bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection
Authors: Giacobbi Nicholas S. , Sluis-Cremer Nicolas 
Published: May 2017

ABSTRACT
Rilpivirine (RPV), dapivirine (DPV), and MIV-150 are in development as microbicides. It is not known whether they will block infection of circulating nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant human immunodeficiency virus type 1 (HIV-1) variants. Here, we demonstrate that the activity of DPV and MIV-150 is compromised by many resistant viruses containing single or double substitutions. High DPV genital tract concentrations from DPV ring use may block replication of resistant viruses. However, MIV-150 genital tract concentrations may be insufficient to inhibit many resistant viruses, including those harboring K103N or Y181C.
Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients
Authors: van't Boveneind-Vrubleuskaya Natasha , Seuruk Tatiana , van Hateren Kai , van der Laan Tridia , Kosterink Jos G. W. , van der Werf Tjip S. , van Soolingen Dick , van den Hof Susan , Skrahina Alena , Alffenaar Jan-Willem C. 
Published: May 2017

ABSTRACT

Pharmacodynamics are especially important in the treatment of multidrug- and extensively drug-resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to MIC (
f
AUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter for predicting the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for
f
AUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of the treatment regimen at a dose of 15 mg/kg administered once daily. Blood samples obtained at steady state before and 1, 2, 3, 4, 7, and 12 h after drug administration were measured by validated liquid chromatography-tandem mass spectrometry. The MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 years (interquartile range [IQR] = 27 to 35 years) were enrolled in this study. The median AUC
0–24
was 98.8 mg/h/liter (IQR = 84.8 to 159.6 mg/h/liter). The MIC median value for LFX was 0.5 mg/liter with a range of 0.25 to 2.0 mg/liter, and the median
f
AUC
0–24
/MIC ratio was 109.5 (IQR = 48.5 to 399.4). In 4 of the 20 patients, the value was below the target value of ≥100. When MICs of 0.25, 0.5, 1.0, and 2.0 mg/liter were applicable, 19, 18, 3, and no patients, respectively, had an
f
AUC/MIC ratio that exceeded 100. We observed a large variability in AUC. An
f
AUC
0–24
/MIC of ≥100 was only observed when the MIC values for LFX were 0.25 to 0.5 mg/liter. Dosages exceeding 15 mg/kg should be considered for target attainment if exposures are assumed to be safe. (This study has been registered at ClinicalTrials.gov under registration no. NCT02169141.)
Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-
O
-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus
Authors: Merino-Ramos Teresa , Jiménez de Oya Nereida , Saiz Juan-Carlos , Martín-Acebes Miguel A. 
Published: May 2017

ABSTRACT

Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-
O
-methyl nordihydroguaiaretic acid (M
4
N), on the infection of WNV. Both compounds inhibited the infection of WNV, likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway may constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M
4
N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M
4
N, as potential candidates for further antiviral development against medically relevant flaviviruses.
Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae Mediated by Chromosomal Integration of Plasmid DNA
Authors: Cienfuegos-Gallet Astrid V. , Chen Liang , Kreiswirth Barry N. , Jiménez J. Natalia 
Published: May 2017

ABSTRACTHere we describe the spread of colistin resistance in clinical isolates of carbapenem-resistantKlebsiella pneumoniaein Medellín, Colombia. Among 32 isolates collected between 2012 and 2014, 24 showed genetic alterations inmgrB. Nineteen isolates belonged to sequence type 512 (ST512) (or its single locus variant [SLV]) and harbored an 8.1-kbhsdMSRinsertion corresponding to ISKpn25, indicating a clonal expansion of the resistant strain. The insertion region showed 100% identity to several plasmids, suggesting that the colistin resistance is mediated by chromosomal integration of plasmid DNA.
Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway
Authors: Leitherer Sabine , Clos Joachim , Liebler-Tenorio Elisabeth M. , Schleicher Ulrike , Bogdan Christian , Soulat Didier 
Published: May 2017

ABSTRACTSimilar to other intracellular pathogens,Leishmaniaparasites are known to evade the antimicrobial effector functions of host immune cells. To date, however, only a few virulence factors have been described forLeishmania major, one of the causative agents of cutaneous leishmaniasis. Here, we have characterized the expression and function of anL. majorphosphatase, which we termed LmPRL-1. This enzyme shows a strong structural similarity to the human phosphatases of regenerating liver (PRL-1, -2, and -3) that regulate the proliferation, differentiation, and motility of cells. The biochemical characterization of theL. majorphosphatase revealed that the enzyme is redox sensitive. When analyzing the subcellular localization of LmPRL-1 in promastigotes, amastigotes, and infected macrophages, we found that the phosphatase was predominantly expressed and secreted by promastigotes via the exosome route. Finally, we observed that ectopic expression of LmPRL-1 inL. majorled to an increased number of parasites in macrophages. From these data, we conclude that theL. majorphosphatase LmPRL-1 contributes to the intracellular survival of the parasites in macrophages.
Antibodies against
In Vivo
-Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei
Authors: Zimmerman Shawn M. , Dyke Jeremy S. , Jelesijevic Tomislav P. , Michel Frank , Lafontaine Eric R. , Hogan Robert J. 
Published: May 2017

ABSTRACT

Burkholderia mallei
, a facultative intracellular bacterium and tier 1 biothreat, causes the fatal zoonotic disease glanders. The organism possesses multiple genes encoding autotransporter proteins, which represent important virulence factors and targets for developing countermeasures in pathogenic Gram-negative bacteria. In the present study, we investigated one of these autotransporters, BatA, and demonstrate that it displays lipolytic activity, aids in intracellular survival, is expressed
in vivo
, elicits production of antibodies during infection, and contributes to pathogenicity in a mouse aerosol challenge model. A mutation in the
batA
gene of wild-type strain ATCC 23344 was found to be particularly attenuating, as BALB/c mice infected with the equivalent of 80 median lethal doses cleared the organism. This finding prompted us to test the hypothesis that vaccination with the
batA
mutant strain elicits protective immunity against subsequent infection with wild-type bacteria. We discovered that not only does vaccination provide high levels of protection against lethal aerosol challenge with
B. mallei
ATCC 23344, it also protects against infection with multiple isolates of the closely related organism and causative agent of melioidosis,
Burkholderia pseudomallei
. Passive-transfer experiments also revealed that the protective immunity afforded by vaccination with the
batA
mutant strain is predominantly mediated by IgG antibodies binding to antigens expressed exclusively
in vivo
. Collectively, our data demonstrate that BatA is a target for developing medical countermeasures and that vaccination with a mutant lacking expression of the protein provides a platform to gain insights regarding mechanisms of protective immunity against
B. mallei
and
B. pseudomallei
, including antigen discovery.
Conformational Changes of an Interdomain Linker Mediate Mechanical Signal Transmission in Sensor Kinase BvgS
Authors: Lesne Elodie , Dupré Elian , Locht Camille , Antoine Rudy , Jacob-Dubuisson Françoise 
Published: May 2017

ABSTRACT

The whooping cough agent,
Bordetella pertussis
, controls the expression of its large virulence regulon in a coordinated manner through the two-component system BvgAS. BvgS is a dimeric, multidomain sensor kinase. Each monomer comprises, in succession, tandem periplasmic Venus flytrap (VFT) domains, a transmembrane segment, a cytoplasmic Per-Arnt-Sim (PAS) domain, a kinase module, and additional phosphorelay domains. BvgS shifts between kinase and phosphatase modes of activity in response to chemical modulators that modify the clamshell motions of the VFT domains. We have shown previously that this regulation involves a shift between distinct states of conformation and dynamics of the two-helix coiled-coil linker preceding the enzymatic module. In this work, we determined the mechanism of signal transduction across the membrane via a first linker, which connects the VFT and PAS domains of BvgS, using extensive cysteine cross-linking analyses and other approaches. Modulator perception by the periplasmic domains appears to trigger a small, symmetrical motion of the transmembrane segments toward the periplasm, causing rearrangements of the noncanonical cytoplasmic coiled coil that follows. As a consequence, the interface of the PAS domains is modified, which affects the second linker and eventually causes the shift of enzymatic activity. The major features of this first linker are well conserved among BvgS homologs, indicating that the mechanism of signal transduction unveiled here is likely to be generally relevant for this family of sensor kinases.

IMPORTANCE
Bordetella pertussis
produces virulence factors coordinately regulated by the two-component system BvgAS. BvgS is a sensor kinase, and BvgA is a response regulator that activates gene transcription when phosphorylated by BvgS. Sensor kinases homologous to BvgS are also found in other pathogens. Our goal is to decipher the mechanisms of BvgS signaling, since these sensor kinases may represent new targets for antibacterial agents. Signal perception by the sensor domains of BvgS triggers small motions of the helical linker region underneath. The protein domain that follows this linker undergoes a large conformational change that amplifies the initial signal, causing a shift of activity from kinase to phosphatase. Because BvgS homologs harbor similar regions, these signaling mechanisms are likely to apply generally to that family of sensor kinases.
Modular Organization of the NusA- and NusG-Stimulated RNA Polymerase Pause Signal That Participates in the Bacillus subtilis trp Operon Attenuation Mechanism
Authors: Mondal Smarajit , Yakhnin Alexander V. , Babitzke Paul 
Published: May 2017

ABSTRACT

The
Bacillus subtilis trpEDCFBA
operon is regulated by a transcription attenuation mechanism in which tryptophan-activated TRAP binds to the nascent transcript and blocks the formation of an antiterminator structure such that the formation of an overlapping intrinsic terminator causes termination in the 5′ untranslated region (5′ UTR). In the absence of bound TRAP, the antiterminator forms and transcription continues into the
trp
genes. RNA polymerase pauses at positions U107 and U144 in the 5′ UTR. The general transcription elongation factors NusA and NusG stimulate pausing at both positions. NusG-stimulated pausing at U144 requires sequence-specific contacts with a T tract in the nontemplate DNA (ntDNA) strand within the paused transcription bubble. Pausing at U144 participates in a
trpE
translation repression mechanism. Since U107 just precedes the critical overlap between the antiterminator and terminator structures, pausing at this position is thought to participate in attenuation. Here we carried out
in vitro
pausing and termination experiments to identify components of the U107 pause signal and to determine whether pausing affects the termination efficiency in the 5′ UTR. We determined that the U107 and U144 pause signals are organized in a modular fashion containing distinct RNA hairpin, U-tract, and T-tract components. NusA-stimulated pausing was affected by hairpin strength and the U-tract sequence, whereas NusG-stimulated pausing was affected by hairpin strength and the T-tract sequence. We also determined that pausing at U107 results in increased TRAP-dependent termination in the 5′ UTR, implying that NusA- and NusG-stimulated pausing participates in the
trp
operon attenuation mechanism by providing additional time for TRAP binding.

IMPORTANCE
The expression of several bacterial operons is controlled by regulated termination in the 5′ untranslated region (5′ UTR). Transcription attenuation is defined as situations in which the binding of a regulatory molecule promotes transcription termination in the 5′ UTR, with the default being transcription readthrough into the downstream genes. RNA polymerase pausing is thought to participate in several attenuation mechanisms by synchronizing the position of RNA polymerase with RNA folding and/or regulatory factor binding, although this has only been shown in a few instances. We found that NusA- and NusG-stimulated pausing participates in the attenuation mechanism controlling the expression of the
Bacillus subtilis trp
operon by increasing the TRAP-dependent termination efficiency. The pause signal is organized in a modular fashion containing RNA hairpin, U-tract, and T-tract components.
Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis
Authors: Hilfiker Roger , Meichtry Andre , Eicher Manuela , Nilsson Balfe Lina , Knols Ruud H , Verra Martin L , Taeymans Jan 
Published: May 2017

AimTo assess the relative effects of different types of exercise and other non-pharmaceutical interventions on cancer-related fatigue (CRF) in patients during and after cancer treatment.DesignSystematic review and indirect-comparisons meta-analysis.Data sourcesArticles were searched in PubMed, Cochrane CENTRAL and published meta-analyses.Eligibility criteria for selecting studiesRandomised studies published up to January 2017 evaluating different types of exercise or other non-pharmaceutical interventions to reduce CRF in any cancer type during or after treatment.Study appraisal and synthesisRisk of bias assessment with PEDro criteria and random effects Bayesian network meta-analysis.ResultsWe included 245 studies. Comparing the treatments with usual care during cancer treatment, relaxation exercise was the highest ranked intervention with a standardisedmean difference (SMD) of −0.77 (95% Credible Interval (CrI) −1.22 to −0.31), while massage (−0.78; −1.55 to −0.01), cognitive–behavioural therapy combined with physical activity (combined CBT, −0.72; −1.34 to −0.09), combined aerobic and resistance training (−0.67; −1.01 to −0.34), resistance training (−0.53; −1.02 to −0.03), aerobic (−0.53; −0.80 to −0.26) and yoga (−0.51; −1.01 to 0.00) all had moderate-to-large SMDs. After cancer treatment, yoga showed the highest effect (−0.68; −0.93 to −0.43). Combined aerobic and resistance training (−0.50; −0.66 to −0.34), combined CBT (−0.45; −0.70 to −0.21), Tai-Chi (−0.45; −0.84 to −0.06), CBT (−0.42; −0.58 to −0.25), resistance training (−0.35; −0.62 to −0.08) and aerobic (−0.33; −0.51 to −0.16) showed all small-to-moderate SMDs.ConclusionsPatients can choose among different effective types of exercise and non-pharmaceutical interventions to reduce CRF.
Mechanical properties of a dissimilar aluminum alloy joint welded by hybrid laser–MIG welding
Authors: Wang Qiuying , Chen Hui , Zhu Zongtao , Cui Yunlong 
Published: May 2017

Two dissimilar Al alloys, 5083-H111 and 6005A-T6, were joined by hybrid laser–MIG welding method. Mechanical properties of the welded joint were investigated and compared. The results show that the tensile strength of the dissimilar joint is 219.8 MPa, 11.7% higher than that of 6005A-T5 joint. After statistical analysis of the fatigue data, the [Formula: see text]–[Formula: see text]–[Formula: see text] curves of the dissimilar joint were obtained. The mean fatigue strength at [Formula: see text] of the dissimilar joint is 112.5 MPa. The fatigue strength at [Formula: see text] of the dissimilar joint for a given 10% probability of failure, at a confidence level of 95%, is 101.4 MPa. The fatigue strength at [Formula: see text] of the dissimilar joint is almost same as that of the 6005A-T6 joint. In welded structure designing, different [Formula: see text]–[Formula: see text]–[Formula: see text] curves should be chosen according to the different service conditions and reliability requirements.
Synthesis of organic soluble poly(substituted-aniline) from 2-methyl-6-ethylaniline tar
Authors: Liu Yuan , Li Shu-Bai , Yao Pei , Zhang Qi-Meng 
Published: May 2017

Organic soluble poly(substituted-aniline) was synthesized by chemical oxidative polymerization from 2-methyl-6-ethylaniline tar. The structural information of samples was characterized using FT-IR and SEM techniques. The influences of acid concentration, mole ratio of oxidants to tar, reaction time and temperature were investigated. The solubility of polymers was also studied. The results indicate that the conductivity of poly(substituted-aniline) could reach 2.51 [Formula: see text] S ⋅ cm[Formula: see text] under the reaction conditions with 1 mol./L hydrochloric acid, mole ratio of oxidants to tar = 1, and at 10[Formula: see text]C for 3 h. The polymers show better solubility than polyaniline in most organic solvents.
Design of a charge pump for high voltage driver applications based on 0.35 μm BCD technology
Authors: Zhu Tiezhu , Zhang Yuning , Ji Rendong 
Published: May 2017

Based on the switched capacitor system theory, a new charge pump is designed as the driver of the H-bridge power circuits. The proposed circuit is added with the output feedback control module to realize the steady output, lower the ripple and power noise, and improve the transforming efficiency. Simulation based on 0.35 [Formula: see text] BCD350GE process demonstrates that the circuit has a ripple voltage as low as 200 mV and reaches a high efficiency up to 70% with a load as much as 20 mA when the supply voltage changes from 8 V to 36 V.
An Improved Three-Stage Classifier for Activity Recognition
Authors: Garcia-Ceja Enrique , Brena Ramon F. 
Published: May 2017

Recently, Human Activity Recognition (HAR) has become an important research area because of its wide range of applications in several domains such as health care, elder care, sports monitoring systems, etc. The use of wearable sensors — specifically the use of inertial sensors such as accelerometers and gyroscopes — has become the most common approach to recognize physical activities because of their unobtrusiveness and ubiquity. Overall, the process of building a HAR system starts with a feature extraction phase and then a classification model is trained. In the work of Siirtola et al. is proposed an intermediate clustering step to find the homogeneous groups of activities. For the recognition step, an instance is assigned to one of the groups and the final classification is performed inside that group. In this work we evaluate the clustering-based approach for activity classification proposed by Siirtola with two additional improvements: automatic selection of the number of groups and an instance reassignment procedure. In the original work, they evaluated their method using decision trees on a sports activities dataset. For our experiments, we evaluated seven different classification models on four public activity recognition datasets. Our results with 10-fold Cross Validation showed that the method proposed by Siirtola with our additional two improvements performed better in the majority of cases as compared to using the single classification model under consideration. When using Leave One User Out Cross Validation (user independent model) we found no differences between the proposed method and the single classification model.
Progression from Injection to Surgery for Trigger Finger: A Statistical Analysis
Authors: Ota Hideyuki , Iwatsuki Katsuyuki , Kurimoto Shigeru , Iida Koji , Hirata Hitoshi 
Published: May 2017

Background: The purpose of this study was to identify predictive factors of poor response to intra-flexoral sheath corticosteroid injection, as well as to identify factors associated with patients’ decisions to undergo surgical treatment. Methods: Data from 112 patients who received steroid injection treatment for trigger finger were reviewed retrospectively. Logistic regression was used to assess the prognostic value of factors assumed to affect prognosis (age, sex, underlying disease, history of illness, presence of carpal tunnel syndrome, multiple digit involvement, and pre- and post-operative disability scores). Results: Multiple digits were affected in 42 patients. Associated and underlying conditions were carpal tunnel syndrome (n = 36), hypertension (n = 23), hyperlipidemia (n = 14), and history of malignant tumor (n = 10). Logistic regression analysis showed that multiple digit involvement and Froimson clinical severity score were factors significantly associated with surgical treatment after intra-flexoral sheath corticosteroid injection treatment. These two factors were also found to be associated with the patients’ decisions to undergo surgical treatment. Conclusions: Although local corticosteroid injection is useful in most cases, providers need to counsel patients with multiple digit involvement and/or severe cases about the possibility of requiring additional surgical treatment.