stem profile showed curvature in the regions affected by reduced leaf area. These findings demonstrate that branch and stem growth is sensitive to minor changes in leaf area. The results emphasize the localized contribution of branches to stem growth.
Structural–Activity Relationship of Ginsenosides from Steamed Ginseng in the Treatment of Erectile Dysfunction
Authors: Ying Ang , Yu Qing-Tao , Guo Li , Zhang Wen-Song , Liu Jin-Feng , Li Yun , Song Hong , Li Ping , Qi Lian-Wen , Ge Ya-Zhong , Liu E-Hu , Liu Qun
Published: January 2018

Ginseng has been reported to have diverse pharmacological effects. One of the therapeutic claims for ginseng is to enhance sexual function. Ginsenosides are considered as the major active constituents. A steaming process can alter the ginsenoside profile of ginseng products. The structure–function relationship of ginsenosides in the treatment of erectile dysfunction (ED) has not been investigated yet. In this work, 15 different processed ginsengs are produced by steaming, and 13 major ginsensosides are quantified by liquid chromatography with UV detection, including Rg1, Re, Rf, Rb1, Rc, Rb2, Rf, Rk3, Rh4, 20S-Rg3, 20R-Rg3, Rk1, and Rg5. Their anti-ED activities are screened using hydrocortisone-induced mice model (Kidney Yang Deficiency Syndrome in Chinese Medicine) and primary corpus cavernosum smooth muscle cells (CCSMCs). A processed ginseng with steaming treatment at 120[Formula: see text]C for 4[Formula: see text]h and five times possesses abundant ginsenosides Rk1, Rk3, Rh4 and Rg5 transformed via deglycosylation and dehydroxylation, and produces optimal activity against ED. The number of sugar molecules, structure of hydroxyl groups and stereoselectivity in ginsenosides affect their anti-ED activity. Among the 13 ginsenosides, Rk1, Rk3, Rh4 and Rg5 are the most efficient in decreasing intracellular calcium levels by inhibiting phosphodiesterase 5A (PDE5A) to reduce the degradation of cyclic guanosine monophosphate (cGMP) in CCSMCs. Rg5 also restrain hypoxia inducible factor-1[Formula: see text] (HIF-1[Formula: see text] expression in hypoxia state, and increase endothelial nitric oxide synthase (eNOS) expression in isolated rat cavernous tissue. These observations suggest a role for steamed ginseng containing two pairs of geometric isomers (i.e., Rk1/Rg5 and Rk3/Rh4) in the treatment of ED.
On electrical and interfacial properties of iron and platinum Schottky barrier diodes on (111) n-type Si0.65Ge0.35
Authors: Hamri D. , Teffahi A. , Djeghlouf A. , Chalabi D. , Saidane A.
Published: January 2018

Current–voltage (I–V), capacitance–voltage–frequency (C–V–f) and conductance–voltage–frequency (G/[Formula: see text]–V–f) characteristics of Molecular Beam Epitaxy (MBE)-deposited Fe/n-Si[Formula: see text]Ge[Formula: see text] (FM1) and Pt/[Formula: see text]-Si[Formula: see text]Ge[Formula: see text](PM2) (111) orientated Schottky barrier diodes (SBDs) have been investigated at room-temperature. Barrier height ([Formula: see text]), ideality factor (n) and series resistance (R[Formula: see text]) were extracted. Dominant current conduction mechanisms were determined. They revealed that Poole–Frenkel-type conduction mechanism dominated reverse current. Differences in shunt resistance confirmed the difference found in leakage current. Under forward bias, quasi-ohmic conduction is found at low voltage regions and space charge-limited conduction (SCLC) at higher voltage regions for both SBDs. Density of interface states (N[Formula: see text]) indicated a difference in interface reactivity. Distribution profiles of series resistance (R[Formula: see text]) with bias gives a peak in depletion region at low-frequencies that disappears with increasing frequencies. These results show that interface states density and series resistance of Schottky diodes are important parameters that strongly influence electrical properties of FM1 and PM2 structures.
Electronic structures and magnetic properties of Fe3Si films epitaxial on Si(001)
Authors: Xie Jing , Xie Quan
Published: January 2018

The electronic structures and magnetic properties of Fe3Si films epitaxial on Si(001) were systematically investigated by using the first-principle calculations on plane-wave pseudo-potential theory. The calculated results show that Fe3Si films epitaxial on Si(001) have the most stable equilibrium state at the lattice constant c = 5.63 Å. The negative heat of formation and cohesive energy of Fe3Si(001)//Si(001) imply that Fe3Si films epitaxial on Si(001) formed in this manner have high structural stability. The calculated spin polarized energy band structures and density of states indicate that Fe3Si films epitaxial on Si(001) have characteristic of metal, whose bonding modes are covalent bond and metallic bond. The band through Fermi level is mainly due to the Fe 3d states and the Si 3p states. Ferromagnetic properties of Fe3Si(001)//Si(001) are attributed to 3d states of the Fe atoms. The atomic magnetic moments of Fe[A,C] and Fe[B] are different from each other, likewise implying Fe3Si films epitaxial on Si(001) is ferromagnetic.
An extension of the coupled derivative nonlinear Schrödinger hierarchy
Authors: Xu Siqi , Geng Xianguo , Xue Bo
Published: January 2018

In this paper, a 3 × 3 matrix spectral problem with six potentials is considered. With the help of the compatibility condition, a hierarchy of new nonlinear evolution equations which can be reduced to the coupled derivative nonlinear Schrödinger (CDNLS) equations is obtained. By use of the trace identity, it is proved that all the members in this new hierarchy have generalized bi-Hamiltonian structures. Moreover, infinitely many conservation laws of this hierarchy are constructed.
Revisit on the thermodynamic stability of Hořava–Lifshitz black hole
Authors: Meng Xudong , Wang Ruihong
Published: January 2018

We study the thermodynamic properties of the black hole derived in Hořava–Lifshitz (HL) gravity without the detailed-balance condition. The parameter [Formula: see text] in the HL black hole plays the same role as that of the electric charge in the Reissner–Nordström-anti-de Sitter (RN-AdS) black hole. By analogy, we treat the parameter [Formula: see text] as the thermodynamic variable and obtain the first law of thermodynamics for the HL black hole. Although the HL black hole and the RN-AdS black hole have the similar mass and temperature, due to their very different entropy, the two black holes have very different thermodynamic properties. By calculating the heat capacity and the free energy, we analyze the thermodynamic stability of the HL black hole.