bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamics of volume‐averaged intracellular Ca2+ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations
Authors: Lin Kun‐Han , Taschenberger Holger , Neher Erwin 
Published: December 2016

Key points
The intracellular concentration of free calcium ions ([Ca2+]i) in a nerve terminal controls both transmitter release and synaptic plasticity.
The rapid triggering of transmitter release depends on the local micro‐ or nanodomain of highly elevated [Ca2+]i in the vicinity of open voltage‐gated Ca2+ channels, whereas short‐term synaptic plasticity is often controlled by global changes in residual [Ca2+]i, averaged over the whole nerve terminal volume.
Here we describe dynamic changes of such global [Ca2+]i in the calyx of Held – a giant mammalian glutamatergic nerve terminal, which is particularly suited for biophysical studies.
We provide quantitative data on Ca2+ inflow, Ca2+ buffering and Ca2+ clearance.
These data allow us to predict changes in [Ca2+]i in the nerve terminal in response to a wide range of stimulus protocols at high temporal resolution and provide a basis for the modelling of short‐term plasticity of glutamatergic synapses.
AbstractMany aspects of short‐term synaptic plasticity (STP) are controlled by relatively slow changes in the presynaptic intracellular concentration of free calcium ions ([Ca2+]i) that occur in the time range of a few milliseconds to several seconds. In nerve terminals, [Ca2+]i equilibrates diffusionally during such slow changes, such that the globally measured, residual [Ca2+]i that persists after the collapse of local domains is often the appropriate parameter governing STP. Here, we study activity‐dependent dynamic changes in global [Ca2+]i at the rat calyx of Held nerve terminal in acute brainstem slices using patch‐clamp and microfluorimetry. We use low concentrations of a low‐affinity Ca2+ indicator dye (100 μm Fura‐6F) in order not to overwhelm endogenous Ca2+ buffers. We first study voltage‐clamped terminals, dialysed with pipette solutions containing minimal amounts of Ca2+ buffers, to determine Ca2+ binding properties of endogenous fixed buffers as well as the mechanisms of Ca2+ clearance. Subsequently, we use pipette solutions including 500 μm EGTA to determine the Ca2+ binding kinetics of this chelator. We provide a formalism and parameters that allow us to predict [Ca2+]i changes in calyx nerve terminals in response to a wide range of stimulus protocols. Unexpectedly, the Ca2+ affinity of EGTA under the conditions of our measurements was substantially lower (KD = 543 ± 51 nm) than measured in vitro, mainly as a consequence of a higher than previously assumed dissociation rate constant (2.38 ± 0.20 s−1), which we need to postulate in order to model the measured presynaptic [Ca2+]i transients.
A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis
Authors: Fofana Mariam O. , Shrestha Sourya , Knight Gwenan M. , Cohen Ted , White Richard G. , Cobelens Frank , Dowdy David W. 
Published: December 2016

ABSTRACT

Several infectious diseases of global importance—e.g., HIV infection and tuberculosis (TB)—require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the
de novo
emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of
Mycobacterium tuberculosis
transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB—defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)—exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.
Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults
Authors: Griffin M. Pamela , Khan Anis A. , Esser Mark T. , Jensen Kathryn , Takas Therese , Kankam Martin K. , Villafana Tonya , Dubovsky Filip 
Published: December 2016

ABSTRACT

Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (
n
= 102) or placebo (
n
= 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.)
Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
Authors: Castro María del Mar , Gomez Maria Adelaida , Kip Anke E. , Cossio Alexandra , Ortiz Eduardo , Navas Adriana , Dorlo Thomas P. C. , Saravia Nancy Gore 
Published: December 2016

ABSTRACT

An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up.
Leishmania
(
Viannia
)
panamensis
predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments (
P
< 0.01).
Leishmania
persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination.
In vitro
miltefosine susceptibility was similar for
Leishmania
strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.)
Tet38 Efflux Pump Affects Staphylococcus aureus Internalization by Epithelial Cells through Interaction with CD36 and Contributes to Bacterial Escape from Acidic and Nonacidic Phagolysosomes
Authors: Truong-Bolduc Q. C. , Khan N. S. , Vyas J. M. , Hooper D. C. 
Published: December 2016

ABSTRACT

We previously reported that the Tet38 efflux pump is involved in internalization of
Staphylococcus aureus
by A549 lung epithelial cells. A lack of
tet38
reduced bacterial uptake by A549 cells to 36% of that of the parental strain RN6390. Using invasion assays coupled with confocal microscopy imaging, we studied the host cell receptor(s) responsible for bacterial uptake via interaction with Tet38. We also assessed the ability of
S. aureus
to survive following alkalinization of the phagolysosomes by chloroquine. Antibody to the scavenger receptor CD36 reduced the internalization of
S. aureus
RN6390 by A549 cells, but the dependence on CD36 was reduced in QT7
tet38
, suggesting that an interaction between Tet38 and CD36 contributed to
S. aureus
internalization. Following fusion of the
S. aureus
-associated endosomes with lysosomes, alkalinization of the acidic environment with chloroquine led to a rapid increase in the number of
S. aureus
RN6390 bacteria in the cytosol, followed by a decrease shortly thereafter. This effect of chloroquine was not seen in the absence of intact Tet38 in mutant QT7. These data taken together suggest that Tet38 plays a role both in bacterial internalization via interaction with CD36 and in bacterial escape from the phagolysosomes.
Storage filters upland suspended sediment signals delivered from watersheds
Authors: Pizzuto James , Keeler Jeremy , Skalak Katherine , Karwan Diana 
Published: December 2016

Abstract
Climate change, tectonics, and humans create long- and short-term temporal variations in the supply of suspended sediment to rivers. These signals, generated in upland erosional areas, are filtered by alluvial storage before reaching the basin outlet. We quantified this filter using a random walk model driven by sediment budget data, a power-law distributed probability density function (PDF) to determine how long sediment remains stored, and a constant downstream drift velocity during transport of 157 km/yr. For 25 km of transport, few particles are stored, and the median travel time is 0.2 yr. For 1000 km of transport, nearly all particles are stored, and the median travel time is 2.5 m.y. Both travel-time distributions are power laws. The 1000 km travel-time distribution was then used to filter sinusoidal input signals with periods of 10 yr and 104 yr. The 10 yr signal is delayed by 12.5 times its input period, damped by a factor of 380, and is output as a power law. The 104 yr signal is delayed by 0.15 times its input period, damped by a factor of 3, and the output signal retains its sinusoidal input form (but with a power-law “tail”). Delivery time scales for these two signals are controlled by storage; in-channel transport time is insignificant, and low-frequency signals are transmitted with greater fidelity than high-frequency signals. These signal modifications are essential to consider when evaluating watershed restoration schemes designed to control sediment loading, and where source-area geomorphic processes are inferred from the geologic record.
Dual Inhibition of Key Proliferation Signaling Pathways in Triple-Negative Breast Cancer Cells by a Novel Derivative of Taiwanin A
Authors: Kuo Yueh-Hsiung , Chiang En-Pei Isabel , Chao Che-Yi , Rodriguez Raymond L. , Chou Pei-Yu , Tsai Shu-Yao , Pai Man-Hui , Tang Feng-Yao 
Published: December 2016

Abstract
The treatment of breast cancer cells obtained by blocking the aberrant activation of the proliferation signaling pathways PI3K/Akt/mTOR and MEK/ERK has received considerable attention in recent years. Previous studies showed that Taiwanin A inhibited the proliferation of several types of cancer cells. In this study, we report that 3,4-bis-3,4,5-trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell-cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of β-catenin, cdc2 and the cell-cycle regulatory proteins, cyclin A, cyclin D1, and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation of the Akt and ERK1/2 signaling pathways. Moreover, BTMB induced cell apoptosis through an increase in the expression of BAX, cleaved caspase-3, and cleaved PARP. Moreover, BTMB inhibited TNBC cell colony formation and sensitized TNBC cells to cisplatin, a chemotherapeutic drug. In a TNBC mouse xenograft model, BTMB significantly inhibited the growth of mammary carcinomas through decreased expression of cyclin D1. BTMB was shown to significantly suppress the growth of mammary carcinoma and therefore to have potential as an anticancer therapeutic agent. Mol Cancer Ther; 16(3); 480–93. ©2016 AACR.
Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events
Authors: Cooper Leroy L. , Palmisano Joseph N. , Benjamin Emelia J. , Larson Martin G. , Vasan Ramachandran S. , Mitchell Gary F. , Hamburg Naomi M. 
Published: December 2016

Background—
Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Inter-relations of aortic stiffness and vasodilator function with incident CVD remain incompletely studied.

Methods and Results—

We used proportional hazards models to relate individual measures of vascular function to incident CVD in 4547 participants (mean age, 51±11 years; 54% women) in 2 generations of Framingham Heart Study participants. During follow-up (0.02–13.83 years), 232 participants (5%) experienced new-onset CVD events. In multivariable models adjusted for cardiovascular risk factors, both higher carotid-femoral pulse wave velocity (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.07–1.63;
P
=0.01) and lower hyperemic mean flow velocity (HR, 0.84; 95% CI, 0.71–0.99;
P
=0.04) were associated significantly with incident CVD, whereas primary pressure wave amplitude (HR, 1.12; 95% CI, 0.99–1.27;
P
=0.06), baseline brachial diameter (HR, 1.09; 95% CI, 0.90–1.31;
P
=0.39), and flow-mediated vasodilation (HR, 0.85; 95% CI, 0.69–1.04;
P
=0.12) were not. In mediation analyses, 8% to 13% of the relation between aortic stiffness and CVD events was mediated by hyperemic mean flow velocity.

Conclusions—
Our results suggest that associations between aortic stiffness and CVD events are mediated by pathways that include microvascular damage and remodeling.
Impacts of the Award of the Arbitral Tribunal in the Case between the Philippines and China
Authors: Thang Long Tran 
Published: December 2016

The article analyses the Award of the Arbitral Tribunal established under Annex vii of the United Nations Convention on the Law of the Sea (unclos) dated 12 July 2016. On that basis, the article analyses impacts of the Award on Vietnam’s sovereignty, sovereign rights and jurisdiction.
Although the Arbitral Tribunal’s Award has not mentioned and resolved disputes relating to sovereign questions, it has critical impacts on the exercise of Vietnam’s lawful sovereignty, sovereign rights and jurisdiction in the South China Sea. The Award also provides legal suggestions and important experiences for Vietnam in the utilization of judicial measures and using legal arguments in such measures in the future. The paper analyses impacts on Vietnam from contents of the Award and proposes solutions for Vietnam concerning approach, study and use of this Award.
Introducing the New Generation of Chinese Geostationary Weather Satellites, Fengyun-4
Authors: Yang Jun , Zhang Zhiqing , Wei Caiying , Lu Feng , Guo Qiang 
Published: December 2016

Abstract
China is developing a new generation of geostationary meteorological satellites called Fengyun-4 (FY-4), which is planned for launch beginning in 2016. Following upon the current FY-2 satellite series, FY-4 will carry four new instruments: the Advanced Geosynchronous Radiation Imager (AGRI), the Geosynchronous Interferometric Infrared Sounder (GIIRS), the Lightning Mapping Imager (LMI), and the Space Environment Package (SEP). The first satellite of the FY-4 series launched on 11 December 2016 is experimental, and the following four or more satellites will be operational.
The main objectives of the FY-4 series are to monitor rapidly changing weather systems and to improve warning and forecasting capabilities. The FY-4 measurements are aimed at accomplishing 1) high temporal and spatial resolution imaging in 14 spectral bands from the visible, near-infrared, and infrared (IR) spectral regions; 2) lightning imaging; and 3) high-spectral-resolution IR sounding observations over China and adjacent regions. FY-4 will also enhance the space weather monitoring and warning with SEP. Current products from FY-2 will be improved by FY-4, and a number of new products will also be introduced. FY-4’s sounding and imaging data will be used to improve applications in a wide range of ocean, land, and atmosphere monitoring plus forecasting extreme weather (especially typhoons and thunderstorms); overall, FY-4 will contribute to more accurate understanding and forecasting of China’s weather, climate, environment, and natural disasters. This new generation of Chinese geostationary weather satellites is being developed in parallel with the new generation of geostationary meteorological satellite systems from the international community of satellite providers and is intended to be an important contribution to the global observing system.
Physician Characteristics Associated With Sugar-Sweetened Beverage Counseling Practices
Authors: VanFrank Brenna K. , Park Sohyun , Foltz Jennifer L. , McGuire Lisa C. , Harris Diane M. 
Published: December 2016

Purpose: Frequent sugar-sweetened beverage (SSB) consumption is associated with chronic disease. Although physician counseling can positively affect patient behavior, physicians’ personal characteristics may influence counseling practices. We explored SSB-related topics physicians discuss when counseling overweight/obese patients and examined associations between physicians’ SSB-related counseling practices and their personal and medical practice characteristics. Design: Cross-sectional survey. Setting: DocStyles survey, 2014. Participants: A total of 1510 practicing US physicians. Measures: Physician’s SSB counseling on calories, added sugars, obesity/weight gain, health effects, consumption frequency, water substitution, and referral. Analysis: Adjusted odds ratios (aORs) were calculated with multivariable logistic regression, adjusting for physician’s personal and medical practice characteristics. Results: Most physicians (98.5%) reported SSB-related counseling. The most reported topic was obesity/weight gain (81.4%); the least reported were added sugars (53.1%) and referral (35.0%). Physicians in adult-focused specialties had lower odds than pediatricians of counseling on several topics (aOR range: 0.26-0.64). Outpatient physicians had higher odds than inpatient physicians of counseling on consumption frequency and water substitution (aOR range: 1.60-2.01). Physicians consuming SSBs ≥1 time/day (15.7%) had lower odds than nonconsumers of counseling on most topics (aOR range: 0.58-0.68). Conclusion: Most physicians reported SSB-related counseling; obesity/weight gain was discussed most frequently. Counseling opportunities remain in other topic areas. Opportunities also exist to strengthen SSB counseling practices in adult-focused specialties, inpatient settings, and among physicians who consume SSBs daily.
Angiotensin-converting enzyme insertion/deletion gene polymorphism in Egyptian children with systemic lupus erythematosus: a possible relation to proliferative nephritis
Authors: Hammad A , Yahia S , Laimon W , Hamed S M , Shouma A , Shalaby N M , Abdel-Hady D , Ghanem R , El-Farahaty R M , El-Bassiony S R , Hammad E M 
Published: December 2016

Introduction Angiotensin-converting enzyme (ACE) is crucial in the pathogenesis of systemic lupus erythematosus through angiotensin II which regulates vascular tone and endothelial functions. Objectives To study the frequency of ACE insertion/deletion (I/D) gene polymorphism in Egyptian children with systemic lupus erythematosus and its possible relation to the renal pathology in cases with lupus nephritis. Subjects and methods The frequency of ACE gene insertion/deletion polymorphism genotypes was determined in 78 Egyptian children with systemic lupus erythematosus and compared to a matched group of 140 healthy controls using polymerase chain reaction. Results The DD genotype of the ACE gene was higher in systemic lupus erythematosus patients when compared to controls ( P<0.0001; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.7–3.3) and the D allele was more frequent than the I allele in systemic lupus erythematosus patients in comparison to controls ( P < 0.0001; OR = 2.2; 95% CI = (1.6–3.1). In the lupus nephritis group, the DD genotype was significantly higher in those with proliferative lupus nephritis when compared to those with non-proliferative lupus nephritis ( P = 0.02; OR = 1.45; 95% CI = 1.4–1.6). Also, patients with proliferative lupus nephritis showed a higher frequency of the D allele ( P < 0.001; OR = 1.98; 95% CI = 1.3–2.9). Conclusion The D allele and DD genotype of the ACE gene appear to be a risk factor for the susceptibility of systemic lupus erythematosus and occurrence of proliferative nephritis in Egyptian children.