bluuebunny/crossref_metadata_2025 huggingface dataset:
The motion of a spring released from uniform circular motion
Authors: Dooling Thomas , Regester Jeffrey , Carnaghi Matthew , Titus Aaron
Published: August 2016

A weak spring is connected to the end of a rotor rotating at constant angular velocity. The spring extends to a stretched length as determined by the spring mass, rest length, spring constant, rotor radius, and rotor angular velocity. When released from the rotor, captured video shows the inner end of the spring pulling away as expected, causing a wave to travel down the spring as it collapses. During this collapse, the outer end of the spring continues to move along its original circular path in uniform circular motion, as if the spring were still connected to the rotor. Values from a numerical model and measurements from video analysis show that after release the inner end travels along a circle of similar radius as the outer end. Simulation results are presented that agree with the video analysis.
Structural analysis of a signal peptide inside the ribosome tunnel by DNP MAS NMR
Authors: Lange Sascha , Franks W. Trent , Rajagopalan Nandhakishore , Döring Kristina , Geiger Michel A. , Linden Arne , van Rossum Barth-Jan , Kramer Günter , Bukau Bernd , Oschkinat Hartmut
Published: August 2016

DNP-enhanced MAS NMR reveals extended conformations for the DsbA signal peptide within the ribosome exit tunnel.
Visualizing weakly bound surface Fermi arcs and their correspondence to bulk Weyl fermions
Authors: Batabyal Rajib , Morali Noam , Avraham Nurit , Sun Yan , Schmidt Marcus , Felser Claudia , Stern Ady , Yan Binghai , Beidenkopf Haim
Published: August 2016

Fermi arc states on the surface of a Weyl semimetal are revealed by the structure of their wave function.
Local Environmental Factors Drive Divergent Grassland Soil Bacterial Communities in the Western Swiss Alps
Authors: Yashiro Erika , Pinto-Figueroa Eric , Buri Aline , Spangenberg Jorge E. , Adatte Thierry , Niculita-Hirzel Hélène , Guisan Antoine , van der Meer Jan Roelof
Published: August 2016

Mountain ecosystems are characterized by a diverse range of climatic and topographic conditions over short distances and are known to shelter a high biodiversity. Despite important progress, still little is known on bacterial diversity in mountain areas. Here, we investigated soil bacterial biogeography at more than 100 sampling sites randomly stratified across a 700-km2area with 2,200-m elevation gradient in the western Swiss Alps. Bacterial grassland communities were highly diverse, with 12,741 total operational taxonomic units (OTUs) across 100 sites and an average of 2,918 OTUs per site. Bacterial community structure was correlated with local climatic, topographic, and soil physicochemical parameters with high statistical significance. We found pH (correlated with % CaO and % mineral carbon), hydrogen index (correlated with bulk gravimetric water content), and annual average number of frost days during the growing season to be among the groups of the most important environmental drivers of bacterial community structure. In contrast, bacterial community structure was only weakly stratified as a function of elevation. Contrasting patterns were discovered for individual bacterial taxa.Acidobacteriaresponded both positively and negatively to pH extremes. Various families within theBacteroidetesresponded to available phosphorus levels. Different verrucomicrobial groups responded to electrical conductivity, total organic carbon, water content, and mineral carbon contents. Alpine grassland bacterial communities are thus highly diverse, which is likely due to the large variety of different environmental conditions. These results shed new light on the biodiversity of mountain ecosystems, which were already identified as potentially fragile to anthropogenic influences and climate change.

IMPORTANCEThis article addresses the question of how microbial communities in alpine regions are dependent on local climatic and soil physicochemical variables. We benefit from a unique 700-km2study region in the western Swiss Alps region, which has been exhaustively studied for macro-organismal and fungal ecology, and for topoclimatic modeling of future ecological trends, but without taking into account soil bacterial diversity. Here, we present an in-depth biogeographical characterization of the bacterial community diversity in this alpine region across 100 randomly stratified sites, using 56 environmental variables. Our exhaustive sampling ensured the detection of ecological trends with high statistical robustness. Our data both confirm previously observed general trends and show many new detailed trends for a wide range of bacterial taxonomic groups and environmental parameters.
Role of Phosphate Transport System Component PstB1 in Phosphate Internalization by Nostoc punctiforme
Authors: Hudek L. , Premachandra D. , Webster W. A. J. , Bräu L.
Published: August 2016

In bacteria, limited phosphate availability promotes the synthesis of active uptake systems, such as the Pst phosphate transport system. To understand the mechanisms that facilitate phosphate accumulation in the cyanobacterium
Nostoc punctiforme
, phosphate transport systems were identified, revealing a redundancy of Pst phosphate uptake systems that exists across three distinct operons. Four separate PstB system components were identified.
pstB1
was determined to be a suitable target for creating phenotypic mutations that could result in the accumulation of excessive levels of phosphate through its overexpression or in a reduction of the capacity to accumulate phosphate through its deletion. Using quantitative real-time PCR (qPCR), it was determined that
pstB1
mRNA levels increased significantly over 64 h in cells cultured in 0 mM added phosphate and decreased significantly in cells exposed to high (12.8 mM) phosphate concentrations compared to the level in cells cultured under normal (0.8 mM) conditions. Possible compensation for the loss of PstB1 was observed when
pstB2
,
pstB3
, and
pstB4
mRNA levels increased, particularly in cells starved of phosphate. The overexpression of
pstB1
increased phosphate uptake by
N. punctiforme
and was shown to functionally complement the loss of PstB in
E. coli
PstB knockout (PstB
−
) mutants. The knockout of
pstB1
in
N. punctiforme
did not have a significant effect on cellular phosphate accumulation or growth for the most part, which is attributed to the compensation for the loss of PstB1 by alterations in the
pstB2
,
pstB3
, and
pstB4
mRNA levels. This study provides novel
in vivo
evidence that PstB1 plays a functional role in phosphate uptake in
N. punctiforme
.

IMPORTANCE
Cyanobacteria have been evolving over 3.5 billion years and have become highly adept at growing under limiting nutrient levels. Phosphate is crucial for the survival and prosperity of all organisms. In bacteria, limited phosphate availability promotes the synthesis of active uptake systems. The Pst phosphate transport system is one such system, responsible for the internalization of phosphate when cells are in phosphate-limited environments. Our investigations reveal the presence of multiple Pst phosphate uptake systems that exist across three distinct operons in
Nostoc punctiforme
and functionally characterize the role of the gene product PstB1 as being crucial for the maintenance of phosphate accumulation. We demonstrate that the genes
pstB2
,
pstB3
, and
pstB4
show alterations in expression to compensate for the deletion of
pstB1
. The overall outcomes of this work provide insights as to the complex transport mechanisms that exist in cyanobacteria like
N. punctiforme
, allowing them to thrive in low-phosphate environments.
Population Genetics of Hirsutella rhossiliensis, a Dominant Parasite of Cyst Nematode Juveniles on a Continental Scale
Authors: Wang Niuniu , Zhang Yongjie , Jiang Xianzhi , Shu Chi , Hamid M. Imran , Hussain Muzammil , Chen Senyu , Xu Jianping , Xiang Meichun , Liu Xingzhong
Published: August 2016

Hirsutella rhossiliensis
is a parasite of juvenile nematodes, effective against a diversity of plant-parasitic nematodes. Its global distribution on various nematode hosts and its genetic variation for several geographic regions have been reported, while the global population genetic structure and factors underlying patterns of genetic variation of
H. rhossiliensis
are unclear. In this study, 87
H. rhossiliensis
strains from five nematode species (
Globodera
sp.,
Criconemella xenoplax
,
Rotylenchus robustus
,
Heterodera schachtii
, and
Heterodera glycines
) in Europe, the United States, and China were investigated by multilocus sequence analyses. A total of 280 variable sites (frequency, 0.6%) at eight loci and six clustering in high accordance with geographic populations or host nematode-associated populations were identified. Although
H. rhossiliensis
is currently recognized as an asexual fungus, recombination events were frequently detected. In addition, significant genetic isolation by geography and nematode hosts was revealed. Overall, our analyses showed that recombination, geographic isolation, and nematode host adaptation have played significant roles in the evolutionary history of
H. rhossiliensis
.

IMPORTANCE
H. rhossiliensis
has great potential for use as a biocontrol agent to control nematodes in a sustainable manner as an endoparasitic fungus. Therefore, this study has important implications for the use of
H. rhossiliensis
as a biocontrol agent and provides interesting insights into the biology of this species.
Borneol Dehydrogenase from Pseudomonas sp. Strain TCU-HL1 Catalyzes the Oxidation of (+)-Borneol and Its Isomers to Camphor
Authors: Tsang Hoi-Lung , Huang Jui-Lin , Lin Yu-Hsuan , Huang Kai-Fa , Lu Pei-Luen , Lin Guang-Huey , Khine Aye Aye , Hu Anren , Chen Hao-Ping
Published: August 2016

Most plant-produced monoterpenes can be degraded by soil microorganisms. Borneol is a plant terpene that is widely used in traditional Chinese medicine. Neither microbial borneol dehydrogenase (BDH) nor a microbial borneol degradation pathway has been reported previously. One borneol-degrading strain,
Pseudomonas
sp. strain TCU-HL1, was isolated by our group. Its genome was sequenced and annotated. The genome of TCU-HL1 consists of a 6.2-Mbp circular chromosome and one circular plasmid, pTHL1 (12.6 kbp). Our results suggest that borneol is first converted into camphor by BDH in TCU-HL1 and is further decomposed through a camphor degradation pathway. The recombinant BDH was produced in the form of inclusion bodies. The apparent

K
m

values of refolded recombinant BDH for (+)-borneol and (−)-borneol were 0.20 ± 0.01 and 0.16 ± 0.01 mM, respectively, and the
k
cat
values for (+)-borneol and (−)-borneol were 0.75 ± 0.01 and 0.53 ± 0.01 s
−1
, respectively. Two plant BDH genes have been reported previously. The
k
cat
and
k
cat
/

K
m

values of lavender BDH are about 1,800-fold and 500-fold lower, respectively, than those of TCU-HL1 BDH.

IMPORTANCE
The degradation of borneol in a soil microorganism through a camphor degradation pathway is reported in this study. We also report a microbial borneol dehydrogenase. The
k
cat
and
k
cat
/

K
m

values of lavender BDH are about 1,800-fold and 500-fold lower, respectively, than those of TCU-HL1 BDH. The indigenous borneol- and camphor-degrading strain isolated,
Pseudomonas
sp. strain TCU-HL1, reminds us of the time 100 years ago when Taiwan was the major producer of natural camphor in the world.
Simultaneous Transformation of Commingled Trichloroethylene, Tetrachloroethylene, and 1,4-Dioxane by a Microbially Driven Fenton Reaction in Batch Liquid Cultures
Authors: Sekar Ramanan , Taillefert Martial , DiChristina Thomas J.
Published: August 2016

Improper disposal of 1,4-dioxane and the chlorinated organic solvents trichloroethylene (TCE) and tetrachloroethylene (also known as perchloroethylene [PCE]) has resulted in widespread contamination of soil and groundwater. In the present study, a previously designed microbially driven Fenton reaction system was reconfigured to generate hydroxyl (HO˙) radicals for simultaneous transformation of source zone levels of single, binary, and ternary mixtures of TCE, PCE, and 1,4-dioxane. The reconfigured Fenton reaction system was driven by fed batch cultures of the Fe(III)-reducing facultative anaerobe
Shewanella oneidensis
amended with lactate, Fe(III), and contaminants and exposed to alternating anaerobic and aerobic conditions. To avoid contaminant loss due to volatility, the Fe(II)-generating, hydrogen peroxide-generating, and contaminant transformation phases of the microbially driven Fenton reaction system were separated. The reconfigured Fenton reaction system transformed TCE, PCE, and 1,4-dioxane either as single contaminants or as binary and ternary mixtures. In the presence of equimolar concentrations of PCE and TCE, the ratio of the experimentally derived rates of PCE and TCE transformation was nearly identical to the ratio of the corresponding HO˙ radical reaction rate constants. The reconfigured Fenton reaction system may be applied as an
ex situ
platform for simultaneous degradation of commingled TCE, PCE, and 1,4-dioxane and provides valuable information for future development of
in situ
remediation technologies.

IMPORTANCE
A microbially driven Fenton reaction system [driven by the Fe(III)-reducing facultative anaerobe
S. oneidensis
] was reconfigured to transform source zone levels of TCE, PCE, and 1,4-dioxane as single contaminants or as binary and ternary mixtures. The microbially driven Fenton reaction may thus be applied as an
ex situ
platform for simultaneous degradation of at least three (and potentially more) commingled contaminants. Additional targets for
ex situ
and
in situ
degradation by the microbially driven Fenton reaction developed in the present study include multiple combinations of environmental contaminants susceptible to attack by Fenton reaction-generated HO˙ radicals, including commingled plumes of 1,4-dioxane, pentachlorophenol (PCP), PCE, TCE, 1,1,2-trichloroethane (TCA), and perfluoroalkylated substances (PFAS).
Metformin and other glucose-lowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a Danish nationwide population-based cohort study
Authors: Mor Anil , Petersen Irene , Sørensen Henrik T , Thomsen Reimar W
Published: August 2016

Objective

Data on early risk of infection in patients receiving their first treatment for type 2 diabetes are limited. We examined rates of community-based antibiotic use and hospital-treated infection in initiators of metformin and other glucose-lowering drugs (GLDs).

Design

Population-based cohort study using medical databases.

Setting

General practice and hospitals in Denmark.

Participants

131 949 patients with type 2 diabetes who initiated pharmacotherapy with a GLD between 2005 and 2012.

Exposure

Initial GLD used for pharmacotherapy.

Main outcome measures

We computed rates and adjusted HRs of community-based antibiotic use and hospital-treated infection associated with choice of initial GLD with reference to metformin initiation, using an intention-to-treat approach.

Results

The rate of community-based antibiotic use was 362 per 1000 patient-years at risk (PYAR) and that for hospital-treated infection was 51 per 1000 PYAR. Compared with metformin, the risk of hospital-treated infection was slightly higher in sulfonylurea initiators (HR 1.12, 95% CI 1.08 to 1.16) and substantially higher in insulin initiators (HR 1.63, 95% CI 1.54 to 1.72) initiators after adjustment for comorbid conditions, comedications and other confounding factors. In contrast, virtually no difference was observed for overall community-based antibiotic use (HR 1.02, 95% CI 1.01 to 1.04, for sulfonylurea initiators; and 1.04, 95% CI 1.01 to 1.07, for insulin initiators).

Conclusions

Rates of community-based antibiotic treatment and hospitalisation for infection were high in patients receiving their first treatment for type 2 diabetes and differed with the choice of initial GLD used for pharmacotherapy.
Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) trial: the protocol for a large pilot study
Authors: Abdelaziz Tarek Samy , Lindenmeyer Antje , Baharani Jyoti , Mistry Hema , Sitch Alice , Temple R Mark , Perkins Gavin , Thomas Mark
Published: August 2016

Introduction

Acute kidney injury (AKI) contributes to morbidity and mortality, and its care is often suboptimal and/or delayed. The Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) study is a large pilot testing provision of early specialist advice, to improve outcomes for patients with AKI.

Methods and analysis

This before and after study will test an Outreach service for adult patients with AKI, identified using the national algorithm. During the 2-month before phase, AKI outcomes (30-day mortality, need for dialysis or AKI stage deterioration) will be observed in the intervention and control hospitals and their respective community areas; no interventions will be delivered. Patients will receive good standard care. During the 5-month after phase, the intervention will be delivered to patients with AKI in the intervention hospital and its area. Patients with AKI in the control hospital and its area will continue to have good standard care only. Patients already on dialysis and at end of life will be excluded. The interventions will be initially delivered via a phone call, with or without a visit to the primary clinician, aiming at rapidly establishing the aetiology, correcting reversible causes and conducting further appropriate investigation. Surviving stage 3 patients will be followed-up in an AKI clinic. We will conduct qualitative research using focus group-based discussions with primary and secondary care clinicians during the early and late phases of the trial. This will help break down potential barriers and improve care delivery.

Ethics and dissemination

Patients will be contacted about the study allowing them to ‘opt out’. The work of an Outreach team, guided by AKI alerts and delivering timely advice to clinicians, may improve outcomes. If the results suggest that benefits are delivered by an AKI Outreach team, this study will lead to a full cluster randomised trial.

Trial registration number

NCT02398682: Pre-results.
EGFRmutation detection on lung cancer cytological specimens by the novel fully automated PCR-based IdyllaEGFRMutation Assay
Authors: De Luca Caterina , Gragnano Gianluca , Pisapia Pasquale , Vigliar Elena , Malapelle Umberto , Bellevicine Claudio , Troncone Giancarlo
Published: August 2016

Aims

In everyday practice, epidermal growth factor receptor (EGFR) testing is centralised in referral laboratories that receive paucicellular cytological specimens. Ideally,EGFRtesting should be carried out in the centre where the patient is diagnosed such that the most cellular slide can be selected from in-house collected cytological material. However, available techniques are little standardised and difficult to be implemented in settings with little expertise in molecular testing. The IdyllaEGFRprototype assay is a rapid and fully automated test which may easily be adopted by a wider number of pathological centres. This study assessed whether an IdyllaEGFRprototype assay can be reliably applied to cytological lung cancer specimens.

Methods

The limit of detection (LOD) of the IdyllaEGFRprototype assay was assessed by cell line dilution studies. A total of 10 ng was directly placed inside an IdyllaEGFRprototype assay cartridge. Idylla results were compared with fragment length (exon 19 del) and Taqman assays.

Results

The IdyllaEGFRprototype assay showed an LOD of 1% mutant allele and yielded valid results in 74/76 (97.3%) samples, detecting all the mutant cases (n=32) identified by standard techniques; in addition, Idylla detected two low abundanceEGFRexon 19 deletions and two G719X exon 18 point mutations, not covered by our standard reference method.

Conclusions

IdyllaEGFRprototype assay is sensitive on extracted DNA and can reliably be applied on cytological samples, enabling implementation ofEGFRtesting even in less experienced diagnostic units.
Breath in the technoscientific imaginary
Authors: Rose Arthur
Published: August 2016

Breath has a realist function in most artistic media. It serves to remind the reader, the viewer or the spectator of the exigencies of the body. In science fiction (SF) literature and films, breath is often a plot device for human encounters with otherness, either with alien peoples, who may not breathe oxygen, or environments, where there may not be oxygen to breathe. But while there is a technoscientific quality to breath in SF, especially in its attention to physiological systems, concentrating on the technoscientific threatens to occlude other, more affective aspects raised by the literature. In order to supplement the tendency to read SF as a succession of technoscientific accounts of bodily experience, this paper recalls how SF texts draw attention to the affective, non-scientific qualities of breath, both as a metonym for life and as a metaphor for anticipation. Through an engagement with diverse examples from SF literature and films, this article considers the tension between technoscientific and affective responses to breath in order to demonstrate breath's co-determinacy in SF's blending of scientific and artistic discourses.
Canadian Registry of LVIS Jr for Treatment of Intracranial Aneurysms (CaRLA)
Authors: Shankar Jai Jai Shiva , Quateen Aiman , Weill Alain , Tampieri Donatella , Del Pilar Cortes Maria , Fahed Robert , Patro Satya , Kaderali Zul , Lum Cheemun , Lesiuk Howard , Ahmed Uzair , Peeling Lissa , Kelly Michael E , Iancu Daniela
Published: August 2016

Introduction

Stents reduce the rate of angiographic recurrence of intracranial aneurysms. The newest stent for intracranial use is the Low-profile Visible Intraluminal Support device (LVIS Jr).

Objective

To assess the efficacy of the new stent in a multicenter retrospective registry.

Materials and method

Centers across Canada using LVIS Jr were contacted and asked to participate in a retrospective registry of consecutive patients treated with LVIS Jr for intracranial aneurysms between January 2013 and July 2015.

Results

A total of 102 patients, with saccular aneurysms in 100 patients (72 women; age range 21–78 years; mean 56.0 years; median 57.5 years) were treated with a LVIS Jr stent. The mean maximum diameter of the dome and neck of the aneurysm and dome to neck ratios were 8.3 mm±7.7 mm, 4.4 mm±1.9 mm, and 1.86±1.22, respectively. Angiographic complications arose in 23 patients, clinical complications in 9 patients, and only 3% of permanent neurological deficits occurred. Death occurred in 1 patient, unrelated to the stent. The ruptured status of the aneurysms (OR=3.29; p=0.046) and use of LVIS Jr for bailout (OR=2.54; p=0.053) showed a trend towards significant association with higher angiographic complications. At the last available follow-up, 68 class I, 20 class II, and 12 class III results were seen.

Conclusions

The LVIS Jr stent is a safe and effective device for stent-assisted coiling, with 3% permanent neurological complications. Stent-assisted coiling continues to be technically challenging in cases of ruptured aneurysms and bailout situations.
Jointed pipeline response to tunneling-induced ground deformation
Authors: Wham Brad P. , Argyrou Christina , O’Rourke Thomas D.
Published: August 2016

This paper focuses on the effect of tunneling-induced ground deformation on the response of jointed cast iron and ductile iron pipelines that (i) cross the settlement profile perpendicular to the tunnel centerline and (ii) connect through 90° tees with a pipeline parallel to the tunnel centerline. The modeling involves two-dimensional finite element analyses that account for coupled forces both parallel and perpendicular to the pipeline, and incorporates the results of large-scale laboratory tests to characterize the joints. Pipeline response is quantified with respect to joint rotation and pullout at various leakage levels as well as the allowable tensile strain. The paper describes soil displacements induced by a 6.1 m (20 ft.) diameter tunnel in clay and sand. Joint rotations and maximum tensile strains for pipelines in sand exceed those in clay by up to three for the same geometric conditions. Cast iron pipelines crossing the tunnel centerline are most vulnerable to leakage from joint rotation; ductile iron pipelines have sufficient capacity against joint leakage in all cases studied. Cast iron pipelines that connect with 90° tees are highly vulnerable to leakage from pullout due to lateral soil movement. Guidance is provided for risk assessment, design, and utility operations.
Combustion and Engine-Core Noise
Authors: Ihme Matthias
Published: August 2016

The implementation of advanced low-emission aircraft engine technologies and the reduction of noise from airframe, fan, and jet exhaust have made noise contributions from an engine core increasingly important. Therefore, meeting future ambitious noise-reduction goals requires the consideration of engine-core noise. This article reviews progress on the fundamental understanding, experimental analysis, and modeling of engine-core noise; addresses limitations of current techniques; and identifies opportunities for future research. After identifying core-noise contributions from the combustor, turbomachinery, nozzles, and jet exhaust, they are examined in detail. Contributions from direct combustion noise, originating from unsteady combustion, and indirect combustion noise, resulting from the interaction of flow-field perturbations with mean-flow variations in turbine stages and nozzles, are analyzed. A new indirect noise-source contribution arising from mixture inhomogeneities is identified by extending the theory. Although typically omitted in core-noise analysis, the impact of mean-flow variations and nozzle-upstream perturbations on the jet-noise modulation is examined, providing potential avenues for future core-noise mitigation.
PCSK9: Regulation and Target for Drug Development for Dyslipidemia
Authors: Burke Amy C. , Dron Jacqueline S. , Hegele Robert A. , Huff Murray W.
Published: August 2016

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.
Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction
Authors: Wang Wei , Zhang Fuyang , Xia Yunlong , Zhao Shihao , Yan Wenjun , Wang Helin , Lee Yan , Li Congye , Zhang Ling , Lian Kun , Gao Erhe , Cheng Hexiang , Tao Ling
Published: August 2016

Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF.
Cardiac neural crest ablation results in early endocardial cushion and hemodynamic flow abnormalities
Authors: Ma Pei , Gu Shi , Karunamuni Ganga H. , Jenkins Michael W. , Watanabe Michiko , Rollins Andrew M.
Published: August 2016

Cardiac neural crest cell (CNCC) ablation creates congenital heart defects (CHDs) that resemble those observed in many syndromes with craniofacial and cardiac consequences. The loss of CNCCs causes a variety of great vessel defects, including persistent truncus arteriosus and double-outlet right ventricle. However, because of the lack of quantitative volumetric measurements, less severe defects, such as great vessel size changes and valve defects, have not been assessed. Also poorly understood is the role of abnormal cardiac function in the progression of CNCC-related CHDs. CNCC ablation was previously reported to cause abnormal cardiac function in early cardiogenesis, before the CNCCs arrive in the outflow region of the heart. However, the affected functional parameters and how they correlate with the structural abnormalities were not fully characterized. In this study, using a CNCC-ablated quail model, we contribute quantitative phenotyping of CNCC ablation-related CHDs and investigate abnormal early cardiac function, which potentially contributes to late-stage CHDs. Optical coherence tomography was used to assay early- and late-stage embryos and hearts. In CNCC-ablated embryos at four-chambered heart stages, great vessel diameter and left atrioventricular valve leaflet volumes are reduced. Earlier, at cardiac looping stages, CNCC-ablated embryos exhibit abnormally twisted bodies, abnormal blood flow waveforms, increased retrograde flow percentage, and abnormal cardiac cushions. The phenotypes observed in this CNCC-ablation model were also strikingly similar to those found in an established avian fetal alcohol syndrome model, supporting the contribution of CNCC dysfunction to the development of alcohol-induced CHDs.
There is blood in the water: hemolysis, hemoglobin, and heme in acute lung injury
Authors: Gaggar Amit , Patel Rakesh P.
Published: August 2016

The major role of red blood cells (RBCs) is to deliver oxygen and remove carbon dioxide within organisms through the unique properties of hemoglobin. Although beneficial within RBCs, when outside hemoglobin and its breakdown products (heme, iron) induce proinflammatory responses affecting various cellular responses. Although these effects are considered to be prominent in disorders with increased hemolysis, recent evidence suggests that this process may be active in nonhemolytic disorders such as acute lung injury/acute respiratory distress syndrome. This perspectives article focuses on data related to red cell products in nonhemolytic disorders and the potential to target these factors in acute lung injury/acute respiratory distress syndrome.
ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors
Authors: Hertz Daniel L. , Henry N. Lynn , Kidwell Kelley M. , Thomas Dafydd , Goddard Audrey , Azzouz Faouzi , Speth Kelly , Li Lang , Banerjee Mousumi , Thibert Jacklyn N. , Kleer Celina G. , Stearns Vered , Hayes Daniel F. , Skaar Todd C. , Rae James M.
Published: August 2016

Hormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analyzed for ESR1 and PGR gene transcript expression by the reverse transcription polymerase chain reaction based Oncotype DX assay and for ERα and PgR protein expression by immunohistochemistry (IHC) and an automated quantitative immunofluorescence assay (AQUA). Germline genotypes for SNPs in ESR1 ( n = 41) and PGR ( n = 8) were determined by allele-specific TaqMan assays. One SNP in ESR1 (rs9322336) was significantly associated with ESR1 gene transcript expression ( P = 0.006) but not ERα protein expression ( P > 0.05). A PGR SNP (rs518162) was associated with decreased PGR gene transcript expression ( P = 0.003) and PgR protein expression measured by IHC ( P = 0.016), but not AQUA ( P = 0.054). There were modest, but statistically significant correlations between gene and protein expression for ESR1/ERα and PGR/PgR and for protein expression measured by IHC and AQUA (Pearson correlation = 0.32–0.64, all P < 0.001). Inherited ESR1 and PGR genotypes may affect tumor ESR1/ERα and PGR/PgR expression, respectively, which are moderately correlated. This work supports further research into germline predictors of tumor characteristics and treatment effectiveness, which may someday inform selection of hormonal treatments for patients with HR+ breast cancer.
Stepping in Place While Voluntarily Turning Around Produces a Long-Lasting Posteffect Consisting in Inadvertent Turning While Stepping Eyes Closed
Authors: Sozzi Stefania , Schieppati Marco
Published: August 2016

Training subjects to step in place on a rotating platform while maintaining a fixed body orientation in space produces a posteffect consisting in inadvertent turning around while stepping in place eyes closed (podokinetic after-rotation, PKAR). We tested the hypothesis that voluntary turning around while stepping in place also produces a posteffect similar to PKAR. Sixteen subjects performed 12 min of voluntary turning while stepping around their vertical axis eyes closed and 12 min of stepping in place eyes open on the center of a platform rotating at 60°/s (pretests). Then, subjects continued stepping in place eyes closed for at least 10 min (posteffect). We recorded the positions of markers fixed to head, shoulder, and feet. The posteffect of voluntary turning shared all features of PKAR. Time decay of angular velocity, stepping cadence, head acceleration, and ratio of angular velocity after to angular velocity before were similar between both protocols. Both postrotations took place inadvertently. The posteffects are possibly dependent on the repeated voluntary contraction of leg and foot intrarotating pelvic muscles that rotate the trunk over the stance foot, a synergy common to both protocols. We propose that stepping in place and voluntary turning can be a scheme ancillary to the rotating platform for training body segment coordination in patients with impairment of turning synergies of various origin.
An Integrated Nanotechnology-Enabled Transbronchial Image-Guided Intervention Strategy for Peripheral Lung Cancer
Authors: Jin Cheng S. , Wada Hironobu , Anayama Takashi , McVeigh Patrick Z. , Hu Hsin Pei , Hirohashi Kentaro , Nakajima Takahiro , Kato Tatsuya , Keshavjee Shaf , Hwang David , Wilson Brian C. , Zheng Gang , Yasufuku Kazuhiro
Published: August 2016

Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current nonsurgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460, and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon nonsurgical treatment of early-stage peripheral lung cancer. Cancer Res; 76(19); 5870–80. ©2016 AACR.
Preclinical Efficacy of the Auristatin-Based Antibody–Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors
Authors: Sommer Anette , Kopitz Charlotte , Schatz Christoph A. , Nising Carl F. , Mahlert Christoph , Lerchen Hans-Georg , Stelte-Ludwig Beatrix , Hammer Stefanie , Greven Simone , Schuhmacher Joachim , Braun Manuela , Zierz Ruprecht , Wittemer-Rump Sabine , Harrenga Axel , Dittmer Frank , Reetz Frank , Apeler Heiner , Jautelat Rolf , Huynh Hung , Ziegelbauer Karl , Kreft Bertolt
Published: August 2016

The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody–drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line–based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331–9. ©2016 AACR.
Association between Vitamin D Deficiency and Antinuclear Antibodies in Middle-Aged and Older U.S. Adults
Authors: Meier Helen C.S. , Sandler Dale P. , Simonsick Eleanor M. , Parks Christine G.
Published: August 2016

Background: Vitamin D deficiency is associated with cancer and autoimmune diseases, but little is known about the association between vitamin D and antinuclear antibodies (ANA), a biomarker of immune dysfunction in healthy populations. The objective of this study was to determine whether vitamin D deficiency is associated with ANA in middle-aged and older U.S. adults.

Methods: A cross-sectional analysis using the National Health and Nutrition Examination Survey (NHANES) 2001–2004 was conducted. Data were available for 1,012 adults aged 50 years and older. Serum 25-hydroxyvitamin D levels were measured by radioimmunoassay. ANA was measured in a 1:80 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4+).

Results: Greater vitamin D deficiency was associated with higher ANA prevalence in the unadjusted (Ptrend = 0.0002) logistic regression model and after adjustment for sex, age, education, race/ethnicity, season, and NHANES cycle (Ptrend = 0.04). After adjustment, those with severe vitamin D deficiency (<10 ng/mL) had 2.99 (95% CI, 1.25–7.15) times the odds of ANA compared with having normal vitamin D levels (≥30 ng/mL), while deficient and insufficient individuals had twice the odds of ANA.

Conclusions: Among U.S. residents ages 50 and older, vitamin D deficiency was associated with higher prevalence of ANA. Vitamin D sufficiency may be important for preventing immune dysfunction in older populations.

Impact: Our findings support the growing evidence that vitamin D is an important immune modulator. Vitamin D deficiency in older adults may increase vulnerability to cancer by contributing to immune dysfunction. Cancer Epidemiol Biomarkers Prev; 25(12); 1559–63. ©2016 AACR.
Presurgical Biomarker Performance in the Detection of Gleason Upgrading in Prostate Cancer
Authors: Wittig Kristina , Yamzon Johnathan L. , Smith David D. , Jeske Daniel R. , Smith Steven S.
Published: August 2016

Background: Gleason Score (GS) upgrading is generally considered a trigger for exit to definitive treatment during active surveillance (AS). Predicting the potential for GS upgrading would be of value in assessing AS eligibility.

Methods: We assessed the performance of biomarkers in presurgical specimens of expressed prostatic secretion (EPS) in this setting.

Results: Although EPS volume, total recovered RNA, and RNA expression biomarkers (TMPRSS2: ERG, PCA3, PSA) have been successful in both biopsy outcome prediction, and in the prediction of upstaging in active surveillance eligible patients, they were unable to predict upgrading in patients eligible for active surveillance under National Comprehensive Cancer Network guidelines.

Conclusions: These biomarkers do not improve the prediction of upgrading over indications from standard clinical parameters.

Impact: Additional biomarkers will be needed in this area. Cancer Epidemiol Biomarkers Prev; 25(12); 1643–5. ©2016 AACR.
A Threshold of Systemic MAGE-A Gene Expression Predicting Survival in Resected Non–Small Cell Lung Cancer
Authors: Mecklenburg Ingo , Sienel Wulf , Schmid Severin , Passlick Bernward , Kufer Peter
Published: August 2016

Purpose: Quantitative measurement of minimal residual disease predicting recurrence in individual cancer patients is available only in very few indications, such as acute lymphoblastic leukemia, but is still missing in most solid tumors, including non–small cell lung cancer (NSCLC).

Experimental Design: MAGE-A expression levels in blood and bone marrow determined as calibrator-normalized relative ratios by quantitative multimarker real-time RT-PCR for transcript amplification of MAGE-A1, -A2, -A3/6, -A4, -A10, and -A12 in 94 patients with completely resected NSCLC were correlated with survival in a clinical study.

Results: Patients with MAGE-A expression levels ≥0.2 in at least one sample of bone marrow or blood at tumor surgery had a significantly reduced overall (P = 0.007), cancer-free (P = 0.002), and distant metastasis–free survival (P < 0.001) versus patients below 0.2 in all samples without significant difference in locoregional recurrence–free survival. The corresponding HRs (≥0.2 vs. <0.2) for death, cancer-related death, and development of distant metastasis were 2.56 [95% confidence interval (CI), 1.42–4.63], 3.32 (95% CI, 1.66–6.61), and 4.03 (95% CI, 1.77–9.18), respectively. Five-year Kaplan–Meier estimates of distant metastasis–free survival were 43% (MAGE-A ≥ 0.2) versus 87% (MAGE-A < 0.2).

Conclusions: MAGE-A expression in blood or bone marrow at tumor surgery is an independent predictor of survival in resected NSCLC. The reliable prediction of distant metastasis in individual patients with a statistically proven impact on overall survival may help to refine patient selection for adjuvant therapy urgently needed, especially in the clinical management of elderly patients. Clin Cancer Res; 23(5); 1213–9. ©2016 AACR.
Rock, apatia e violência
Authors: Gutierrez Maria Alzuguir
Published: August 2016

Neste artigo serão analisados os filmes Rodrigo D. No futuro e ¿Cómo ves?, que abordam um assunto recorrente no cinema da América Latina: a juventude marginalizada. Nas décadas de 1980 e 1990, com o avanço do neoliberalismo e a crise dos projetos de esquerda, a representação do tema ganhou novos contornos. A crítica apontou, nestes filmes, um afastamento em relação ao cinema moderno. Em nossa análise, estabeleceremos um diálogo com tal crítica na reflexão sobre estas obras, que tomam a música como elo de ligação com o público jovem e procuram se aproximar da vida interior de seus personagens através do recurso à “subjetiva indireta livre”.