bluuebunny/crossref_metadata_2025 huggingface dataset:
The monophyly of Euparkeriidae (Reptilia: Archosauriformes) and the origins of Archosauria: a revision of Dorosuchus neoetus from the Mid‐Triassic of Russia
Authors: Sookias Roland B. , Sennikov Andrey G. , Gower David J. , Butler Richard J.
Published: May 2014

Euparkeria capensis is resolved as the sister taxon to Archosauria in many cladistic phylogenies and provides a key outgroup which may approximate the ancestral archosaur morphology. Several other taxa have been referred to the family Euparkeriidae, but the monophyly of this taxon remains doubtful and largely untested. To test this monophyly, the archosauriform and putative euparkeriid Dorosuchus neoetus from the Mid‐Triassic of Russia is re‐examined in the light of recent work on the evolution of stem archosaurs. Dorosuchus neoetus is found to possess a number of morphological features that place it close to Archosauria, including a sigmoidal femur with a clear attachment region for the m. caudifemoralis musculature, but no unambiguous archosaurian apomorphies. Dorosuchus neoetus is included for the first time in a numerical cladistic analysis and is recovered as the sole sister taxon to Archosauria + Phytosauria. A monophyletic Euparkeriidae including D. neoetus and E. capensis is slightly less parsimonious. In addition, a mandible and pterygoid that were previously referred to D. neoetus subsequent to the original description of the species are also included separately within the phylogenetic analysis and are recovered within Archosauria, possibly raising questions as to their correct taxonomic referral. However, this phylogenetic placement is based primarily on the absence of palatal teeth, but the presence or absence of palatal teeth exhibits considerable homoplasy within Archosauriformes. Based on other aspects of their morphology, we do not reject the referral of these elements to D. neoetus.
Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child
Authors: Alhosh Rabea , Genyk Yuri , Alexopoulos Sophoclis , Thomas Daniel , Zhou Shengmei , Yanni George , Kerkar Nanda
Published: May 2014

HPS is a significant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non‐cirrhotic portal hypertension, is characterized by diffuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no fibrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three‐yr‐old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was confirmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT.
Asymptotic Permutation Tests in General Factorial Designs
Authors: Pauly Markus , Brunner Edgar , Konietschke Frank
Published: May 2014

In general factorial designs where no homoscedasticity or a particular error distribution is assumed, the well-known Wald-type statistic is a simple asymptotically valid procedure. However, it is well known that it suffers from a poor finite sample approximation since the convergence to its χ  2 limit distribution is quite slow. This becomes even worse with an increasing number of factor levels. The aim of the paper is to improve the small sample behaviour of the Wald-type statistic, maintaining its applicability to general settings as crossed or hierarchically nested designs by applying a modified permutation approach. In particular, it is shown that this approach approximates the null distribution of the Wald-type statistic not only under the null hypothesis but also under the alternative yielding an asymptotically valid permutation test which is even finitely exact under exchangeability. Finally, its small sample behaviour is compared with competing procedures in an extensive simulation study.
Does repeated reading predict reading development over time? A study of children from Grade 3 to 4
Authors: Gellert Anna S.
Published: May 2014

The purpose of this study was to investigate whether immediate gains in reading fluency achieved during repeated reading of text can predict long‐term reading development over and above traditional predictors of reading development. Eighty‐one Grade 3 children read texts three times consecutively and were instructed either to read as quickly as possible (speed‐focused repeated reading), or to retell the text afterwards (meaning‐focused repeated reading). Measures of text reading fluency, sentence reading fluency, and text comprehension were administered to the children in Grades 3 and 4 to assess their reading development over time. The results indicate that children's immediate response to repeated reading can contribute to the prediction of their development of reading fluency over time. Even after controlling for individual differences in general cognitive ability, word reading fluency, rapid automatized naming, and vocabulary, the experimental measure with meaning‐focused repeated reading remained a significant predictor.
Molecular structures identified in serologically D– samples of an admixed population
Authors: Trucco Boggione Carolina , Luján Brajovich Melina E. , Tarragó Marcel , Mattaloni Stella M. , Biondi Claudia S. , Muñiz‐Díaz Eduardo , Nogués Núria , Cotorruelo Carlos M.
Published: May 2014

Background

The D– phenotype is mainly caused by the complete deletion of the RHD gene in Caucasians. However, a plethora of allelic variants have been described among D– individuals from different ethnic groups.

Study Design and Methods

A cohort of 1314 routine serologically D– samples from white Argentineans was studied by molecular methods.

Results

Among the 1314 D– samples, 2.1% showed RHD‐specific amplifications. One hybrid Rhesus box was detected in all D–/RHD+ samples, suggesting a hemizygous status. The RHDΨ was found in 0.7% of rr samples while DEL and null variants were detected in 16.7% of the D– samples expressing C and/or E antigens. The variants associated with the C antigen were seven RHD‐CE‐Ds, two RHD(1‐2)‐CE(2‐9)‐D(10), two previously unreported RHD(329T>C)‐CE(3‐9)‐D null alleles, one RHD(M295I), and one new RHCE(1‐2)‐RHD(3361del11‐10) null allele whereas those associated with the E antigen were five RHD(46T>C) and one novel RHD(581insG) null allele responsible for a premature stop codon.

Conclusions

The prevalence of D–/RHD+ samples is higher than that observed in Europeans. More than 50% of the RHD alleles found were represented by RHDψ and RHD‐CE‐Ds showing the African contribution to the genetic pool of the admixed population analyzed. Interestingly, three new alleles were found, two of them being hybrid structures between previously described RHD variants recombined with RHCE sequences. The knowledge of the RHD allele repertoire in our population allowed the implementation of reliable typing and transfusion strategies for a better management of patients and pregnant women.
Cryptic diversity, diversification and vicariance in two species complexes ofTomocerus(Collembola,Tomoceridae) fromChina
Authors: Zhang Feng , Yu Daoyuan , Luo Yongzheng , Ho Simon Y. W. , Wang Beixing , Zhu Chaodong
Published: May 2014

Springtails (Collembola) are a group of arthropods that are found in terrestrial ecosystems throughout the world. Two species complexes,Tomocerus ocreatusandT. nigruscomplexes, are widely distributed in the southern and northern parts of easternChina, respectively. There is a poor understanding of the species diversity within these complexes and of the factors affecting their diversification and dispersal. Species delimitation using a general mixedYule coalescent model and aBayesian multilocus approach recognized 22DNA‐based species. This supports the presence of extensive cryptic diversity in species that are geographically widespread. In addition to genetic differences, we discovered corresponding morphological differences in jumping organs among the major clades. Analyses of divergence times and historical biogeographical processes revealed thatocreatusandnigruscomplexes originated in southern and northernChina, respectively. We estimated their divergence at 27.8–44.9 Mya during theEocene–Oligocene, at the time when the transmeridionalQinling–DabieMountains uplifted and formed the north–south geographical boundary of easternChina. Diversification analyses suggest that the subsequent orogenesis of theQinghai–TibetanPlateau in westernChina had little impact on divergences within the two species complexes so that they maintained their geographical patterns from the Paleogene to the present day. Our findings also point to a potentially important influence of theQinling–Dabie Mountains on patterns of animal speciation and distribution inChina.
A weak∗‐topological dichotomy with applications in operator theory
Authors: Kania Tomasz , Koszmider Piotr , Laustsen Niels Jakob
Published: May 2014

Denote by the locally compact Hausdorff space consisting of all countable ordinals, equipped with the order topology, and let be the Banach space of scalar‐valued, continuous functions which are defined on and vanish eventually. We show that a weak‐compact subset of the dual space of is either uniformly Eberlein compact, or it contains a homeomorphic copy of a particular form of the ordinal interval .

This dichotomy yields a unifying approach to most of the existing studies of the Banach space and the Banach algebra of bounded, linear operators acting on it, and it leads to several new results, as well as to stronger versions of known ones. Specifically, we deduce that a Banach space which is a quotient of can either be embedded in a Hilbert‐generated Banach space, or it is isomorphic to the direct sum of and a subspace of a Hilbert‐generated Banach space; and we obtain several equivalent conditions describing the Loy–Willis ideal , which is the unique maximal ideal of , including the following: an operator belongs to if and only if it factors through the Banach space . Among the consequences of these characterizations of is that has a bounded left approximate identity; this resolves a problem left open by Loy and Willis.
A Parametric Computational Fluid Dynamics Analysis of the Valve Pocket Losses in Reciprocating Compressors
Authors: Balduzzi Francesco , Ferrara Giovanni , Maleci Riccardo , Babbini Alberto , Pratelli Guido
Published: May 2014

The reduction of pressure losses is one of the most important challenges for the efficiency increase of a reciprocating compressor. Since the absorbed power is strongly affected by the losses through pocket valves and cylinder ducts, an accurate prediction of these losses is essential. The use of computational fluid dynamics (CFD) simulation has shown great potential for the study of the entire reciprocating compressor, but is still limited by high computational costs. Recently, the authors have presented a simplified CFD approach: the actual valve geometry is replaced with an equivalent porous region, which has significantly increased the speed of calculation while ensuring accuracy as well. Based on this approach, a new methodology for the evaluation of pocket valve losses is presented. A set of CFD simulations using a parameterized geometry of the pocket valve was performed to evaluate the relationship between the losses of the pocket and its geometrical features. An analytical response surface (RS) was defined using the values of the geometrical dimensions as inputs and the pocket flow coefficient as output. Finally, the response surface was validated through a set of test cases performed on different geometries with the actual valve and the results have shown good predictability of the tool.
Dependence of Anisotropy of Human Lumbar Vertebral Trabecular Bone on Quantitative Computed Tomography-Based Apparent Density
Authors: Aiyangar Ameet K. , Vivanco Juan , Au Anthony G. , Anderson Paul A. , Smith Everett L. , Ploeg Heidi-Lynn
Published: May 2014

Most studies investigating human lumbar vertebral trabecular bone (HVTB) mechanical property–density relationships have presented results for the superior–inferior (SI), or “on-axis” direction. Equivalent, directly measured data from mechanical testing in the transverse (TR) direction are sparse and quantitative computed tomography (QCT) density-dependent variations in the anisotropy ratio of HVTB have not been adequately studied. The current study aimed to investigate the dependence of HVTB mechanical anisotropy ratio on QCT density by quantifying the empirical relationships between QCT-based apparent density of HVTB and its apparent compressive mechanical properties— elastic modulus (Eapp), yield strength (σy), and yield strain (εy)—in the SI and TR directions for future clinical QCT-based continuum finite element modeling of HVTB. A total of 51 cylindrical cores (33 axial and 18 transverse) were extracted from four L1 human lumbar cadaveric vertebrae. Intact vertebrae were scanned in a clinical resolution computed tomography (CT) scanner prior to specimen extraction to obtain QCT density, ρCT. Additionally, physically measured apparent density, computed as ash weight over wet, bulk volume, ρapp, showed significant correlation with ρCT [ρCT = 1.0568 × ρapp, r = 0.86]. Specimens were compression tested at room temperature using the Zetos bone loading and bioreactor system. Apparent elastic modulus (Eapp) and yield strength (σy) were linearly related to the ρCT in the axial direction [ESI = 1493.8 × (ρCT), r = 0.77, p < 0.01; σY,SI = 6.9 × (ρCT) − 0.13, r = 0.76, p < 0.01] while a power-law relation provided the best fit in the transverse direction [ETR = 3349.1 × (ρCT)1.94, r = 0.89, p < 0.01; σY,TR = 18.81 × (ρCT)1.83, r = 0.83, p < 0.01]. No significant correlation was found between εy and ρCT in either direction. Eapp and σy in the axial direction were larger compared to the transverse direction by a factor of 3.2 and 2.3, respectively, on average. Furthermore, the degree of anisotropy decreased with increasing density. Comparatively, εy exhibited only a mild, but statistically significant anisotropy: transverse strains were larger than those in the axial direction by 30%, on average. Ability to map apparent mechanical properties in the transverse direction, in addition to the axial direction, from CT-based densitometric measures allows incorporation of transverse properties in finite element models based on clinical CT data, partially offsetting the inability of continuum models to accurately represent trabecular architectural variations.
Determination of Holonomic and Nonholonomic Constraint Reactions in an Index-3 Augmented Lagrangian Formulation With Velocity and Acceleration Projections
Authors: Dopico Daniel , González Francisco , Cuadrado Javier , Kövecses József
Published: May 2014

Index-3 augmented Lagrangian formulations with projections of velocities and accelerations represent an efficient and robust method to carry out the forward-dynamics simulation of multibody systems modeled in dependent coordinates. Existing formalisms, however, were only established for holonomic systems, for which the expression of the constraints at the position-level is known. In this work, an extension of the original algorithms for nonholonomic systems is introduced. Moreover, projections of velocities and accelerations have two side effects: they modify the kinetic energy of the system and they contribute to the constraint reaction forces. Although the effects of the projections on the energy have been studied by several authors, their role in the calculation of the reaction forces has not been described so far. In this work, expressions to determine the constraint reactions from the Lagrange multipliers of the dynamic equations and the Lagrange multipliers of the velocity and acceleration projections are introduced. Simulation results show that the proposed strategy can be used to expand the capabilities of index-3 augmented Lagrangian algorithms, making them able to deal with nonholonomic constraints and provide correct reaction efforts.
Parallel Profiling of the Transcriptome, Cistrome, and Epigenome in the Cellular Response to Ionizing Radiation
Authors: Rashi-Elkeles Sharon , Warnatz Hans-Jörg , Elkon Ran , Kupershtein Ana , Chobod Yuliya , Paz Arnon , Amstislavskiy Vyacheslav , Sultan Marc , Safer Hershel , Nietfeld Wilfried , Lehrach Hans , Shamir Ron , Yaspo Marie-Laure , Shiloh Yosef
Published: May 2014

Deep sequencing identifies the epigenetic and transcriptional dynamics of the cellular response to ionizing radiation.
T Cells for Epithelial Tumors
Authors: Mueller Kristen L.
Published: May 2014

T cells specific for a mutation expressed by tumor cells show antitumor activity in a patient with an epithelial cancer.
WNTs Hitch a Ride
Authors: Berndt Jason D.
Published: May 2014

Migratory neural crest cells deliver WNTs from the dorsal neural tube to developing muscle myotubes to promote polarization.
One Swell Ion Channel
Authors: McCartney Melissa
Published: May 2014

Components of an elusive swelling-activated anion channel are identified and form a structurally new class of channel.
Inhibition of Aminoglycoside 6′-
N
-Acetyltransferase Type Ib by Zinc: Reversal of Amikacin Resistance in Acinetobacter baumannii and Escherichia coli by a Zinc Ionophore
Authors: Lin David L. , Tran Tung , Alam Jamal Y. , Herron Steven R. , Ramirez Maria Soledad , Tolmasky Marcelo E.
Published: May 2014

In vitro
activity of the aminoglycoside 6′-
N
-acetyltransferase type Ib [AAC(6′)-Ib] was inhibited by ZnCl
2
with a 50% inhibitory concentration (IC
50
) of 15 μM. Growth of
Acinetobacter baumannii
or
Escherichia coli
harboring
aac
(
6
′)-
Ib
in cultures containing 8 μg/ml amikacin was significantly inhibited by the addition of 2 μM Zn
2+
in complex with the ionophore pyrithione (ZnPT).
Pharmacokinetic and Pharmacodynamic Evaluation of AZD5847 in a Mouse Model of Tuberculosis
Authors: Balasubramanian V. , Solapure Suresh , Shandil Radha , Gaonkar Sheshagiri , Mahesh K. N. , Reddy Jitender , Deshpande Abhijeet , Bharath Sowmya , Kumar Naveen , Wright Lindsay , Melnick David , Butler Scott L.
Published: May 2014

AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular
Mycobacterium tuberculosis
. Oral administration of AZD5847 to mice infected with
M. tuberculosis
H37Rv in a chronic-infection model resulted in a 1.0-log
10
reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater.
Molecular Epidemiology of KPC-Producing Escherichia coli: Occurrence of ST131-
fimH30
Subclone Harboring pKpQIL-Like IncFIIk Plasmid
Authors: O'Hara Jessica A. , Hu Fupin , Ahn Chulsoo , Nelson Jeremy , Rivera Jesabel I. , Pasculle Anthony W. , Doi Yohei
Published: May 2014

Of 20
Klebsiella pneumoniae
carbapenemase (KPC)-producing
Escherichia coli
isolates identified at hospitals in western Pennsylvania, 60% belonged to the epidemic ST131-
fimH30
subclone. IncFIIk was the most common replicon type for the
bla
KPC
-carrying plasmids (
n
= 8). All IncFIIk plasmids possessed a scaffold similar to that of pKpQIL, and seven of them were borne by ST131-
fimH30
isolates. IncN plasmids conferred resistance to trimethoprim-sulfamethoxazole, and IncA/C plasmids conferred resistance to gentamicin. Three
bla
KPC
-carrying plasmids (IncA/C and IncN) possessed
bla
SHV-7/12
and
qnrA1
or
qnrS1
.
Isoniazid Mediates the
CYP2B6*6
Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6
Authors: Court Michael H. , Almutairi Fawziah E. , Greenblatt David J. , Hazarika Suwagmani , Sheng Hongyan , Klein Kathrin , Zanger Ulrich M. , Bourgea Joanne , Patten Christopher J. , Kwara Awewura
Published: May 2014

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the
CYP2B6*6/*6
genotype (but not the
CYP2B6*1/*1
genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction.
In vitro
studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [

K
i

] = 368 μM) and pyrazinamide (

K
i

= 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [

K
I

] = 30 μM; maximal rate constant of inactivation [
k
inact
] = 0.023 min
−1
) and recombinant CYP2A6 (

K
I

= 15 μM;
k
inact
= 0.024 min
−1
) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or
CYP2B6*6
genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.
Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases
Authors: Debnath Anjan , Shahinas Dea , Bryant Clifford , Hirata Ken , Miyamoto Yukiko , Hwang Grace , Gut Jiri , Renslo Adam R. , Pillai Dylan R. , Eckmann Lars , Reed Sharon L. , McKerrow James H.
Published: May 2014

Entamoeba histolytica
and
Giardia lamblia
are anaerobic protozoan parasites that cause amebiasis and giardiasis, two of the most common diarrheal diseases worldwide. Current therapy relies on metronidazole, but resistance has been reported and the drug has significant adverse effects. Therefore, it is critical to search for effective, better-tolerated antiamebic and antigiardial drugs. We synthesized several examples of a recently reported class of Hsp90 inhibitors and evaluated these compounds as potential leads for antiparasitic chemotherapy. Several of these inhibitors showed strong
in vitro
activity against both
E. histolytica
and
G. lamblia
trophozoites. The inhibitors were rescreened to discriminate between amebicidal and giardicidal activity and general cytotoxicity toward a mammalian cell line. No mammalian cytotoxicity was found at >100 μM for 48 h for any of the inhibitors. To understand the mechanism of action, a competitive binding assay was performed using the fluorescent ATP analogue bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt) and recombinant
E. histolytica
Hsp90 preincubated in both the presence and absence of Hsp90 inhibitors. There was significant reduction in fluorescence compared to the level in the control, suggesting that
E. histolytica
Hsp90 is a selective target. The
in vivo
efficacy and safety of one Hsp90 inhibitor in a mouse model of amebic colitis and giardiasis was demonstrated by significant inhibition of parasite growth at a single oral dose of 5 mg/kg of body weight/day for 7 days and 10 mg/kg/day for 3 days. Considering the results for
in vitro
activity and
in vivo
efficacy, Hsp90 inhibitors represent a promising therapeutic option for amebiasis and giardiasis.
Reclaiming the Efficacy of β-Lactam–β-Lactamase Inhibitor Combinations: Avibactam Restores the Susceptibility of CMY-2-Producing Escherichia coli to Ceftazidime
Authors: Papp-Wallace Krisztina M. , Winkler Marisa L. , Gatta Julian A. , Taracila Magdalena A. , Chilakala Sujatha , Xu Yan , Johnson J. Kristie , Bonomo Robert A.
Published: May 2014

CMY-2 is a plasmid-encoded Ambler class C cephalosporinase that is widely disseminated in
Enterobacteriaceae
and is responsible for expanded-spectrum cephalosporin resistance. As a result of resistance to both ceftazidime and β-lactamase inhibitors in strains carrying
bla
CMY
, novel β-lactam–β-lactamase inhibitor combinations are sought to combat this significant threat to β-lactam therapy. Avibactam is a bridged diazabicyclo [3.2.1]octanone non-β-lactam β-lactamase inhibitor in clinical development that reversibly inactivates serine β-lactamases. To define the spectrum of activity of ceftazidime-avibactam, we tested the susceptibilities of
Escherichia coli
clinical isolates that carry
bla
CMY-2
or
bla
CMY-69
and investigated the inactivation kinetics of CMY-2. Our analysis showed that CMY-2-containing clinical isolates of
E. coli
were highly susceptible to ceftazidime-avibactam (MIC
90
, ≤0.5 mg/liter); in comparison, ceftazidime had a MIC
90
of >128 mg/liter. More importantly, avibactam was an extremely potent inhibitor of CMY-2 β-lactamase, as demonstrated by a second-order onset of acylation rate constant (
k
2
/
K
) of (4.9 ± 0.5) × 10
4
M
−1
s
−1
and the off-rate constant (
k
off
) of (3.7 ± 0.4) ×10
−4
s
−1
. Analysis of the reaction of avibactam with CMY-2 using mass spectrometry to capture reaction intermediates revealed that the CMY-2–avibactam acyl-enzyme complex was stable for as long as 24 h. Molecular modeling studies raise the hypothesis that a series of successive hydrogen-bonding interactions occur as avibactam proceeds through the reaction coordinate with CMY-2 (e.g., T316, G317, S318, T319, S343, N346, and R349). Our findings support the microbiological and biochemical efficacy of ceftazidime-avibactam against
E. coli
containing plasmid-borne CMY-2 and CMY-69.
Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases
Authors: Coen Natacha , Duraffour Sophie , Haraguchi Kazuhiro , Balzarini Jan , van den Oord Joost J. , Snoeck Robert , Andrei Graciela
Published: May 2014

The emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivity
in vitro
. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.
Structural Analysis of Base Substitutions in Thermus thermophilus 16S rRNA Conferring Streptomycin Resistance
Authors: Demirci Hasan , Murphy Frank V. , Murphy Eileen L. , Connetti Jacqueline L. , Dahlberg Albert E. , Jogl Gerwald , Gregory Steven T.
Published: May 2014

Streptomycin is a bactericidal antibiotic that induces translational errors. It binds to the 30S ribosomal subunit, interacting with ribosomal protein S12 and with 16S rRNA through contacts with the phosphodiester backbone. To explore the structural basis for streptomycin resistance, we determined the X-ray crystal structures of 30S ribosomal subunits from six streptomycin-resistant mutants of
Thermus thermophilus
both in the apo form and in complex with streptomycin. Base substitutions at highly conserved residues in the central pseudoknot of 16S rRNA produce novel hydrogen-bonding and base-stacking interactions. These rearrangements in secondary structure produce only minor adjustments in the three-dimensional fold of the pseudoknot. These results illustrate how antibiotic resistance can occur as a result of small changes in binding site conformation.
Clinical Outcomes of Hospital-Acquired Infection with Acinetobacter nosocomialis and Acinetobacter pittii
Authors: Chusri Sarunyou , Chongsuvivatwong Virasakdi , Rivera Jesabel I. , Silpapojakul Kachornsakdi , Singkhamanan Kamonnut , McNeil Edward , Doi Yohei
Published: May 2014

The role of
Acinetobacter nosocomialis
and
Acinetobacter pittii
, which belong to the
A. calcoaceticus
-
A. baumannii
complex, in hospital-acquired infections is increasingly recognized. Here we describe a retrospective cohort study of hospital-acquired
A. calcoaceticus
-
A. baumannii
complex infections at a university hospital in Thailand. A total of 222 unique cases were identified between January 2010 and December 2011. The genomospecies of the
A. calcoaceticus
-
A. baumannii
complex isolates were classified as follows:
A. baumannii
, 197 (89%);
A. nosocomialis
, 18 (8%); and
A. pittii
, 7 (3%). All
A. nosocomialis
and
A. pittii
isolates were susceptible to imipenem and meropenem. The patients infected with
A. nosocomialis
and
A. pittii
had lower 30-day mortality than those infected with carbapenem-susceptible
A. baumannii
(
P
= 0.025) and carbapenem-resistant
A. baumannii
(
P
= 0.013). The factors influencing 30-day mortality were infection with non-
baumannii A. calcoaceticus
-
A. baumannii
complex (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.03 to 0.51;
P
= 0.004), infection with carbapenem-resistant
A. baumannii
(HR, 1.57; 95% CI, 0.89 to 2.79;
P
= 0.105), appropriate empirical antimicrobial therapy (HR, 0.38; 95% CI, 0.23 to 0.61;
P
< 0.001), and higher acute physiology and chronic health evaluation II (APACHE II) score (HR, 1.15; 95% CI, 1.10 to 1.19;
P
< 0.001). In
Galleria mellonella
assays, the survival rates were significantly higher for the larvae infected with
A. nosocomialis
or
A. pittii
than for those infected with either carbapenem-susceptible
A. baumannii
or carbapenem-resistant
A. baumannii
, but no differences in survival rates were observed between carbapenem-susceptible
A. baumannii
and carbapenem-resistant
A. baumannii
. These findings suggest intrinsic differences in virulence between non-
baumannii A. calcoaceticus
-
A. baumannii
complex species and
A. baumannii
but not between carbapenem-susceptible and resistant
A. baumannii
.
Phase-Variable Expression of
lptA
Modulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides
Authors: Kandler Justin L. , Joseph Sandeep J. , Balthazar Jacqueline T. , Dhulipala Vijaya , Read Timothy D. , Jerse Ann E. , Shafer William M.
Published: May 2014

Phosphoethanolamine (PEA) decoration of lipid A produced by
Neisseria gonorrhoeae
has been linked to bacterial resistance to cationic antimicrobial peptides/proteins (CAMPs) and
in vivo
fitness during experimental infection. We now report that the
lptA
gene, which encodes the PEA transferase responsible for this decoration, is in an operon and that high-frequency mutation in a polynucleotide repeat within
lptA
can influence gonococcal resistance to CAMPs.
Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii
Authors: Dey Sumanta , Mazumder Somnath , Siddiqui Asim Azhar , Iqbal M. Shameel , Banerjee Chinmoy , Sarkar Souvik , De Rudranil , Goyal Manish , Bindu Samik , Bandyopadhyay Uday
Published: May 2014

The liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected with
Plasmodium yoelii
(45% parasitemia) were treated with the antimalarial α/β-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.
Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response
Authors: Bayry Jagadeesh , Beaussart Audrey , Dufrêne Yves F. , Sharma Meenu , Bansal Kushagra , Kniemeyer Olaf , Aimanianda Vishukumar , Brakhage Axel A. , Kaveri Srini V. , Kwon-Chung Kyung J. , Latgé Jean-Paul , Beauvais Anne
Published: May 2014

In
Aspergillus fumigatus
, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the
A. fumigatus
conidial surface.
Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection
Authors: Brant Fatima , Miranda Aline S. , Esper Lisia , Rodrigues David Henrique , Kangussu Lucas Miranda , Bonaventura Daniella , Soriani Frederico Marianetti , Pinho Vanessa , Souza Danielle G. , Rachid Milene Alvarenga , Weiss Louis M. , Tanowitz Herbert B. , Teixeira Mauro Martins , Teixeira Antônio Lucio , Machado Fabiana Simão
Published: May 2014

Infection with
Plasmodium falciparum
may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality.
Plasmodium berghei
Anka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected with
P. berghei
Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, and
P. berghei
Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.
Deficiency of Lymph Node-Resident Dendritic Cells (DCs) and Dysregulation of DC Chemoattractants in a Malnourished Mouse Model of Leishmania donovani Infection
Authors: Ibrahim Marwa K. , Barnes Jeffrey L. , Osorio E. Yaneth , Anstead Gregory M. , Jimenez Fabio , Osterholzer John J. , Travi Bruno L. , Ahuja Seema S. , White A. Clinton , Melby Peter C.
Published: May 2014

Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan
Leishmania donovani
. We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of
L. donovani
. In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of
L. donovani
-infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of
L. donovani
is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.
Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection
Authors: Krishna Sruti , Yang Jialong , Wang Hongxia , Qiu Yurong , Zhong Xiao-Ping
Published: May 2014

The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) integrates various environmental cues such as the presence of antigen, inflammation, and nutrients to regulate T cell growth, metabolism, and function. The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of an mTOR-containing multiprotein complex called mTOR complex 1. Recent studies have revealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial homeostasis. Given the emerging role of mTOR activity in the regulation of the quantity and quality of CD8 T cell responses, in this study, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and memory CD8 T cell responses to bacterial infection. Using an established model system of transgenic CD8 cell adoptive transfer and challenge with
Listeria monocytogenes
expressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell responses, resulting in weak expansion, exaggerated contraction, and poor memory generation. Poor expansion of TSC1-deficient cells was associated with defects in survival and proliferation
in vivo
, while enhanced contraction was correlated with an increased ratio of short-lived effectors to memory precursors in the effector cell population. This perturbation of effector-memory differentiation was concomitant with decreased expression of eomesodermin among activated TSC1 knockout cells. Upon competitive adoptive transfer with wild-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in expansion but not cytokine production. Taken together, these findings provide direct evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and memory responses.
Amyloidosis in bilateral external auditory canals
Authors: Hosoi Takahiro , Dhaliwal Gurpreet , Tokuda Yasuharu
Published: May 2014

We report a 76-year-old man, a retired farmer, presenting with bilateral external auditory canal obstruction. Skin examination revealed multiple pruritic nodules and periorbital purpura. Ear canal opening surgery was performed. Skin and ear canal biopsy revealed extensive amyloid depositions. Immunoelectrophoresis for urinary Bence-Jones protein was positive, and bone marrow examination showed plasma cell dyscrasia. He received chemotherapy for amyloid light-chain amyloidosis secondary to light-chain multiple myeloma but died from myeloma progression. This case demonstrated how infiltrative conditions such as amyloidosis can lead to bilateral auditory canal obstruction and that the diagnosis of amyloidosis can be missed if a clinician focuses solely on a single organ.
Symptomatic anterior subtalar arthrosis after ankle arthrodesis
Authors: Lui Tun Hing
Published: May 2014

A 76-year-old man reported right lateral heel pain 11 years after ankle arthrodesis. Clinically, there was tenderness in the right sinus tarsi and over the junction point between the talonavicular and calcaneocuboid joints. Radiographs showed that the joint spaces of the posterior subtalar joint and the talonavicular joint were preserved although there were osteophytes at both joints. Arthroscopic findings showed degeneration of the anterior subtalar and talonavicular joints. The symptoms subsided after arthroscopic debridement.
Anosmia and hypogeusia in Churg-Strauss syndrome
Authors: Tallab Hussam F , Doty Richard L
Published: May 2014

Churg-Strauss syndrome is a rare disorder that is often misdiagnosed. In this report we describe a 57-year-old man with Churg-Strauss syndrome who presented with symptoms of lessened smell and taste function that occurred approximately 3 months before the onset of his neurological symptoms. Psychophysical testing using a battery of well-validated smell and taste tests revealed that the patient had total anosmia and marked hypogeusia. While one anecdotal report exists in the Spanish literature that alludes to the presence of anosmia in a single case of this syndrome, no further confirmation of such dysfunction has appeared in the literature. These findings support the concept that smell and taste loss may be an early sign of this disorder.
Final results from the Betaseron (interferon β-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events
Authors: Coyle P K , Sinclair S M , Scheuerle A E , Thorp J M , Albano J D , Rametta M J
Published: May 2014

Objective

Women with multiple sclerosis are often diagnosed and treated during their reproductive years. Limited data are available on the safety of treatment during pregnancy. The Betaseron Pregnancy Registry prospectively monitored women exposed to interferon β-1b (IFNβ-1b) during pregnancy to estimate the rates of birth defects, spontaneous abortions (SABs) and other negative outcomes in this population.

Design

From 2006 to 2011, this observational registry enrolled women exposed prior to conception or during pregnancy (but prior to or without abnormalities on prenatal screening). Follow-up continued from enrolment through the 4-month paediatric visit.

Setting

Patients in the USA who met these criteria were enrolled in the registry.

Results

The registry enrolled 99 pregnant women; 3 were lost to follow-up. The earliest exposure to IFNβ-1b occurred during the first trimester for 95 pregnancies and in the third trimester for 1 pregnancy. There were 99 birth outcomes (3 twins), including 86 (86.9%) live births, 11 (11.1%) SABs and 2 (2%) stillbirths. Birth defects were reported in five (5.1%) cases. Rates of birth defects and SAB were not significantly different from population comparators. No developmental concerns were identified at the 4-month paediatric visit.

Conclusions

The small sample size limits the ability to draw definitive conclusions; however, there was no pattern to suggest increased negative outcomes with IFNβ-1b.

Clinical trials registration number

NCT00317564.
Efficacy of a pectin‐lecithin complex for treatment and prevention of gastric ulcers in horses
Authors: Sanz M. G. , Viljoen A. , Saulez M. N. , Olorunju S. , Andrews F. M.
Published: May 2014

The objective of this study was to evaluate the effect of a commercial feed supplement containing pectin‐lecithin on squamous mucosa ulceration in horses exposed to an experimental ulceration model. Five mares were treated while five mares were controls for this crossover, blinded study. The mares were fed concentrates and hay and were stabled with a two‐hour turn out per day for a period of four weeks. The pectin‐lecithin complex was fed for the duration of the study on the treated group. At the end of a four‐week period, all mares underwent a seven‐day alternating feed deprivation (week 5). The study was repeated again after a four‐week washout period. Gastroscopy was performed on days 1, 28 and 35 of the study and was digitally recorded. Independent evaluation of the recordings and scoring of the lesions using the Equine Gastric Ulcer Syndrome (EGUS), severity and number scores were performed by three experienced gastroscopists. The prevalence and severity of squamous ulcers significantly increased after intermittent feed deprivation (P<0.001). No significant effect of the treatment was observed (P>0.05). In this study, the addition of a commercially available pectin‐lecithin complex to the feed of horses for five weeks did not prevent or minimise the risk for gastric ulceration of the squamous mucosa.