bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimal weights of Hilbert modular forms in characteristic
Authors: Diamond Fred , Kassaei Payman L 
Published: June 2017

We consider mod $p$ Hilbert modular forms associated to a totally real field of degree $d$ in which $p$ is unramified. We prove that every such form arises by multiplication by partial Hasse invariants from one whose weight (a $d$-tuple of integers) lies in a certain cone contained in the set of non-negative weights, answering a question of Andreatta and Goren. The proof is based on properties of the Goren–Oort stratification on mod $p$ Hilbert modular varieties established by Goren and Oort, and Tian and Xiao.
Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections
Authors: Xie Jiao , Roberts Jason A. , Alobaid Abdulaziz S. , Roger Claire , Wang Yan , Yang Qianting , Sun Jinyao , Dong Haiyan , Wang Xue , Xing Jianfeng , Lipman Jeffrey , Dong Yalin 
Published: June 2017

ABSTRACT

We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC
0–24
/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m
2
, respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h; volume in the central compartment, 72.50 ± 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h
−1
; and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h
−1
. A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for
Enterobacter cloacae
,
Escherichia coli
,
Klebsiella pneumoniae
, and methicillin-resistant
Staphylococcus aureus
for an AUC
0–24
/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.
Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis
Authors: Chirehwa Maxwell T. , McIlleron Helen , Rustomjee Roxana , Mthiyane Thuli , Onyebujoh Philip , Smith Peter , Denti Paolo 
Published: June 2017

ABSTRACTPyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively.
Resistance to the Cyclotide Cycloviolacin O2 in Salmonella enterica Caused by Different Mutations That Often Confer Cross-Resistance or Collateral Sensitivity to Other Antimicrobial Peptides
Authors: Malik Sohaib Z. , Linkevicius Marius , Göransson Ulf , Andersson Dan I. 
Published: June 2017

ABSTRACT

Antimicrobial peptides (AMPs) are essential components of innate immunity in all living organisms, and these potent broad-spectrum antimicrobials have inspired several antibacterial development programs in the past 2 decades. In this study, the development of resistance to the Gram-negative bacterium-specific peptide cycloviolacin O2 (cyO2), a member of the cyclotide family of plant miniproteins, was characterized in
Salmonella enterica
serovar Typhimurium LT2. Mutants isolated from serial passaging experiments in increasing concentrations of cyO2 were characterized by whole-genome sequencing. The identified mutations were genetically reconstituted in a wild-type background. The additive effect of mutations was studied in double mutants. Fitness costs, levels of resistance, and cross-resistance to another cyclotide, other peptide and nonpeptide antibiotics, and AMPs were determined. A variety of resistance mutations were identified. Some of these reduced fitness and others had no effect on fitness
in vitro
, in the absence of cyO2. In mouse competition experiments, four of the cyO2-resistant mutants showed a significant fitness advantage, whereas the effects of the mutations in the others appeared to be neutral. The level of resistance was increased by combining several individual resistance mutations. Several cases of cross-resistance and collateral sensitivity between cyclotides, other AMPs, and antibiotics were identified. These results show that resistance to cyclotides can evolve via several different types of mutations with only minor fitness costs and that these mutations often affect resistance to other AMPs.
Antibiotic-Mediated Modulations of Outer Membrane Vesicles in Enterohemorrhagic Escherichia coli O104:H4 and O157:H7
Authors: Bauwens Andreas , Kunsmann Lisa , Karch Helge , Mellmann Alexander , Bielaszewska Martina 
Published: June 2017

ABSTRACT

Ciprofloxacin, meropenem, fosfomycin, and polymyxin B strongly increase production of outer membrane vesicles (OMVs) in
Escherichia coli
O104:H4 and O157:H7. Ciprofloxacin also upregulates OMV-associated Shiga toxin 2a, the major virulence factor of these pathogens, whereas the other antibiotics increase OMV production without the toxin. These two effects might worsen the clinical outcome of infections caused by Shiga toxin-producing
E. coli
. Our data support the existing recommendations to avoid antibiotics for treatment of these infections.
Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities
Authors: Fedrigo Nayara Helisandra , Mazucheli Josmar , Albiero James , Shinohara Danielle Rosani , Lodi Fernanda Gomes , Machado Ana Cristina dos Santos , Sy Sherwin K. B. , Tognim Maria Cristina Bronharo 
Published: June 2017

ABSTRACT

Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI), and it has recently been recommended that fosfomycin be used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimens has not been analyzed. The MIC of fosfomycin for 245 Gram-negative bacterial isolates, consisting of 158
Escherichia coli
isolates and 87
Klebsiella
isolates which were collected from patients with urinary tract infections, were determined at pH 6.0 and 7.0 using the agar dilution method. Monte Carlo simulation of the urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3,000 mg fosfomycin and the MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against
E. coli
(MIC
90
≤ 16 μg/ml) but not against
Klebsiella
spp. (MIC
90
> 512 μg/ml). Acidification of the environment increased the susceptibility of 71% of the bacterial isolates and resulted in a statistically significant decrease in bacterial survival. The use of a regimen consisting of a single oral dose of fosfomycin against an
E. coli
isolate with an MIC of ≤64 mg/liter was able to achieve a PTA of ≥90% for a target pharmacodynamic index (AUC/MIC) of 23 in urine; PTA was not achieved when the MIC was higher than 64 mg/liter. The cumulative fractions of the bacterial responses (CFR) were 99% and 55% against
E. coli
and
Klebsiella
spp., respectively, based on simulated drug exposure in urine with an acidic pH of 6.0. A decrease of the pH from 7.0 to 6.0 improved the PTA and CFR of the target pharmacodynamic index in both
E. coli
and
Klebsiella
isolates.
Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production
Authors: Gratacap Remi L. , Scherer Allison K. , Seman Brittany G. , Wheeler Robert T. 
Published: June 2017

ABSTRACT

Candida albicans
is a ubiquitous mucosal commensal that is normally prevented from causing acute or chronic invasive disease. Neutrophils contribute to protection in oral infection but exacerbate vulvovaginal candidiasis. To dissect the role of neutrophils during mucosal candidiasis, we took advantage of a new, transparent zebrafish swim bladder infection model. Intravital microscopic tracking of individual animals revealed that the blocking of neutrophil recruitment leads to rapid mortality in this model through faster disease progression. Conversely, artificial recruitment of neutrophils during early infection reduces disease pressure. Noninvasive longitudinal tracking showed that mortality is a consequence of
C. albicans
breaching the epithelial barrier and invading surrounding tissues. Accordingly, we found that a hyperfilamentous
C. albicans
strain breaches the epithelial barrier more frequently and causes mortality in immunocompetent zebrafish. A lack of neutrophils at the infection site is associated with less fungus-associated extracellular DNA and less damage to fungal filaments, suggesting that neutrophil extracellular traps help to protect the epithelial barrier from
C. albicans
breach. We propose a homeostatic model where
C. albicans
disease pressure is balanced by neutrophil-mediated damage of fungi, maintaining this organism as a commensal while minimizing the risk of damage to host tissue. The unequaled ability to dissect infection dynamics at a high spatiotemporal resolution makes this zebrafish model a unique tool for understanding mucosal host-pathogen interactions.
Positive- and Negative-Control Pathways by Blood Components for Intermedilysin Production in Streptococcus intermedius
Authors: Tomoyasu Toshifumi , Yamasaki Takahiro , Chiba Shinya , Kusaka Shingo , Tabata Atsushi , Whiley Robert A. , Nagamune Hideaki 
Published: June 2017

ABSTRACT

Streptococcus intermedius
is an opportunistic bacterial pathogen secreting a human-specific cytolysin called intermedilysin (ILY) as a major pathogenic factor. This bacterium can degrade glycans into monosaccharides using two glycosidases, multisubstrate glycosidase A (MsgA) and neuraminidase (NanA). Here, we detected a stronger hemolytic activity mediated by ILY when
S. intermedius
PC574 was cultured in fetal bovine serum (FBS) than when it was grown in the standard culture medium. FBS-cultured cells also showed higher MsgA and NanA activity, although overproduction of ILY in FBS was undetectable in mutants
nanA
-null and
msgA
-null. Addition of purified MsgA and NanA to the FBS resulted in a release of 2.8 mM galactose and 4.3 mM
N
-acetylneuraminic acid; these sugar concentrations were sufficient to upregulate the expression of ILY, MsgA, and NanA. Conversely, when strain PC574 was cultured in human plasma, no similar increase in hemolytic activity was observed. Moreover, addition of human plasma to the culture in FBS appeared to inhibit the stimulatory effect of FBS on ILY, MsgA, and NanA, although there were individual differences among the plasma samples. We confirmed that human plasma contains immunoglobulins that can neutralize ILY, MsgA, and NanA activities. In addition, human plasma had a neutralizing effect on cytotoxicity of
S. intermedius
toward HepG2 cells in FBS, and a higher concentration of human plasma was necessary to reduce the cytotoxicity of an ILY-high-producing strain than an ILY-low-producing strain. Overall, our data show that blood contains factors that stimulate and inhibit ILY expression and activity, which may affect pathogenicity of
S. intermedius
.
Mechanisms of Pyocyanin Toxicity and Genetic Determinants of Resistance in Staphylococcus aureus
Authors: Noto Michael J. , Burns William J. , Beavers William N. , Skaar Eric P. 
Published: June 2017

ABSTRACT

Pseudomonas aeruginosa
and
Staphylococcus aureus
are commonly isolated from polymicrobial infections, such as wound infections and chronic respiratory infections of persons with cystic fibrosis. Despite their coisolation,
P. aeruginosa
produces substances toxic to
S. aureus
, including pyocyanin, a blue-pigmented molecule that functions in
P. aeruginosa
virulence. Pyocyanin inhibits
S. aureus
respiration, forcing it to derive energy from fermentation and adopt a small-colony variant (SCV) phenotype. The mechanisms by which
S. aureus
sustains infection in the presence of pyocyanin are not clear. We sought to clarify the mechanisms of pyocyanin toxicity in
S. aureus
as well as identify the staphylococcal factors involved in its resistance to pyocyanin toxicity. Nonrespiring
S. aureus
SCVs are inhibited by pyocyanin through pyocyanin-dependent reactive oxygen species (ROS) production, indicating that pyocyanin toxicity is mediated through respiratory inhibition and ROS generation. Selection on pyocyanin yielded a menadione auxotrophic SCV capable of growth on high concentrations of pyocyanin. Genome sequencing of this isolate identified mutations in four genes, including
saeS
,
menD
, NWMN_0006, and
qsrR
. QsrR is a quinone-sensing repressor of quinone detoxification genes. Inactivation of
qsrR
resulted in significant pyocyanin resistance, and additional pyocyanin resistance was achieved through combined inactivation of
qsrR
and menadione biosynthesis. Pyocyanin-resistant
S. aureus
has an enhanced capability to inactivate pyocyanin, suggesting QsrR-regulated gene products may degrade pyocyanin to alleviate toxicity. These findings demonstrate pyocyanin-mediated ROS generation as an additional mechanism of pyocyanin toxicity and define QsrR as a key mediator of pyocyanin resistance in
S. aureus
.

IMPORTANCE
Many bacterial infections occur in the presence of other microbes, where interactions between different microbes and the host impact disease. In patients with cystic fibrosis, chronic lung infection with multiple microbes results in the most severe disease manifestations.
Staphylococcus aureus
and
Pseudomonas aeruginosa
are prevalent cystic fibrosis pathogens, and infection with both is associated with worse outcomes. These organisms have evolved mechanisms of competing with one another. For example,
P. aeruginosa
produces pyocyanin, which inhibits
S. aureus
growth. Our research has identified how pyocyanin inhibits
S. aureus
growth and how
S. aureus
can adapt to survive in the presence of pyocyanin. Understanding how
S. aureus
sustains infection in the presence of
P. aeruginosa
may identify means of disrupting these microbial communities.
A
priA
Mutant Expressed in Two Pieces Has Almost Full Activity in Escherichia coli K-12
Authors: Leroux Maxime , Jani Niketa , Sandler Steven J. 
Published: June 2017

ABSTRACT

The ability to restart broken DNA replication forks is essential across all domains of life. In
Escherichia coli
, the
priA
,
priB
,
priC
, and
dnaT
genes encode the replication restart proteins (RRPs) to accomplish this task. PriA plays a critical role in replication restart such that its absence reveals a dramatic phenotype: poor growth, high basal levels of SOS expression, poorly partitioned nucleoids (Par
−
), UV sensitivity, and recombination deficiency (Rec
−
). PriA has 733 amino acids, and its structure is composed of six domains that enable it to bind to DNA replication fork-like structures, remodel the strands of DNA, interact with SSB (single-stranded DNA binding protein), PriB, and DnaT, and display ATPase, helicase, and translocase activities. We have characterized a new
priA
mutation called
priA316
::
cat
. It is a composite mutation involving an insertion that truncates the protein within the winged-helix domain (at the 154th codon) and an ACG (Thr)-to-ATG (Met) mutation that allows reinitiation of translation at the 157th codon such that PriA is expressed in two pieces.
priA316
::
cat
phenotypes are like those of the wild type for growth, recombination, and UV resistance, revealing only a slightly increased level of SOS expression and defects in nucleoid partitioning in the mutant. Both parts of PriA are required for activity, and the N-terminal fragment can be optimized to yield wild-type activity. A deletion of the
lon
protease suppresses
priA316
::
cat
phenotypes. We hypothesize the two parts of PriA form a complex that supplies most of the PriA activity needed in the cell.

IMPORTANCE
PriA is a highly conserved multifunctional protein that plays a crucial role in the essential process of replication restart. Here we characterize an insertion mutation of
priA
with an intragenic suppressor such that it is now made in two parts. These two pieces split the winged-helix domain to separate the N-terminal 3′ DNA-binding domain from the C-terminal domain of PriA. It is hypothesized that the two pieces form a complex that is capable of almost wild type
priA
function. The composite mutation leads to a moderate level of SOS expression and defects in partitioning of the chromosomes. Full function is restored by deletion of
lon
, suggesting that stability of this complex may be a reason for the partial phenotypes seen.
Pitfalls of the duplex system: the mystery of the missing stone
Authors: Nyanhongo Donald Kudakwashe , Antil Satpal , Nasir Syed 
Published: June 2017

A duplex ureter constitutes about 1% of the renal tract anomalies.A 39-year-old man presented with a 4-week history of left loin pain and microscopic haematuria. Investigation with a non-contrast CT KUB revealed a 6 mm non-obstructing calculus in the left distal ureter.Left ureteroscopy and lithotripsy was planned. However, ureteroscopy failed to identify the calculus. A double J ureteric stent was left in situ and the procedure abandoned in favour of further assessment with a CT urogram. Imaging surprisingly showed a left duplex ureter with the calculus in the non-stented ureter.Repeat ureteroscopy noted the second ureter opening within the distal intramural part of the stented ureter. The calculus was identified and laser lithotripsy performed. A double J stent was appropriately reinserted and removed 2 weeks later.Our case highlights the importance of contrasted imaging prior to performing ureteroscopy for calculus disease.
Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort
Authors: Yang Peizeng , Wan Wenjuan , Du Liping , Zhou Qingyun , Qi Jian , Liang Liang , Wang Chaokui , Wu Lili , Kijlstra Aize 
Published: June 2017

AimsTo characterise the clinical features of human leucocyte antigen (HLA)-B27+acute anterior uveitis (AAU) patients with or without ankylosing spondylitis (AS) and investigate the retinal vascular involvement in these patients.MethodsA total of 1056 HLA-B27+ AAU patients (1525 eyes) were retrospectively studied from April 2008 to February 2016. Patients were divided into human leucocyte antigen (HLA)-B27+AS+ and HLA-B27+AS− group. Clinical features including the onset of uveitis, laterality, the age at first attack, clinical examinations, best corrected visual acuity (BCVA), abnormalities in fundus fluorescence angiography (FFA) and complications were determined and compared between these two groups.ResultsThere were 581 (55.0%) and 475 (45.0%) patients respectively classified into HLA-B27+AS+ and HLA-B27+AS− group. Males had a higher prevalence than females in the HLA-B27+AS+ group (75.2%) as compared with the HLA-B27+AS− group (51.8%, p<0.001). The HLA-B27+AS+ patients showed a higher percentage of bilateral/alternating involvement (47.3%) as compared with the HLA-B27+AS− group (36.6%, p=0.001). A higher percentage of fibrinous exudation, synechiae as well as complications including complicated cataract and secondary glaucoma were found in the HLA-B27+AS+ group as compared with the HLA-B27+AS− group. Worse visual outcome as indicated by a higher percentage of patients with BCVA <0.5 and with BCVA <0.05 was noted in the HLA-B27+AS+ group as compared with the HLA-B27+AS− group both before and after treatment. FFA showed mild capillary fluorescence leakage in the late phase with indistinctly defined margins on the peripheral retina in 39.3% of HLA-B27+ AAU patients. There was no difference concerning the retinal vascular involvement between these two groups.ConclusionsOur study confirmed that HLA-B27+AS+ patients show a higher percentage of males, more common bilateral involvement, a higher frequency of fibrinous exudates, synechiae and secondary glaucoma as compared with HLA-B27+AS− patients. Visual outcome was poorer, possibly due to the higher prevalence of complicated cataract in HLA-B27+AS+ patients. Retinal vascular involvement was not uncommon in HLA-B27+ AAU patients.