bluuebunny/crossref_metadata_2025_split huggingface dataset:
Firing of antagonist small‐diameter muscle afferents reduces voluntary activation and torque of elbow flexors
Authors: Kennedy David S. , McNeil Chris J. , Gandevia Simon C. , Taylor Janet L. 
Published: May 2013

Key points
Maintained firing of fatigue‐sensitive small‐diameter muscle afferents is reported to reduce voluntary activation of the homonymous (fatigued) muscle.
Our study determined if firing of fatigue‐sensitive afferents from elbow extensor muscles reduces voluntary activation and torque of the non‐fatigued elbow flexors.
We examined voluntary activation of the elbow flexors by measuring changes in superimposed twitches evoked by magnetic cortical stimulation during maximal voluntary contractions.
Following a fatiguing contraction of elbow extensors, the voluntary drive to unfatigued flexor muscles was reduced with continued activation of small‐diameter muscle afferents produced by a blood pressure cuff inflated to maintain muscle ischaemia.
Continued discharge of small‐diameter muscle afferents from one muscle can decrease voluntary drive to another muscle in the same limb and can reduce its maximal voluntary torque.
Abstract  During muscle fatigue, firing of small‐diameter muscle afferents can decrease voluntary activation of the fatigued muscle. However, these afferents may have a more widespread effect on other muscles in the exercising limb. We examined if the firing of fatigue‐sensitive afferents from elbow extensor muscles in the same arm reduces torque production and voluntary activation of elbow flexors. In nine subjects we examined voluntary activation of elbow flexors by measuring changes in superimposed twitches evoked by transcranial magnetic stimulation of the motor cortex during brief (2–3 s) maximal voluntary contractions (MVC). Inflation of a blood pressure cuff following a 2‐min sustained MVC blocked blood flow to the fatigued muscle and maintained firing of small‐diameter afferents. After a fatiguing elbow flexion contraction, maximal flexion torque was lower (26.0 ± 4.4%versus 67.9 ± 5.2% of initial maximal torque; means ±s.d.; P < 0.001) and superimposed twitches were larger (4.1 ± 1.1%versus 1.8 ± 0.2% ongoing MVC, P= 0.01) with than without ischaemia. After a fatiguing elbow extensor contraction, maximal flexion torque was also reduced (82.2 ± 4.9%versus 91.4 ± 2.3% of initial maximal torque; P= 0.007), superimposed twitches were larger (2.7 ± 0.7%versus 1.3 ± 0.2% ongoing MVC; P= 0.02) and voluntary activation lower (81.6 ± 8.2%versus 95.5 ± 6.9%; P= 0.04) with than without ischaemia. After a fatiguing contraction, voluntary drive to the fatigued muscles is reduced with continued input from small‐diameter muscle afferents. Furthermore, fatigue of the elbow extensor muscles decreases voluntary drive to unfatigued elbow flexors of the same arm. Therefore, firing of small‐diameter muscle afferents from one muscle can affect voluntary activation and hence torque generation of another muscle in the same limb.
Glucocorticoid exerts its non‐genomic effect on IPSC by activation of a phospholipase C‐dependent pathway in prefrontal cortex of rats
Authors: Teng Zenghui , Zhang Mingyue , Zhao Minggao , Zhang Weiqi 
Published: May 2013

Key points
Activation of the membrane‐binding glucocorticoid receptors enhances spontaneous GABAergic activity and elicits intermittent burst activity in hippocampus and prefrontal cortex of rats.
The burst activities are abolished in the presence of tetrodotoxin.
The time courses of the effects are different between hippocampus and prefrontal cortex, the onset in the latter being much slower.
The nitric oxide (NO) pathway is present and endogenously activated in prefrontal cortex.
The effects of membrane‐binding glucocorticoid receptor on GABAergic synaptic transmission are mediated by both NO and phospholipase C–diacylglycerol pathways in hippocampus and prefrontal cortex of rats.
Abstract  In response to stressor, the brain activates a comprehensive stress system. Among others, this stress system causes release of glucocorticoids that also feed back to the brain. Glucocorticoids affect brain function by activation of both delayed, genomic and rapid, non‐genomic mechanisms in rodents. Here we report that application of the potent glucocorticoid receptor agonist dexamethasone (DEX) caused a rapid increase of spontaneous and miniature inhibitory postsynaptic currents (IPSCs) and elicited intermittent burst activities through a non‐genomic pathway, involving membrane‐located receptors. The onset of the rapid effect in prefrontal cortex (PFC, <15 min) was much slower than in hippocampus (<5 min). The intermittent burst activities were abolished in the presence of TTX. Furthermore, the nitric oxide (NO) pathway was present and endogenously activated in PFC. Part of the rapid DEX effect in PFC remained after blocking NO‐sensitive guanylyl cyclase that was due to activation of a phospholipase C–diacylglycerol‐dependent signalling pathway. Thus, our data demonstrated that glucocorticoids could rapidly enhance IPSCs and evoke burst activities by activation of at least two different signalling pathways in hippocampus and PFC of rats.
Measurement of breast tissue composition with dual energy cone‐beam computed tomography: A postmortem study
Authors: Ding Huanjun , Ducote Justin L. , Molloi Sabee 
Published: May 2013

Purpose:To investigate the feasibility of a three‐material compositional measurement of water, lipid, and protein content of breast tissue with dual kVp cone‐beam computed tomography (CT) for diagnostic purposes.Methods:Simulations were performed on a flat panel‐based computed tomography system with a dual kVp technique in order to guide the selection of experimental acquisition parameters. The expected errors induced by using the proposed calibration materials were also estimated by simulation. Twenty pairs of postmortem breast samples were imaged with a flat‐panel based dual kVp cone‐beam CT system, followed by image‐based material decomposition using calibration data obtained from a three‐material phantom consisting of water, vegetable oil, and polyoxymethylene plastic. The tissue samples were then chemically decomposed into their respective water, lipid, and protein contents after imaging to allow direct comparison with data from dual energy decomposition.Results:Guided by results from simulation, the beam energies for the dual kVp cone‐beam CT system were selected to be 50 and 120 kVp with the mean glandular dose divided equally between each exposure. The simulation also suggested that the use of polyoxymethylene as the calibration material for the measurement of pure protein may introduce an error of −11.0%. However, the tissue decomposition experiments, which employed a calibration phantom made out of water, oil, and polyoxymethylene, exhibited strong correlation with data from the chemical analysis. The average root‐mean‐square percentage error for water, lipid, and protein contents was 3.58% as compared with chemical analysis.Conclusions:The results of this study suggest that the water, lipid, and protein contents can be accurately measured using dual kVp cone‐beam CT. The tissue compositional information may improve the sensitivity and specificity for breast cancer diagnosis.
Accelerated MR whole brain imaging with sheared voxel imaging using aliasing separation gradients
Authors: Kim Min‐Oh , Lee Joonsung , Zho Sang‐Young , Kim Dong‐Hyun 
Published: May 2013

Purpose:To accelerate data acquisition by undersampling phase encoding (PE) lines in MR imaging, an aliasing separation method by applying additional encoding gradients which result in voxel shape modification is proposed.Methods:An imaging technique which achieves two directional accelerations by undersampling both PE lines in 3D imaging with aliasing separation gradients is proposed. A simple and fast reconstruction process using shift correction or gridding is followed. Phantom andin vivo experiments are performed to show the characteristics and acceleration capability of the proposed method. Further acceleration is achieved by combining with parallel acquisition techniques.Results:The proposed technique shows anisotropic resolution pattern due to voxel shearing which increases proportionally with the acceleration factor. This characteristic is analyzed in both image domain and k‐space and is illustrated by grid phantom imaging results. Inin vivo experiment, 3D imaging results are presented with 6× acceleration using the proposed technique and ∼12× acceleration combining with parallel imaging technique.Conclusions:By applying separation gradients along both PE directions in 3D MR imaging, aliasing artifacts have been successfully separated and a high acceleration is achieved for whole brain 3D MR imaging with slight blurring due to voxel shearing.
Factors Required for Activation of Urease as a Virulence Determinant in Cryptococcus neoformans
Authors: Singh Arpita , Panting Robert J. , Varma Ashok , Saijo Tomomi , Waldron Kevin J. , Jong Ambrose , Ngamskulrungroj Popchai , Chang Yun C. , Rutherford Julian C. , Kwon-Chung Kyung J. 
Published: May 2013

ABSTRACT

Urease in
Cryptococcus neoformans
plays an important role in fungal dissemination to the brain and causing meningoencephalitis. Although urea is not required for synthesis of apourease encoded by
URE1
, the available nitrogen source affected the expression of
URE1
as well as the level of the enzyme activity. Activation of the apoenzyme requires three accessory proteins, Ure4, Ure6, and Ure7, which are homologs of the bacterial urease accessory proteins UreD, UreF, and UreG, respectively. A yeast two-hybrid assay showed positive interaction of Ure1 with the three accessory proteins encoded by
URE4
,
URE6
, and
URE7
. Metalloproteomic analysis of cryptococcal lysates using inductively coupled plasma mass spectrometry (ICP-MS) and a biochemical assay of urease activity showed that, as in many other organisms, urease is a metallocentric enzyme that requires nickel transported by Nic1 for its catalytic activity. The Ure7 accessory protein (bacterial UreG homolog) binds nickel likely via its conserved histidine-rich domain and appears to be responsible for the incorporation of Ni
2+
into the apourease. Although the cryptococcal genome lacks the bacterial UreE homolog, Ure7 appears to combine the functions of bacterial UreE and UreG, thus making this pathogen more similar to that seen with the plant system. Brain invasion by the
ure1
,
ure7
, and
nic1
mutant strains that lack urease activity was significantly less effective in a mouse model. This indicated that an activated urease and not the Ure1 protein was responsible for enhancement of brain invasion and that the factors required for urease activation in
C. neoformans
resemble those of plants more than those of bacteria.

IMPORTANCE
Cryptococcus neoformans
is the major fungal agent of meningoencephalitis in humans. Although urease is an important factor for cryptococcal brain invasion, the enzyme activation system has not been studied. We show that urease is a nickel-requiring enzyme whose activity level is influenced by the type of available nitrogen source.
C. neoformans
contains all the bacterial urease accessory protein homologs and nickel transporters except UreE, a nickel chaperone. Cryptococcal Ure7 (a homolog of UreG) apparently functions as both the bacterial UreG and UreE in activating the Ure1 apoenzyme. The cryptococcal urease accessory proteins Ure4, Ure6, and Ure7 interacted with Ure1 in a yeast two-hybrid assay, and deletion of any one of these not only inactivated the enzyme but also reduced the efficacy of brain invasion. This is the first study showing a holistic picture of urease in fungi, clarifying that urease activity, and not Ure1 protein, contributes to pathogenesis in
C. neoformans
Therapeutic Destruction of Insulin Receptor Substrates for Cancer Treatment
Authors: Reuveni Hadas , Flashner-Abramson Efrat , Steiner Lilach , Makedonski Kirill , Song Renduo , Shir Alexei , Herlyn Meenhard , Bar-Eli Menashe , Levitzki Alexander 
Published: May 2013

Abstract
Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors. Cancer Res; 73(14); 4383–94. ©2013 AACR.
A Survivin-Associated Adaptive Response in Radiation Therapy
Authors: Grdina David J. , Murley Jeffrey S. , Miller Richard C. , Mauceri Helena J. , Sutton Harold G. , Li Jian Jian , Woloschak Gayle E. , Weichselbaum Ralph R. 
Published: May 2013

Abstract
Adaptive responses can be induced in cells by very low doses of ionizing radiation resulting in an enhanced resistance to much larger exposures. The inhibitor of apoptosis protein, survivin, has been implicated in many adaptive responses to cellular stress. Computerized axial tomography used in image-guided radiotherapy to position and monitor tumor response uses very low radiation doses ranging from 0.5 to 100 mGy. We investigated the ability of these very low radiation doses administered along with two 2 Gy doses separated by 24 hours, a standard conventional radiotherapy dosing schedule, to initiate adaptive responses resulting in the elevation of radiation resistance in exposed cells. Human colon carcinoma (RKO36), mouse sarcoma (SA-NH), along with transformed mouse embryo fibroblasts, wild type or cells lacking functional tumor necrosis factor receptors 1 and 2 were used to assess their relative ability to express an adaptive response when grown either to confluence in vitro or as tumors in the flank of C57BL/6 mice. The survival of each of these cells was elevated from 5% to 20% (P ≤ 0.05) as compared to cells not receiving a 100 mGy or lesser dose. In addition, the cells exposed to 100 mGy exhibited elevations in survivin levels, reductions in apoptosis frequencies, and loss of an adaptive response if transfected with survivin siRNA. This survivin-mediated adaptive response has the potential for affecting outcomes if regularly induced throughout a course of image guided radiation therapy. Cancer Res; 73(14); 4418–28. ©2013 AACR.
Discovering What Makes STAT Signaling TYK in T-ALL
Authors: Fontan Lorena , Melnick Ari 
Published: May 2013

Abstract
Summary: RNA interference screening establishes TYK2 dependence in T-cell acute lymphoblastic leukemia (T-ALL), leading to identification of TYK2-activating mutations and increased IL-10 receptor signaling in T-ALL cell lines. Cancer Discov; 3(5); 494–6. ©2013 AACR.
See related article by Sanda et al., p. 564
Two Is Better Than One: Combining IGF1R and MEK Blockade as a Promising Novel Treatment Strategy Against KRAS-Mutant Lung Cancer
Authors: Chen Ron , Sweet-Cordero E. Alejandro 
Published: May 2013

Abstract
Summary: A small-molecule inhibitor screen on a panel of human lung cancer cell lines has uncovered an unexpected sensitivity of cells expressing oncogenic KRAS toward insulin-like growth factor 1 receptor (IGF1R) inhibition. Combining IGF1R and MAP-ERK kinase blockade led to significant effects on viability in human non–small cell lung cancer (NSCLC) cell lines and in 2 mouse models of oncogenic KRAS-driven lung cancer. The mechanistic basis for this effect seems to be an increased baseline activation of IGF1R–mediated activation of AKT in cells that express oncogenic KRAS. The studies thus point to a novel approach for treatment of KRAS-driven NSCLC, a particularly difficult subset of patients to treat with existing approaches. Cancer Discov; 3(5); 491–3. ©2013 AACR.
See related article by Molina-Arcas et al., p. 548
Primary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease With Penicillin in South African Children With Pharyngitis
Authors: Irlam James , Mayosi Bongani M. , Engel Mark , Gaziano Thomas A. 
Published: May 2013

Background—
Acute rheumatic fever and subsequent rheumatic heart disease remain significant in developing countries. We describe a cost-effective analysis of 7 strategies for the primary prevention of acute rheumatic fever and rheumatic heart disease in children presenting with pharyngitis in urban primary care clinics in South Africa.

Methods and Results—
We used a Markov model to assess the cost-effectiveness of treatment with intramuscular penicillin using each of the following strategies: (1) empirical (treat all); (2) positive throat culture (culture all); (3) clinical decision rule (CDR) score ≥2 (CDR 2+); (4) CDR score ≥3 (CDR 3+); (5) treating those with a CDR score ≥2 plus those with CDR score <2 and positive cultures (CDR 2+, culture CDR negatives); (6) treating those with a CDR score ≥3 plus those with CDR score <3 and positive cultures (CDR 3+, culture CDR negatives); and (7) treat none. The strategies ranked in order from lowest cost were treat all ($11.19 per child), CDR 2+ ($11.20); the CDR 3+ ($13.00); CDR 2+, culture CDR negatives ($16.42); CDR 3+, culture CDR negatives ($23.89); and culture all ($27.21). The CDR 2+ is the preferred strategy at less than $150/quality-adjusted life year compared with the treat all strategy. A strategy of culturing all children compared with the CDR 2+ strategy costs more than $125 000/quality-adjusted life year gained.

Conclusions—
Treating all children presenting with pharyngitis in urban primary care clinics in South Africa with intramuscular penicillin is the least costly. A strategy of using a clinical decision rule without culturing is overall the preferred strategy. A strategy of culturing all children may be prohibitively expensive.
Trends in Vascular Risk Factor Treatment and Control in US Stroke Survivors
Authors: Shah Nilay S. , Huffman Mark D. , Ning Hongyan , Lloyd-Jones Donald M. 
Published: May 2013

Background—
Treatment and control of vascular risk factors reduce the likelihood of recurrent stroke. Present nationally representative data are sparse regarding secondary prevention treatment and control rates.

Methods and Results—

We evaluated sex- and race-stratified blood pressure, cholesterol, and hemoglobin A1c levels and treatment and control rates in 1154 self-reported stroke survivors from the National Health and Nutrition Examination Surveys 1999 to 2010. We used weighted linear regression to estimate time trends. Participants were 54% to 61% women, 70% to 76% white, and had a mean age of 63 to 66 years. For blood pressure, treatment rates remained unchanged in men, but in women, treatment rates increased from 41% in 1999 to 2000 to 65% in 2009 to 2010 (
P
=0.03), and control rates increased from 23% to 79% (
P
=0.03). Treatment rates remained unchanged in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, although control rates increased in non-Hispanic whites from 50% in 1999 to 2002 to 69% in 2007 to 2010 (
P
=0.04). For cholesterol, treatment rates increased from 30% to 40% in men (
P
=0.02) and from 28% to 36% (
P
<0.01) in women, but control rates increased only in men, from 62% to 87% (
P
<0.01). Cholesterol treatment rates increased only in non-Hispanic blacks, from 18% to 37% (
P
=0.02). By sex and race, there was no change in dysglycemia treatment and control.

Conclusions—
Despite improvements in blood pressure treatment and control and cholesterol treatment for women and cholesterol treatment and control for men, stroke secondary prevention through treatment and control of vascular risk factors remains suboptimal. Urgent action is needed to improve secondary prevention to reduce stroke morbidity and mortality in this high-risk group.
External Validation of the iScore for Predicting Ischemic Stroke Mortality in Patients in China
Authors: Zhang Ning , Liu Gaifen , Zhang Guohua , Fang Jiming , Wang Yilong , Zhao Xingquan , Pan Yuesong , Guo Li , Wang Yongjun 
Published: May 2013

Background and Purpose—
The iScore is a prediction tool developed to estimate the risk of death in patients after hospitalization for an acute ischemic stroke. Our aim was to determine the accuracy of the iScore in patients with ischemic stroke in China.

Methods—
The iScore was used to predict 30-day mortality rate in 11 656 patients and 1-year mortality rate in 11 051 patients with acute ischemic stroke. These patients were identified from the China National Stroke Registry (CNSR) data set. Model discrimination was quantified by calculating the C statistic. The calibration was assessed using Pearson correlation coefficient.

Results—

The 30-day and 1-year mortality rates were 5.4% and 14.3%, respectively. The C statistics were 0.825 (95% confidence interval, 0.807–0.843) for 30-day mortality and 0.822 (95% confidence interval, 0.810–0.833) for 1-year mortality. The plots of observed versus predicted mortality rates showed excellent model calibration in the external validation samples from the CNSR (Pearson correlation coefficient, 0.925 for 30-day and 0.998 for 1-year mortality; both
P
<0.0001).

Conclusions—
The iScore reliably predicts 30-day and 1-year mortality in Chinese patients with ischemic stroke.
Assimilation of Circumpolar Wind Vectors Derived from Highly Elliptical Orbit Imagery: Impact Assessment Based on Observing System Simulation Experiments
Authors: Garand L. , Feng J. , Heilliette S. , Rochon Y. , Trishchenko A. P. 
Published: May 2013

AbstractThere is a well-recognized spatiotemporal meteorological observation gap at latitudes higher than 55°, especially in the region 55°–70°. A possible solution to address this issue is a constellation of four satellites in a highly elliptical orbit (HEO), that is, two satellites for each polar region. An important satellite product to support weather prediction is atmospheric motion wind vectors (AMVs). This study uses observing system simulation experiments (OSSEs) to evaluate the benefit to forecasts resulting from the assimilation of HEO AMVs covering one or both polar regions. The OSSE employs the operational global data assimilation system of the Canadian Meteorological Center. HEO AMVs are assimilated north of 50°N and south of 50°S. From 2-month assimilation cycles, the study examines the following three issues: 1) the impact of AMV assimilation in the real system, and how this compares to the impact seen in the simulated system, 2) the added value of HEO AMVs in the Arctic on top of what is currently available, and 3) the relative impact of HEO AMVs in the Arctic and Antarctic in comparison with no AMVs. Although the simulated impact of currently available AMVs is somewhat higher than the real impact, a firm conclusion is that the added value of Arctic HEO AMVs is substantial, improving predictability at days 3–5 by a few hours in terms of 500-hPa geopotential height. The impact of HEO AMVs is relatively stronger in the Southern Hemisphere. Forecast validation of atmospheric profiles against the simulated “true” state and against analyses generated within the assimilation cycles yields very similar results beyond 48 h.