bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis B Virus Capsid Assembly Modulators, but Not Nucleoside Analogs, Inhibit the Production of Extracellular Pregenomic RNA and Spliced RNA Variants
Authors: Lam Angela M. , Ren Suping , Espiritu Christine , Kelly Mollie , Lau Vincent , Zheng Lingjie , Hartman George D. , Flores Osvaldo A. , Klumpp Klaus 
Published: May 2017

ABSTRACT
The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5′ and 3′ ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA.
MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture
Authors: Wu Vincent H. , Smith Robert A. , Masoum Sara , Raugi Dana N. , Ba Selly , Seydi Moussa , Grobler Jay A. , Gottlieb Geoffrey S. 
Published: May 2017

ABSTRACTThere is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC50] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC50≤ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.
Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding
Authors: Skagseth Susann , Christopeit Tony , Akhter Sundus , Bayer Annette , Samuelsen Ørjan , Leiros Hanna-Kirsti S. 
Published: May 2017

ABSTRACT

Metallo-β-lactamases (MBLs) threaten the effectiveness of β-lactam antibiotics, including carbapenems, and are a concern for global public health. β-Lactam/β-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-β-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1. The role of S228P was studied by comparisons of TMB-1 and TMB-2, and E119 was investigated through the construction of site-directed mutants of TMB-1, E119Q, E119S, and E119A (E119Q/S/A). All TMB variants were characterized through enzyme kinetic studies. Thermostability and crystallization analyses of TMB-1 were performed. Thiol-based inhibitors were investigated by determining the 50% inhibitory concentrations (IC
50
) and binding using surface plasmon resonance (SPR) for analysis of TMB-1. Thermostability measurements found TMB-1 to be stabilized by high NaCl concentrations. Steady-state enzyme kinetics analyses found substitutions of E119, in particular, substitutions associated with the penicillins, to affect hydrolysis to some extent. TMB-2 with S228P showed slightly reduced catalytic efficiency compared to TMB-1. The IC
50
levels of the new thiol-based inhibitors were 0.66 μM (inhibitor 2a) and 0.62 μM (inhibitor 2b), and the equilibrium dissociation constant (

K
D

) of inhibitor 2a was 1.6 μM; thus, both were more potent inhibitors than
l
-captopril (IC
50
= 47 μM;

K
D

= 25 μM). The crystal structure of TMB-1 was resolved to 1.75 Å. Modeling of inhibitor 2b in the TMB-1 active site suggested that the presence of the W64 residue results in T-shaped π-π stacking and R224 cation-π interactions with the phenyl ring of the inhibitor. In sum, the results suggest that residues 119 and 228 affect the catalytic efficiency of TMB-1 and that inhibitors 2a and 2b are more potent inhibitors for TMB-1 than
l
-captopril.
Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen
Authors: Czyż Daniel M. , Willett Jonathan W. , Crosson Sean 
Published: May 2017

ABSTRACT

Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with
Brucella abortus
undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells.
B. abortus
efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect
in vitro
growth of
B. abortus
in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and
B. abortus
uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.

IMPORTANCE
Brucella
spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with
Brucella abortus
undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of
B. abortus
in an
in vitro
infection model; these drugs may be broadly useful therapeutics for intracellular infections.
Comparison of corneal dynamic parameters and tomographic measurements using Scheimpflug imaging in keratoconus
Authors: Chan Tommy CY , Wang Yu Meng , Yu Marco , Jhanji Vishal 
Published: May 2017

AimTo compare the diagnostic ability of corneal tomography and corneal dynamic response measurements in normal and keratoconus eyes.MethodsConsecutive patients with grade II–III keratoconus and age-matched normal subjects were recruited. Corneal imaging was performed using Pentacam (Oculus Optikgeräte, Wetzlar, Germany) and Corvis (Oculus Optikgeräte). A beta version of Corvis software was used with three additional parameters: maximal change of arc length, deformation amplitude (DA) ratio 1 and DA ratio 2. Diagnostic ability of both devices to differentiate normal and keratoconus eyes was evaluated using receiver-operating characteristic (ROC) curves. The areas under the ROC curve (AUC) and partial AUC (pAUC) for specificity ≥80% for each parameter of Corvis and final D value of Belin/Ambrosio Enhanced Ectasia Display (BAD) were compared.ResultsForty-two eyes of 42 patients (21 patients with keratoconus and 21 normal subjects) were included. Both groups were age matched (p=0.760). The ROC analysis showed that the final D value of BAD had the highest AUC (0.994) and pAUC (0.194). Maximum inverse radius had the highest AUC (0.954) but a relatively lower pAUC (0.158), while DA ratio 2 had the second highest AUC (0.946) together with the highest pAUC (0.177) among Corvis parameters. There was no significant difference between AUC and pAUC of BAD compared with those of DA ratio 1 (p≥0.162) and DA ratio 2 (p≥0.208).ConclusionsThe results of our study suggest that Corvis measurements have the potential to differentiate keratoconus and normal eyes. The diagnostic ability of novel parameters on Corvis was comparable to Pentacam.
Noise exposure and auditory thresholds of German airline pilots: a cross-sectional study
Authors: Müller Reinhard , Schneider Joachim 
Published: May 2017

ObjectiveThe cockpit workplace of airline pilots is a noisy environment. This study examines the hearing thresholds of pilots with respect to ambient noise and communication sound.MethodsThe hearing of 487 German pilots was analysed by audiometry in the frequency range of 125 Hz–16 kHz in varying age groups. Cockpit noise (free-field) data and communication sound (acoustic manikin) measurements were evaluated.ResultsThe ambient noise levels in cockpits were found to be between 74 and 80 dB(A), and the sound pressure levels under the headset were found to be between 84 and 88 dB(A).The left–right threshold differences at 3, 4 and 6 kHz show evidence of impaired hearing at the left ear, which worsens by age.In the age groups <40/≥40 years the mean differences at 3 kHz are 2/3 dB, at 4 kHz 2/4 dB and at 6 kHz 1/6 dB.In the pilot group which used mostly the left ear for communication tasks (43 of 45 are in the older age group) the mean difference at 3 kHz is 6 dB, at 4 kHz 7 dB and at 6 kHz 10 dB. The pilots who used the headset only at the right ear also show worse hearing at the left ear of 2 dB at 3 kHz, 3 dB at 4 kHz and at 6 kHz. The frequency-corrected exposure levels under the headset are 7–11 dB(A) higher than the ambient noise with an averaged signal-to-noise ratio for communication of about 10 dB(A).ConclusionsThe left ear seems to be more susceptible to hearing loss than the right ear. Active noise reduction systems allow for a reduced sound level for the communication signal below the upper exposure action value of 85 dB(A) and allow for a more relaxed working environment for pilots.
Future directions in reservoir modelling: new tools and ‘fit-for-purpose’ workflows
Authors: Bentley Mark , Ringrose Philip 
Published: May 2017

Abstract
Reservoir modelling tools can be invaluable for integrating knowledge and for supporting strategic oil field decisions. The pertinent issue is the capability of the modelling toolbox to achieve the required support: does modelling generate insights into the characterization of the subsurface, does it increase or decrease our working efficiency and does it help or hinder us in decision-making? In this respect, we see two directions emerging in reservoir modelling and simulation. One surrounds software technology development and a move towards a grid-independent world. This is a current research issue but some of the components required to complete a new workflow are already in place and tools for certain specific applications may not be far away. The other involves a change in approach to model design. This involves a move away from big, detailed ‘life-cycle’ models to more nimble workflows involving multi-models (either multi-scale or multi-concept) which may or not include full-field modelling exercises. A distinction between ‘resource models’ and ‘decision models’ helps crystallize this, is a positive step towards achieving ‘fit-for-purpose’ models, and is a change of model design strategy which can be achieved immediately.
An improved procedure for pre-drill calculation of fracture pressure
Authors: Lahann Richard W. , Swarbrick Richard E. 
Published: May 2017

Abstract

Pre-drill modelling of fracture pressure (FP) is an essential part of well planning, reserve estimation and evaluation of the potential for inducing seismicity as the result of fluid injection. Estimation of stress ratio or Poisson's ratio values or compaction state with depth is required in frequently used FP models. A new method to estimate FP is proposed which is based on Leak Off (LOT) and pore fluid pressure (Pp) data from offset wells and vertical stress (
S
v
)–depth relationships. LOT/
S
v
ratios observed in intervals of offset wells that are normally pressured (hydrostatic) are used to define an expected FP/
S
v
ratio for hydrostatic Pp conditions for all depths. Typical FP/
S
v
ratios for hydrostatic conditions derived using LOT data range from 0.81 to 0.89. Observed LOT values associated with Pp greater than hydrostatic (overpressured) in offset wells are used to quantify the rate of increase in FP with increasing overpressure (OP). The expected FP for hydrostatic conditions is compared with observed LOT values from depths where the pore fluid is overpressured and a relationship of increased FP, relative to the expected FP for hydrostatic conditions (residual FP (FPr)) with increasing OP is defined. The FPr:OP ratio typically ranges from 0.24 to 0.43. Fracture pressure models developed by this procedure may be used to predict FP for wells in different water depths and with Pp conditions different from those in the offset wells. The use of the model is demonstrated in three case studies taken from different geological settings: the Scotian shelf (offshore Nova Scotia), offshore Central Gulf of Mexico and the chalk interval from the Central North Sea.
State of stress in exhumed basins and implications for fluid flow: insights from the Illizi Basin, Algeria
Authors: English Joseph M. , Finkbeiner Thomas , English Kara L. , Cherif Rachida Yahia 
Published: May 2017

Abstract

The petroleum prospectivity of an exhumed basin is largely dependent on the ability of pre-existing traps to retain oil and gas volumes during and after the exhumation event. Although faults may act as lateral seals in petroleum traps, they may start to become hydraulically conductive again and enable fluid flow and hydrocarbon leakage during fault reactivation. We constrain the present day
in situ
stresses of the exhumed Illizi Basin in Algeria and demonstrate that the primary north–south and NW–SE (vertical strike-slip) fault systems in the study area are close to critical stress (i.e. an incipient state of shear failure). By contrast, the overpressured and unexhumed Berkine Basin and Hassi Messaoud areas to the north do not appear to be characterized by critical stress conditions. We present conceptual models of stress evolution and demonstrate that a sedimentary basin with benign
in situ
stresses at maximum burial may change to being characterized by critical stress conditions on existing fault systems during exhumation. These models are supportive of the idea that the breaching of a closed, overpressured system during exhumation of the Illizi Basin may have been a driving mechanism for the regional updip flow of high-salinity formation water within the Ordovician reservoirs during Eocene–Miocene time. This work also has implications for petroleum exploration in exhumed basins. Fault-bounded traps with faults oriented at a high angle to the maximum principal horizontal stress direction in strike-slip or normal faulting stress regimes are more likely to have retained hydrocarbons in exhumed basins than fault-bounded traps with faults that are more optimally oriented for shear failure and therefore have a greater propensity to become critically stressed during exhumation.
Abnormal Global Longitudinal Strain Predicts Future Deterioration of Left Ventricular Function in Heart Failure Patients With a Recovered Left Ventricular Ejection Fraction
Authors: Adamo Luigi , Perry Andrew , Novak Eric , Makan Majesh , Lindman Brian R. , Mann Douglas L. 
Published: May 2017

Background—
Patients with recovery of left ventricular ejection fraction (LVEF) remain at risk for future deterioration of LVEF. However, there are no tools to risk stratify these patients. We hypothesized that global longitudinal strain (GLS) could predict sustained recovery within this population.

Methods and Results—

We retrospectively identified 96 patients with a reduced LVEF <50% (screening echocardiogram), whose LVEF had increased by at least 10% and normalized (>50%) on evidence-based medical therapies (baseline echocardiogram). We examined absolute GLS on the baseline echocardiogram in relation to changes in LVEF on a follow-up echocardiogram. Patients with recovered LVEF had a wide range of GLS. The GLS on the baseline study correlated with the LVEF at the time of follow-up (
r
=0.33;
P
<0.001). The likelihood of having an LVEF >50% on follow-up increased by 24% for each point increase in absolute GLS on the baseline study (odds ratio, 1.24;
P
=0.001). An abnormal GLS (≤16%) at baseline had a sensitivity of 88%, a specificity of 46%, and an accuracy of 0.67 (
P
<0.001) as a predictor of a decrease in LVEF >5% during follow-up. A normal GLS (>16%) on the baseline study had a sensitivity of 47%, a specificity of 83%, and an accuracy of 0.65 (
P
=0.002) for predicting a stable LVEF (−5% to 5%) on follow-up.

Conclusions—
In patients with a recovered LVEF, an abnormal GLS predicts the likelihood of having a decreased LVEF during follow-up, whereas a normal GLS predicts the likelihood of stable LVEF during recovery.
Ultrasound-Guided Thrombin Injection Is a Safe and Effective Treatment for Femoral Artery Pseudoaneurysm in the Morbidly Obese
Authors: Yoo Taehwan , Starr Jean E. , Go Michael R. , Vaccaro Patrick S. , Satiani Bhagwan , Haurani Mounir J. 
Published: May 2017

Introduction: Ultrasound-guided thrombin injection (UGTI) is a well-established practice for the treatment of femoral artery pseudoaneurysm. This procedure is highly successful but dependent on appropriate pseudoaneurysm anatomy and adequate ultrasound visualization. Morbid obesity can present a significant technical challenge due to increased groin adiposity, resulting in poor visualization of critical structures needed to safely perform the procedure. We aim to evaluate the safety and efficacy of UGTI to treat femoral artery pseudoaneurysm in the morbidly obese. Methods: This is a retrospective cohort study in which all patients who underwent UGTI at The Ohio State University Ross Heart Hospital from 2009 to 2014 were analyzed for patient characteristics and stratified by body mass index (BMI). Patients with BMI ≥ 35 were considered morbidly obese and were compared to patients with a BMI < 35. Outcome was failed treatment resulting in residual pseudoaneurysm. Results: Our cohort consisted of 54 patients who underwent thrombin injection. There were 41 nonmorbidly obese and 13 morbidly obese patients. Mean age was 64.5 years. The cohort was 44.4% male. There were 6 failures, of which 1 underwent successful repeat injection and 5 underwent open surgical repair. There was no statistically significant difference in failure between nonmorbidly obese and morbidly obese patients (9.8% vs 15.4%, P = .45). There were no embolic/thrombotic complications. Conclusion: Ultrasound-guided thrombin injection is a safe and effective therapy in the morbidly obese for the treatment of femoral artery pseudoaneurysm. In the hands of experienced sonographers and surgeons with adequate visualization of the pseudoaneurysm sac, UGTI should remain a standard therapy in the morbidly obese.
The Relationship between Internal and External Stakeholders and Organisational Alignment
Authors: Da Camara Nuno 
Published: May 2017

Reputational Risk is a hot topic and is on the agenda of many boards, but what are the key issues associated with ensuring that it is appropriately managed? Of particular note, the relationship between internal and external stakeholders has been identified as being critical. This is examined in this Henley Manager Update, together with the importance of corporate brand management and the issues central in aligning the risks of internal and external stakeholders.
ACDF Graft Selection by Surgeons: Survey of AOSpine Members
Authors: Yoon S. Tim , Konopka Jeffrey A. , Wang Jeffrey C. , Youssef Jim A. , Meisel Hans Joerg , Brodke Darrel S. , Park Jong-Beom 
Published: May 2017

Study Design: Cross-sectional survey study. Objective: To determine what are the most commonly used graft materials in anterior cervical discectomy and fusion and whether the choice of graft is affected by surgeon’s training, years in practice, geographic location, practice setting, or surgeon’s perceived difficulty in achieving fusion. Methods: A 23-question survey was sent out to 5334 surgeons using the Global AO Spine database. Response data was then stratified into surgeon training, years of practice, practice type, and global region. Results: Overall, surgeons believe that graft selection affects fusion rates (89.3% of surgeons) and affects time to fusion (86.0% of surgeons). The use of a cage is currently the most common structural graft component used worldwide at 64.1%. Of surgeons that use cages, the PEEK Cage makes up 84%. North American surgeons differ from this global trend and use composite allograft more commonly. The choice to add a nonstructural graft component was reported at 74%. This result was similar for performing multilevel fusions at 72.8%. The selection of nonstructural graft material depends on whether the type of surgery is considered simple or complex. Most surgeons are not satisfied with available literature comparing effectiveness of grafts but believed that there was sufficient evidence to support the use of their chosen graft. Conclusion: Almost all surgeons believe that fusion is important to anterior cervical discectomy and fusion surgery outcomes and that most surgeons believe graft choice affects fusion. However, this survey indicates that there is great variability in the type of graft material used by spine surgeons across the world.