bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porphobilinogen deaminase HEMC interacts with the PPR‐protein AtECB2 for chloroplast RNA editing
Authors: Huang Chao , Yu Qing‐Bo , Li Zi‐Ran , Ye Lin‐Shan , Xu Ling , Yang Zhong‐Nan 
Published: August 2017

SUMMARYThe pentatricopeptide repeat‐DYW protein AtECB2 affects plastid RNA editing at seven sites, including accD‐794, accD‐1568, ndhF‐290, ndhG‐50, petL‐5, rpoA‐200 and rpoC1‐488. To understand the mechanism of its involvement in RNA editing, a transgenic line was constructed with AtECB2 fused to a 4xMYC tag that could complement the atecb2 phenotype. RNA immunoprecipitation analysis indicated that AtECB2 is associated with the transcripts of accD, ndhF, ndhG and petL. Co‐immunoprecipitation and mass spectrometry experiments showed that multiple organelle RNA editing factor 2 (MORF2) and porphobilinogen deaminase HEMC are associated with AtECB2. Biochemical analysis showed that AtECB2 directly interacts with HEMC through its E domain, while HEMC interacts with MORF8/RIP1. Deletion analysis showed that the E domain is essential for RNA editing. The hemc‐1 mutant showed an albino and seedling‐lethal phenotype. Of the seven editing sites affected in atecb2, the editing of accD‐794 and ndhF‐290 was also reduced in hemc‐1. RNA immunoprecipitation analysis suggested that HEMC is associated with the editing sites of ndhF transcripts. These results showed that both HEMC and multiple organellar RNA editing factor (MORF) proteins are associated with AtECB2 for RNA editing in plastids.
Retrospective evaluation of the effectiveness of xylazine for inducing emesis in cats: 48 cats (2011–2015)
Authors: Thies Margaret , Bracker Kiko , Sinnott Virginia 
Published: August 2017

AbstractObjectiveTo determine the effectiveness of xylazine for the induction of emesis in cats that were suspected of ingesting potentially toxic substances or foreign objects.DesignRetrospective study.SettingPrivate emergency and specialty referral hospital.AnimalsForty‐eight client‐owned cats that were administered xylazine to induce emesis for decontamination of a toxic substance or expulsion of an ingested foreign object.InterventionsNone.Measurements and Main ResultsThe medical records of 48 cats presenting for known or suspected ingestion of foreign material that underwent decontamination with xylazine were reviewed. Signalment, material ingested, dose and route of xylazine administration, success of emesis and recovery of foreign material ingested, use of a reversal agent, and adverse effects were noted. The induction of emesis was successful in 29/48 (60%) of cats. Sedation was the most common adverse effect and was noted in 15/48 (31%) of patients.ConclusionsXylazine is safe and reasonably effective at inducing emesis in cats.
Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus
Authors: Shekhova Elena , Kniemeyer Olaf , Brakhage Axel A. 
Published: August 2017

ABSTRACT

Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of
Aspergillus fumigatus
with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in
A. fumigatus
challenged with antifungal compounds.
In Vitro
Interactions of Echinocandins with Triazoles against Multidrug-Resistant
Candida auris
Authors: Fakhim Hamed , Chowdhary Anuradha , Prakash Anupam , Vaezi Afsane , Dannaoui Eric , Meis Jacques F. , Badali Hamid 
Published: August 2017

ABSTRACT

We determined the
in vitro
interactions between echinocandins and azoles against 10 multidrug-resistant
Candida auris
strains by use of a microdilution checkerboard technique. Our results suggest synergistic interactions between micafungin and voriconazole with fractional inhibitory concentration index (FICI) values of 0.15 to 0.5, and we observed indifferent interactions when micafungin was combined with fluconazole (FICI, 0.62 to 1.5). Combinations of caspofungin with fluconazole or voriconazole exhibited indifferent interactions. No antagonism was observed for any combination.
When Good Bugs Go Bad: Epidemiology and Antimicrobial Resistance Profiles of Corynebacterium striatum, an Emerging Multidrug-Resistant, Opportunistic Pathogen
Authors: McMullen Allison R. , Anderson Neil , Wallace Meghan A. , Shupe Angela , Burnham Carey-Ann D. 
Published: August 2017

ABSTRACT

Infections with
Corynebacterium striatum
have been described in the literature over the last 2 decades, with the majority being bacteremia, central line infections, and occasionally, endocarditis. In recent years, the frequency of
C. striatum
infections appears to be increasing; a factor likely contributing to this is the increased ease and accuracy of the identification of
Corynebacterium
spp., including
C. striatum
, from clinical cultures. The objective of this study was to retrospectively characterize
C. striatum
isolates recovered from specimens submitted as part of routine patient care at a 1,250-bed, tertiary-care academic medical center. Multiple strain types were recovered, as demonstrated by repetitive-sequence-based PCR. Most of the strains of
C. striatum
characterized were resistant to antimicrobials commonly used to treat Gram-positive organisms, such as penicillin, ceftriaxone, meropenem, clindamycin, and tetracycline. The MIC
50
for ceftaroline was >32 μg/ml. Although there are no interpretive criteria for susceptibility with telavancin, it appeared to have potent
in vitro
efficacy against this species, with MIC
50
and MIC
90
values of 0.064 and 0.125 μg/ml, respectively. Finally, as previously reported in case studies, we demonstrated rapid
in vitro
development of daptomycin resistance in 100% of the isolates tested (
n
= 50), indicating that caution should be exhibited when using daptomycin for the treatment of
C. striatum
infections.
C. striatum
is an emerging, multidrug-resistant pathogen that can be associated with a variety of infection types.
Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran
Authors: Kumar Parag , Gordon Lori A. , Brooks Kristina M. , George Jomy M. , Kellogg Anela , McManus Maryellen , Alfaro Raul M. , Nghiem Khanh , Lozier Jay , Hadigan Colleen , Penzak Scott R. 
Published: August 2017

ABSTRACTDabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.)
Real-Time PCR Targeting the
penA
Mosaic XXXIV Type for Prediction of Extended-Spectrum-Cephalosporin Susceptibility in Clinical Neisseria gonorrhoeae Isolates
Authors: Wong L. K. , Hemarajata P. , Soge O. O. , Humphries R. M. , Klausner J. D. 
Published: August 2017

ABSTRACT

Neisseria gonorrhoeae
isolates with decreased susceptibility to extended-spectrum cephalosporins (ESCs) are increasing. We developed an assay to predict
N. gonorrhoeae
susceptibility to ESCs by targeting
penA
mosaic XXXIV, an allele prevalent among U.S. isolates with elevated ESC MICs. The assay was 97% sensitive and 100% specific for predicting at least one ESC MIC above the CDC alert value among clinical isolates, and it could be multiplexed with a previously validated
gyrA
PCR to predict ciprofloxacin susceptibility.
Extinction of West Nile Virus by Favipiravir through Lethal Mutagenesis
Authors: Escribano-Romero Estela , Jiménez de Oya Nereida , Domingo Esteban , Saiz Juan Carlos 
Published: August 2017

ABSTRACT

Favipiravir is an antiviral agent effective against several RNA viruses. The drug has been shown to protect mice against experimental infection with a lethal dose of West Nile virus (WNV), a mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis for which no antiviral therapy has been licensed; however, the mechanism of action of the drug is still not well understood. Here, we describe the potent
in vitro
antiviral activity of favipiravir against WNV, showing that it decreases virus-specific infectivity and drives the virus to extinction. Two passages of WNV in the presence of 1 mM favipiravir—a concentration that is more than 10-fold lower than its 50% cytotoxic concentration (CC
50
)—resulted in a significant increase in mutation frequency in the mutant spectrum and in a bias toward A→G and G→A transitions relative to the population passaged in the absence of the drug. These data, together with the fact that the drug is already licensed in Japan against influenza virus and in a clinical trial against Ebola virus, point to favipiravir as a promising antiviral agent to fight medically relevant flaviviral infections, such as that caused by WNV.
Genomic Characterization of VIM Metallo-β-Lactamase-Producing Alcaligenes faecalis from Gaza, Palestine
Authors: Al Laham Nahed , Chavda Kalyan D. , Cienfuegos-Gallet Astrid V. , Kreiswirth Barry N. , Chen Liang 
Published: August 2017

ABSTRACT

Carbapenemase-producing Gram-negative bacteria (CP-GNB) have increasingly spread worldwide, and different families of carbapenemases have been identified in various bacterial species. Here, we report the identification of five VIM metallo-β-lactamase-producing
Alcaligenes faecalis
isolates associated with a small outbreak in a large hospital in Gaza, Palestine. Next-generation sequencing analysis showed
bla
VIM-2
is harbored by a chromosomal genomic island among three strains, while
bla
VIM-4
is carried by a novel plasmid in two strains.
Induction of Type I Interferon through a Noncanonical Toll-Like Receptor 7 Pathway during Yersinia pestis Infection
Authors: Dhariwala Miqdad O. , Olson Rachel M. , Anderson Deborah M. 
Published: August 2017

ABSTRACT

Yersinia pestis
causes bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans. Plague develops as a consequence of bacterial neutralization of the host's innate immune response, which permits uncontrolled growth and causes the systemic hyperactivation of the inflammatory response. We previously found that host type I interferon (IFN) signaling is induced during
Y. pestis
infection and contributes to neutrophil depletion and disease. In this work, we show that type I IFN expression is derived from the recognition of intracellular
Y. pestis
by host Toll-like receptor 7 (TLR7). Type I IFN expression proceeded independent of myeloid differentiation factor 88 (MyD88), which is the only known signaling adaptor for TLR7, suggesting that a noncanonical mechanism occurs in
Y. pestis
-infected macrophages. In the murine plague model, TLR7 was a significant contributor to the expression of serum IFN-β, whereas MyD88 was not. Furthermore, like the type I IFN response, TLR7 contributed to the lethality of septicemic plague and was associated with the suppression of neutrophilic inflammation. In contrast, TLR7 was important for defense against disease in the lungs. Together, these data demonstrate that an atypical TLR7 signaling pathway contributes to type I IFN expression during
Y. pestis
infection and suggest that the TLR7-driven type I IFN response plays an important role in determining the outcome of plague.
Pseudomonas aeruginosa Magnesium Transporter MgtE Inhibits Type III Secretion System Gene Expression by Stimulating
rsmYZ
Transcription
Authors: Chakravarty Shubham , Melton Cameron N. , Bailin Adam , Yahr Timothy L. , Anderson Gregory G. 
Published: August 2017

ABSTRACT

Pseudomonas aeruginosa
causes numerous acute and chronic opportunistic infections in humans. One of its most formidable weapons is a type III secretion system (T3SS), which injects powerful toxins directly into host cells. The toxins lead to cell dysfunction and, ultimately, cell death. Identification of regulatory pathways that control T3SS gene expression may lead to the discovery of novel therapeutics to treat
P. aeruginosa
infections. In a previous study, we found that expression of the magnesium transporter gene
mgtE
inhibits T3SS gene transcription. MgtE-dependent inhibition appeared to interfere with the synthesis or function of the master T3SS transcriptional activator ExsA, although the exact mechanism was unclear. We now demonstrate that
mgtE
expression acts through the GacAS two-component system to activate
rsmY
and
rsmZ
transcription. This event ultimately leads to inhibition of
exsA
translation. This inhibitory effect is specific to
exsA
as translation of other genes in the
exsCEBA
operon is not inhibited by
mgtE
. Moreover, our data reveal that MgtE acts solely through this pathway to regulate T3SS gene transcription. Our study reveals an important mechanism that may allow
P. aeruginosa
to fine-tune T3SS activity in response to certain environmental stimuli.

IMPORTANCE
The type III secretion system (T3SS) is a critical virulence factor utilized by numerous Gram-negative bacteria, including
Pseudomonas aeruginosa
, to intoxicate and kill host cells. Elucidating T3SS regulatory mechanisms may uncover targets for novel anti-
P. aeruginosa
therapeutics and provide deeper understanding of bacterial pathogenesis. We previously found that the magnesium transporter MgtE inhibits T3SS gene transcription in
P. aeruginosa
. In this study, we describe the mechanism of MgtE-dependent inhibition of the T3SS. Our report also illustrates how MgtE might respond to environmental cues, such as magnesium levels, to fine-tune T3SS gene expression.
Dedicated paediatric Outpatient Parenteral Antimicrobial Therapy medical support: a pre–post observational study
Authors: Mace Ariel O , McLeod Charlie , Yeoh Daniel K , Vine Julie , Chen Yu-Ping , Martin Andrew C , Blyth Christopher C , Bowen Asha C 
Published: August 2017

ObjectiveDespite the many benefits of paediatric Outpatient Parenteral Antimicrobial Therapy (OPAT) programmes, there are risks associated with delivering inpatient-level care outside of hospital. There is a paucity of evidence defining how best to mitigate these risks. We examined the impact of introducing a dedicated medical team to OPAT, to define the role of increased medical oversight in improving patient outcomes in this cohort.DesignA prospective 24-month pre–post observational cohort study.SettingThe Hospital in the Home (HiTH) programme at Princess Margaret Hospital (PMH) for Children, Western Australia.PatientsAll OPAT admissions to HiTH, excluding haematology/oncology patients.InterventionsPMH introduced a dedicated OPAT medical support team in July 2015 to improve adherence to best-practice guidelines for patient monitoring and review.Main outcome measuresDuration of OPAT, adherence to monitoring guidelines, drug-related and line-related adverse events and readmission to hospital.ResultsThere were a total of 502 OPAT episodes over 24 months, with 407 episodes included in analyses. Following the introduction of the OPAT medical team, adherence to monitoring guidelines improved (OR 4.90, 95% CI 2.48 to 9.66); significantly fewer patients required readmission to hospital (OR 0.45, 95% CI 0.24 to 0.86) and there was a significant reduction in the proportion of patients receiving prolonged (≥7 days) OPAT (OR 0.67, 95% CI 0.45 to 0.99).ConclusionThe introduction of a formal medical team to HiTH demonstrated a positive clinical impact on OPAT patients’ outcomes. These findings support the ongoing utility of medical governance in a nurse-led HiTH service.
Prenatal and perinatal risk factors for disability in a rural Nepali birth cohort
Authors: Haworth Edward J N , Tumbahangphe Kirti M , Costello Anthony , Manandhar Dharma , Adhikari Dhruba , Budhathoki Bharat , Shrestha Dej Krishna , Sagar Khadka , Heys Michelle 
Published: August 2017

BackgroundImproving newborn health remains a global health priority. Little however is known about the neurodevelopmental consequences for survivors of complications in pregnancy, labour and the neonatal period in in low-income countries outside of small selective and typically urban facility studies. We ask which antenatal, birth and neonatal factors are associated with disability in childhood in a large community birth cohort from rural Nepal.Methods6436 infants were recruited during a cluster randomised control trial (RCT) of participatory women's groups (ISRCTN31137309), of whom 6075 survived beyond 28 days. At mean age of 11∙5 years (range 9.5–13.1), 4219 children (27% lost to follow-up) were available for disability screening which was conducted by face-to-face interview using the Module on Child Functioning and Disability produced by the Washington Group/UNICEF. Hypothesised risk factors for disability underwent multivariable regression modelling.FindingsOverall prevalence of disability was 7.4%. Maternal underweight (OR 1.44 (95% CI 1.01–2.08)), maternal cohabitation under 16 years of age (OR 1.50 (1.13–2.00)), standardised infant weight at 1 month (OR 0.82 (0.71–0.95)) and reported infant diarrhoea and vomiting in the first month (OR 2.48 (1.58–3.89)) were significantly associated with disability adjusted for trial allocation. The majority of hypothesised risk factors, including prematurity, were not significant.InterpretationProxies for early marriage and low birth weight and a measure of maternal undernutrition were associated with increased odds of disability. The lack of association of most other recognised risk factors for adverse outcome and disability may be due to survival bias.
Examining the predictors of academic outcomes for indigenous Māori, Pacific and rural students admitted into medicine via two equity pathways: a retrospective observational study at the University of Auckland, Aotearoa New Zealand
Authors: Curtis Elana , Wikaire Erena , Jiang Yannan , McMillan Louise , Loto Robert , Poole Phillippa , Barrow Mark , Bagg Warwick , Reid Papaarangi 
Published: August 2017

ObjectiveTo determine associations between admission markers of socioeconomic status, transitioning, bridging programme attendance and prior academic preparation on academic outcomes for indigenous Māori, Pacific and rural students admitted into medicine under access pathways designed to widen participation. Findings were compared with students admitted via the general (usual) admission pathway.DesignRetrospective observational study using secondary data.Setting 6-year medical programme (MBChB), University of Auckland, Aotearoa New Zealand. Students are selected and admitted into Year 2 following a first year (undergraduate) or prior degree (graduate).Participants1676 domestic students admitted into Year 2 between 2002 and 2012 via three pathways: GENERAL admission (1167), Māori and Pacific Admission Scheme—MAPAS (317) or Rural Origin Medical Preferential Entry—ROMPE (192). Of these, 1082 students completed the programme in the study period.Main outcome measuresGraduated from medical programme (yes/no), academic scores in Years 2–3 (Grade Point Average (GPA), scored 0–9).Results735/778 (95%) of GENERAL, 111/121 (92%) of ROMPE and 146/183 (80%) of MAPAS students graduated from intended programme. The graduation rate was significantly lower in the MAPAS students (p<0.0001). The average Year 2–3 GPA was 6.35 (SD 1.52) for GENERAL, which was higher than 5.82 (SD 1.65, p=0.0013) for ROMPE and 4.33 (SD 1.56, p<0.0001) for MAPAS. Multiple regression analyses identified three key predictors of better academic outcomes: bridging programme attendance, admission as an undergraduate and admission GPA/Grade Point Equivalent (GPE). Attending local urban schools and higher school deciles were also associated with a greater likelihood of graduation. All regression models have controlled for predefined baseline confounders (gender, age and year of admission).ConclusionsThere were varied associations between admission variables and academic outcomes across the three admission pathways. Equity-targeted admission programmes inclusive of variations in academic threshold for entry may support a widening participation agenda, however, additional academic and pastoral supports are recommended.