bluuebunny/crossref_metadata_2025 huggingface dataset:
The Escherichia coli SMC Complex, MukBEF, Shapes Nucleoid Organization Independently of DNA Replication
Authors: Badrinarayanan Anjana , Lesterlin Christian , Reyes-Lamothe Rodrigo , Sherratt David
Published: June 2012

SMC (structuralmaintenance ofchromosomes) complexes function ubiquitously in organizing and maintaining chromosomes. Functional fluorescent derivatives of theEscherichia coliSMC complex, MukBEF, form foci that associate with the replication origin region (ori). MukBEF impairment results in mispositioning oforiand other loci in steady-state cells. These observations led to an earlier proposal that MukBEF positions new replicated sisteroris. We show here that MukBEF generates and maintains the cellular positioning of chromosome loci independently of DNA replication. Rapid impairment of MukBEF function by depleting a Muk component in the absence of DNA replication leads to loss of MukBEF foci as well as mispositioning oforiand other loci, while rapid Muk synthesis leads to rapid MukBEF focus formation but slow restoration of normal chromosomal locus positioning.
Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients
Authors: Chung Jade C. S. , Becq Jennifer , Fraser Louise , Schulz-Trieglaff Ole , Bond Nicholas J. , Foweraker Juliet , Bruce Kenneth D. , Smith Geoffrey P. , Welch Martin
Published: June 2012

The airways of individuals with cystic fibrosis (CF) often become chronically infected with unique strains of the opportunistic pathogenPseudomonas aeruginosa. Several lines of evidence suggest that the infectingP. aeruginosalineage diversifies in the CF lung niche, yet so far this contemporary diversity has not been investigated at a genomic level. In this work, we sequenced the genomes of pairs of randomly selected contemporary isolates sampled from the expectorated sputum of three chronically infected adult CF patients. Each patient was infected by a distinct strain ofP. aeruginosa. Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) were identified in the DNA common to the paired isolates from different patients. The paired isolates from one patient differed due to just 1 SNP and 8 indels. The paired isolates from a second patient differed due to 54 SNPs and 38 indels. The pair of isolates from the third patient both contained amutSmutation, which conferred a hypermutator phenotype; these isolates cumulatively differed due to 344 SNPs and 93 indels. In two of the pairs of isolates, a different accessory genome composition, specifically integrated prophage, was identified in one but not the other isolate of each pair. We conclude that contemporary isolates from a single sputum sample can differ at the SNP, indel, and accessory genome levels and that the cross-sectional genomic variation among coeval pairs ofP. aeruginosaCF isolates can be comparable to the variation previously reported to differentiate between paired longitudinally sampled isolates.
Influence of frequency and duration of strength training for effective management of neck and shoulder pain: a randomised controlled trial
Authors: Andersen Christoffer H , Andersen Lars L , Gram Bibi , Pedersen Mogens Theisen , Mortensen Ole Steen , Zebis Mette Kreutzfeldt , Sjøgaard Gisela
Published: June 2012

Background

Specific strength training can reduce neck and shoulder pain in office workers, but the optimal combination of exercise frequency and duration remains unknown. This study investigates how one weekly hour of strength training for the neck and shoulder muscles is most effectively distributed.

Methods

A total of 447 office workers with and without neck and/or shoulder pain were randomly allocated at the cluster-level to one of four groups; 1×60 (1WS), 3×20 (3WS) or 9×7 (9WS) min a week of supervised high-intensity strength training for 20 weeks, or to a reference group without training (REF). Primary outcome was self-reported neck and shoulder pain (scale 0–9) and secondary outcome work disability (Disability in Arms, Shoulders and Hands (DASH)).

Results

The intention-to-treat analysis showed reduced neck and right shoulder pain in the training groups after 20 weeks compared with REF. Among those with pain ≥3 at baseline (n=256), all three training groups achieved significant reduction in neck pain compared with REF (p<0.01). From a baseline pain rating of 3.2 (SD 2.3) in the neck among neck cases, 1WS experienced a reduction of 1.14 (95% CI 0.17 to 2.10), 3WS 1.88 (0.90 to 2.87) and 9WS 1.35 (0.24 to 2.46) which is considered clinically significant. DASH was reduced in 1WS and 3WS only.

Conclusion

One hour of specific strength training effectively reduced neck and shoulder pain in office workers. Although the three contrasting training groups showed no statistical differences in neck pain reduction, only 1WS and 3WS reduced DASH. This study suggests some flexibility regarding time-wise distribution when implementing specific strength training at the workplace.
Using systematic change management to improve emergency patients' access to specialist care: the Big Squeeze
Authors: Rafman Heidi , Lim Siang Ngin , Quek Swee Chye , Mahadevan Malcolm , Lim Chanelle , Lim Aymeric
Published: June 2012

Background

Delayed access to specialist care for emergency patients is associated with increased risk of morbidity and mortality, and increased patient anxiety.

Objectives

(1) To provide timelier access to inpatient and urgent outpatient specialist care for emergency patients. (2) To influence multiple stakeholders to modify their traditional practices and sustain changes.

Setting

National University Hospital of Singapore, an academic medical centre with 997 beds in Singapore and over 34 sub-specialties.

Methods

A set of six interventions was implemented to meet three goals: (1) provide timely access to urgent outpatient specialist care requested by the emergency department ED; (2) increase early inpatient discharges (in order to better match timing of emergency admissions); and (3) provide earlier defined care by inpatient specialists at the ED. An eight-step organisational change management plan was implemented to ensure all specialties complied with the changes.

Results

The goals were achieved. (1) Specialist outpatient appointments given within the timeframe requested by the ED doctor increased from 51.7% to 80.8%. (2) Early discharges increased from 11.9% to 26.6% and were sustained at 27.2%. (3) 84% of eligible patients received earlier defined specialist care at the ED. The change management achieved excellent clinician compliance rates ranging from 84% to 100%. However the median wait for admission remained unchanged.

Conclusion

The interventions reduced the time for ED patients to access specialist outpatient and inpatient care. The systematic organisational change management approach resulted in sustained compliance.
The epidemiology of adults with severe sepsis and septic shock in Scottish emergency departments
Authors: Gray Alasdair , Ward Kirsty , Lees Fiona , Dewar Colin , Dickie Sarah , McGuffie Crawford ,   On behalf of the STAG steering committee
Published: June 2012

Background

The Surviving Sepsis Campaign (SSC) promotes a bundle approach to the care of septic patients to improve outcome. Some have questioned the capability of delivering the bundle in emergency departments (EDs). The authors report the epidemiology and 6 h bundle compliance of patients with severe sepsis/septic shock presenting to Scottish EDs.

Methods

Analysis of the previously reported Scottish Trauma Audit Group sepsis database was performed including 20 mainland Scottish EDs. A total of 308 910 attendances were screened (between 2 March and 31 May 2009), and 5285 of 27 046 patients were identified after case note review and included on the database. This analysis includes patients who had severe sepsis/septic shock before leaving the ED. Epidemiological, severity of illness criteria, and ED management data were analysed.

Results

626 patients (median age 73; M/F ratio 1:1; 637 presentations) met entrance criteria. The median number of cases per site was 16 (range 3–103). 561 (88.1%) patients arrived by ambulance. The most common source of infection was the respiratory tract (n=411, 64.5%) The most common physiological derangements were heart rate (n=523, 82.1%), respiratory rate (n=452, 71%) and white cell count (n=432, 67.8%). The median hospital stay was 9 days (IQR 4–17 days). 201 (31.6%) patients were admitted to critical care within 2 days, 130 (20.4%) directly from the ED. 180 patients (28.3%) died. There was poor compliance with all aspect of the SSC resuscitation bundle.

Conclusions

Sepsis presentations are of variable frequency but have typical epidemiology and clinical outcomes. SSC bundle resuscitation uptake is poor in Scottish EDs.
Emergent stent-assisted angioplasty of extracranial internal carotid artery and intracranial stent-based thrombectomy in acute tandem occlusive disease: technical considerations
Authors: Cohen José E , Gomori Moshe , Rajz Gustavo , Moscovici Samuel , Leker Ronen R , Rosenberg Shai , Itshayek Eyal
Published: June 2012

Objective

Tandem occlusions of the internal carotid artery (ICA) and a major intracranial artery respond poorly to intravenous thrombolytic therapy, and are usually managed by endovascular means. This study describes experience with stent-assisted endovascular ICA revascularization and stent-based thrombectomy.

Methods

In patients with tandem ICA–middle cerebral artery (MCA)/distal ICA occlusion, the carotid occlusion was recanalized by primary angioplasty and stent implantation, and the distal occlusion by stent-based thrombectomy. Two variant techniques are described.

Results

Seven consecutive patients, mean age 64.1 years (range 49–75) and mean admission National Institutes of Health Stroke Scale score of 23, were included. Occlusion sites were tandem proximal ICA and MCA trunk (six patients) and tandem proximal left ICA and ICA terminus (one patient). Complete recanalization with complete perfusion (Thrombolysis in Myocardial Infarction [TIMI] 3, Thrombolysis in Cerebral Infarction [TICI] 3) was achieved in six patients and partial recanalization with partial perfusion (TIMI 2, TICI 2A) in one. Mean time to therapy was 4.9 h (range 3–6.5); mean time to recanalization was 55 min (range 38–65 min). CT performed 1 day after recanalization showed cortical sparing (>90% of the cortex at risk) in seven patients. Five patients (72%) presented with good clinical outcome (modified Rankin Scale (mRS) score 0–2) at 1 month; one patient (patient No 7) reached an mRS score of 3 and one patient died.

Conclusions

In selected cases of acute ICA occlusion and concomitant major vessel embolic stroke, angioplasty and stenting of the proximal occlusion and stent-based thrombectomy of the intracranial occlusion may be feasible, effective and safe, and provide early neurological improvement. Further experience and prospective studies are warranted.
Knowledge, attitudes, sexual practices and STI/HIV prevalence in male sex workers and other men who have sex in Tel Aviv, Israel: a cross-sectional study
Authors: Mor Zohar , Dan Michael
Published: June 2012

Objective

To explore knowledge, attitudes and sexual practices of male sex workers (MSW) in Tel Aviv in comparison with men who have sex with men (MSM) classified by their risk behaviours and to outline attributes related to sexually transmitted infections (STI)/HIV prevalence.

Methods

MSW were recruited for this cross-sectional study from designated street venues and gay-dating internet site. MSM were recruited from gay-related venues and divided into high-risk MSM (HRMSM) if they performed unprotected anal intercourse in the last 6 months with an HIV-discordant/unknown partner and to low-risk MSM (LRMSM). Each participant completed a questionnaire and was tested for STI/HIV.

Results

Of 87 MSW and 635 MSM approached, 53 (60.9%) and 235 (37.0%) participated, respectively. Street-MSW (N=32) had more female sex partners and were more drug dependent than internet-MSW (N=21). No differences were found in their knowledge regarding STI/HIV transmission, practices and STI/HIV burden. Compared with HRMSM, MSW had different demographic attributes and demonstrated more realistic perception regarding the risk to getting STI/HIV, while no differences were found in their knowledge and sexual practices. STI burden among MSW, HRMSM (N=119) and LRMSM (N=116) were 28.3%, 23.5% and 10.3% (p=0.009) and HIV burden among MSW, HRMSM and LRMSM were 5.6%, 9.2% and 0%, (p=0.001), respectively. Multivariate models evaluating attributes associated with HIV/STI diagnosis did not find sex work to be significant if the variable used was MSW versus HRMSM, regardless of the adjustments performed. However, when MSW versus LRMSM was used in the model, sex work was associated with STI/HIV diagnosis.

Conclusions

Street-MSW and internet-MSW, similar to all MSW and HRMSM, had comparable sexual practices and had no difference in their STI/HIV prevalence.
Reaching black men who have sex with men: a comparison between respondent-driven sampling and time-location sampling
Authors: Wei Chongyi , McFarland Willi , Colfax Grant N , Fuqua Vincent , Raymond H Fisher
Published: June 2012

Objectives

The authors explored whether respondent-driven sampling (RDS) can generate a more diverse sample of black men who have sex with men (MSM) than time-location sampling (TLS) by comparing sample characteristics accrued by each method in two independent studies.

Methods

The first study exclusively recruited black MSM through RDS (N=256), while the second recruited MSM through TLS including a subsample of black MSM (N=69). Crude and adjusted point estimates and 95% CIs were calculated for socio-demographic and behavioural characteristics, HIV prevalence and prevalence of unrecognised infections, and were compared using the Z-test.

Results

The samples differed significantly regarding all socio-demographic and some behavioural characteristics. Compared with TLS, RDS estimated higher proportions of older, less educated, poorer, currently homeless and self-identified bisexual black MSM. Participants in RDS were less likely to have a main partner, had fewer male partners, were more likely to have a female partner and have both male and female partners, and reported greater methamphetamine, crack and heroin use. Prevalence of HIV and unrecognised infections were slightly higher among RDS participants.

Conclusions

The RDS sample comprised black MSM who were more diverse with respect to socio-demographic characteristics and may also be at higher risk for HIV. Thus, RDS has advantages in reaching higher risk black MSM who are most hidden from intervention research and service delivery. Future studies of black MSM using RDS could use steering strategies to recruit younger participants and other subgroups of greatest interest to public health and prevention.
ANALYSIS OF NUCLEUS–NUCLEUS FUSION CROSS-SECTION AT EXTREME SUB-BARRIER ENERGIES
Authors: SAHU BASUDEB , SAHU BIDHUBHUSAN
Published: July 2012

The nucleus–nucleus potential is expressed phenomenologically by a new radial form as an alternative to the conventional Woods–Saxon form. By virtue of novel representation of the surface diffuseness, the potential added with the electrostatic part generates a unique barrier potential which provides simultaneous explanations of two important mechanisms namely elastic scattering and fusion in a heavy-ion reaction within the framework of optical potential model of scattering and region-wise absorption in analytical form. The drastic falloff of experimental results of fusion cross-section (σ fus ) at extreme sub-barrier energy (E) and its manifestation depicting maximum in S( = Eσ fus e2πη) factor and steep rise in L( = d ln (Eσ fus )/dE) factor are explained with remarkable success.
FRACTIONAL ORDER KINETIC EQUATIONS AND HYPOELLIPTICITY
Authors: ALEXANDRE R.
Published: July 2012

We give simple proofs of hypoelliptic estimates for some models of kinetic equations with a fractional order diffusion part. The proofs are based on energy estimates together with the previous ideas of Bouchut and Perthame.
STRUCTURAL, ELECTRONIC AND OPTICAL PROPERTIES OF THIOPHENE AND THIENOTHIOPHENE CONTAINING DIKETO-PYRROLO-PYRROLES (DPPs) IN POLAR APROTIC SOLVENTS
Authors: LIU HONGJUN , KANTCHEV ERIC ASSEN B. , TAN HUEI SHUAN , NORSTEN TYLER B.
Published: July 2012

Thiophene (T) and thienothiophene (TT) containing 2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione (DPP) compounds were prepared according to the succinic ester route from the corresponding heterocyclic nitrile precursors. As is typical of most DPP pigments, the new compounds showed high thermal stability and could be obtained in pure form as determined by elemental analysis. The bulk properties and molecular structure of the compounds were further characterized by thin film, powder XRD and solid state CP-MAS 13 C NMR. Density functional theory (DFT) and time-dependent (TD) DFT were employed to study the geometric and electronic structures of these molecules in the ground state. The optical properties were investigated by UV-Vis absorption and fluorescence spectroscopies in dimethylsulfoxide (DMSO) and N,N-dimethylacetamide (DMA), which revealed that the absorption maximum of the thiophene diketo-pyrrolo-pyrroles (TDPP) and thienothiophene diketo-pyrrolo-pyrroles (TTDPP) in solution were red shifted up to 25 nm and 60 nm, respectively, relative to Pigment Red 255 (PhDPP), while a new absorption band appeared at longer wavelengths in N-methyl pyrolidone (NMP) and N,N′-dimethylpropylene urea (DMPU) which is ascribed to solvent induced charge transfer (CT) complex. The molecular conformations and absorption spectra of TDPP and TTDPP were characterized by quantum chemical methods in order to better understand the observed behavior.
Madagascar: A History of Arrivals, What Happened, and Will Happen Next
Authors: Dewar Robert E. , Richard Alison F.
Published: July 2012

Most of the ancestors of today's human and animal populations reached Madagascar over the last 65 million years, by a variety of routes at a variety of times. Settlers encountered a big, isolated island with an unpredictable climate and a wide array of landscapes. Although patterns of diversification were driven by different mechanisms in humans and animals, the complex interplay between historical contingency and responsiveness to local conditions is evident in both.

Global climate change will affect Madagascar, although exactly how remains unclear, and the immediate impact of human activity on the island is overtaking that of gradual global change. Three themes in this review bear on the future: the continuing impact of recent, cataclysmic events on modern communities of people, plants, and animals; Madagascar's long and dynamic environmental history; and the complicated history of how people settled and interacted with the island's landscapes. A deeper understanding of all three can contribute to wise decision making in the coming years.
Sport, Modernity, and the Body
Authors: Besnier Niko , Brownell Susan
Published: July 2012

Over the past three decades, the important role that anthropological theory has bestowed on the body, modernity, nationalism, the state, citizenship, transnationalism, globalization, gender, and sexuality has placed sports at the center of questions central to the discipline. New approaches to the body, based on practice theory, view the sporting body as more than just a biological entity, allowing us to observe sports as they “travel” transnationally and illuminating issues relevant to such dynamics as colonialism, globalization, sport mega-events, and labor migration. A distinctly anthropological approach, with its unique research methods, approaches to theory, and holistic thinking, can utilize insights from the constitution of sport as human action to illuminate important social issues in a way that no other discipline can. On this foundation, the anthropology of sport is now poised to make significant contributions to our understanding of central problems in anthropology.
Targeting the intrinsic inflammatory pathway: honokiol exerts proapoptotic effects through STAT3 inhibition in transformed Barrett's cells
Authors: Yu Chunhua , Zhang Qiuyang , Zhang Hui Ying , Zhang Xi , Huo Xiaofang , Cheng Edaire , Wang David H. , Arbiser Jack L. , Spechler Stuart Jon , Souza Rhonda F.
Published: June 2012

One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growth-inhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.
Antioxidative properties of paraoxonase 2 in intestinal epithelial cells
Authors: Précourt Louis-Philippe , Marcil Valérie , Ntimbane Thierry , Taha Rame , Lavoie Jean-Claude , Delvin Edgard , Seidman Ernest G. , Beaulieu Jean-François , Levy Emile
Published: June 2012

Paraoxonase (PON) family members seem central to a wide variety of human illnesses, but appreciation of their antioxidative function in the gastrointestinal tract is in its infancy. The major objective of the present work is to highlight the role of the ubiquitously expressed PON2 in the small intestine. With use of pLKO lentiviral vector containing short hairpin RNA (shRNA) lentivirus, PON2 expression was knocked down in intestinal Caco-2/15 cells, where antioxidative status, lipid peroxidation, and degree of inflammation were evaluated. As a consequence of PON2 inactivation in the epithelial cells, we observed 1) imbalanced primary and secondary antioxidative responses, characterized by increased superoxide dismutases and decreased catalase, 2) high concentrations of H2O2and malondialdehyde, along with low glutathione-to-glutathione disulfide ratio, 3) upregulation of TNF-α, IL-6, and monocyte chemoattractant protein-1 gene expression after induction of oxidative stress, and 4) raised level of the activation of transcription factor NF-κB, which was likely implicated in exacerbation of the inflammatory activation. These results suggest that PON2 is involved in the antioxidative and anti-inflammatory response in intestinal epithelial cells.
Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease
Authors: Hoffman Sidra M. , Tully Jane E. , Lahue Karolyn G. , Anathy Vikas , Nolin James D. , Guala Amy S. , van der Velden Jos. L. J. , Ho Ye-Shih , Aliyeva Minara , Daphtary Nirav , Lundblad Lennart K. A. , Irvin Charles G. , Janssen-Heininger Yvonne M. W.
Published: June 2012

Protein- S-glutathionylation (PSSG) is an oxidative modification of reactive cysteines that has emerged as an important player in pathophysiological processes. Under physiological conditions, the thiol transferase, glutaredoxin-1 (Glrx1) catalyses deglutathionylation. Although we previously demonstrated that Glrx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/PSSG in the development of allergic airways disease remains unknown. In the present study we examined the impact of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness (AHR) in mice. Glrx1 −/− or WT mice were subjected to the antigen, ovalbumin (OVA), and parameters of allergic airways disease were evaluated 48 h after three challenges, and 48 h or 7 days after six challenges with aerosolized antigen. Although no clear increases in PSSG were observed in WT mice in response to OVA, marked increases were detected in lung tissue of mice lacking Glrx1 48 h following six antigen challenges. Inflammation and expression of proinflammatory mediators were decreased in Glrx1 −/− mice, dependent on the time of analysis. WT and Glrx1 −/− mice demonstrated comparable increases in AHR 48 h after three or six challenges with OVA. However, 7 days postcessation of six challenges, parameters of AHR in Glrx1 −/− mice were resolved to control levels, accompanied by marked decreases in mucus metaplasia and expression of Muc5AC and GOB5. These results demonstrate that the Glrx1/ S-glutathionylation redox status in mice is a critical regulator of AHR, suggesting that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.
Aluminium Toxicity Targets in Plants
Authors: Silva Sónia
Published: July 2012

Aluminium (Al) is the third most abundant metallic element in soil but becomes available to plants only when the soil pH drops below 5.5. At those conditions, plants present several signals of Al toxicity. As reported by literature, major consequences of Al exposure are the decrease of plant production and the inhibition of root growth. The root growth inhibition may be directly/indirectly responsible for the loss of plant production. In this paper the most remarkable symptoms of Al toxicity in plants and the latest findings in this area are addressed. Root growth inhibition, ROS production, alterations on root cell wall and plasma membrane, nutrient unbalances, callose accumulation, and disturbance of cytoplasmic Ca2+ homeostasis, among other signals of Al toxicity are discussed, and, when possible, the behavior of Al-tolerant versus Al-sensitive genotypes under Al is compared.
Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis
Authors: Urushihara Maki , Kinoshita Yukiko , Kondo Shuji , Kagami Shoji
Published: July 2012

The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.
Underwater Localization and Tracking of Physical Systems
Authors: Carroll Patrick , Zhou Shengli , Zhou Hao , Xu Xiaoka , Cui Jun-Hong , Willett Peter
Published: July 2012

We investigate the problem of localizing an underwater sensor node based on message broadcasting from multiple surface nodes. With the time‐of‐arrival measurements from a DSP‐based multicarrier modem, each sensor node localizes itself based on the travel time differences among multiple senders to the receiver. Using one‐way message passing, such a solution can scale to accommodate a large number of nodes in a network. We consider the issue from not only the physical layer, but also at the node processing layer by incorporating a tracking solution. We present simulation results, testing results in a swimming pool featuring both stationary and moving receivers, and results from a lake test with a mobile receiver.
Mis- or Missed Diagnosis: A Series of Four Cases
Authors: Sreedharan Sheela , Govinda Bhat Sangeetha , Krishnan Iyer Satishkumar , Krishna Kumar Kavita
Published: July 2012

Diagnosis forms the backbone of treatment planning. Accurate diagnosis is essential to initiate the appropriate treatment at the apt time. Diagnosis involves eliciting the signs and symptoms of the patient and their accurate interpretations. The subtle signs that can go unnoticed lead to misdiagnosis and subsequent agony to the patient. Alertness on part of the clinician is important to avoid this error. Reported in this paper are four cases that were wrongly diagnosed either due to lack of clinical experience or due to omission of careful clinical, radiographic, and histopathological examinations.
microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF-β Signaling in Glioblastoma
Authors: Genovese Giannicola , Ergun Ayla , Shukla Sachet A. , Campos Benito , Hanna Jason , Ghosh Papia , Quayle Steven N. , Rai Kunal , Colla Simona , Ying Haoqiang , Wu Chang-Jiun , Sarkar Sharmistha , Xiao Yonghong , Zhang Jianhua , Zhang Hailei , Kwong Lawrence , Dunn Katherine , Wiedemeyer Wolf Ruprecht , Brennan Cameron , Zheng Hongwu , Rimm David L. , Collins James J. , Chin Lynda
Published: June 2012

Leveraging The Cancer Genome Atlas (TCGA) multidimensional data in glioblastoma, we inferred the putative regulatory network between microRNA and mRNA using the Context Likelihood of Relatedness modeling algorithm. Interrogation of the network in context of defined molecular subtypes identified 8 microRNAs with a strong discriminatory potential between proneural and mesenchymal subtypes. Integrative in silico analyses, a functional genetic screen, and experimental validation identified miR-34a as a tumor suppressor in proneural subtype glioblastoma. Mechanistically, in addition to its direct regulation of platelet-derived growth factor receptor-alpha (PDGFRA), promoter enrichment analysis of context likelihood of relatedness–inferred mRNA nodes established miR-34a as a novel regulator of a SMAD4 transcriptional network. Clinically, miR-34a expression level is shown to be prognostic, where miR-34a low-expressing glioblastomas exhibited better overall survival. This work illustrates the potential of comprehensive multidimensional cancer genomic data combined with computational and experimental models in enabling mechanistic exploration of relationships among different genetic elements across the genome space in cancer.

Significance: We illustrate here that network modeling of complex multidimensional cancer genomic data can generate a framework in which to explore the biology of cancers, leading to discovery of new pathogenetic insights as well as potential prognostic biomarkers. Specifically in glioblastoma, within the context of the global network, promoter enrichment analysis of network edges uncovered a novel regulation of TGF-β signaling via a Smad4 transcriptomic network by miR-34a. Cancer Discov; 2(8); 736–49. ©2012 AACR.

Read the Commentary on this article by Babic et al., p. 676.

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Parallel Down-Regulation of FOXO1, PPARγ and Adiponectin mRNA Expression in Visceral Adipose Tissue of Class III Obese Individuals
Authors: Hammes Thais Ortiz , Costa Cíntia dos Santos , Rohden Francieli , Margis Rogério , Almeida Jussara Carnevale de , Padoin Alexandre Vontobel , Mottin Cláudio Cora , Guaragna Regina Maria
Published: July 2012

Objective: Adipose tissue is responsible for secretion of several cytokines that mediate systemic effects on obesity and insulin resistance. Subcutaneous abdominal adipose tissue (SAT) and visceral adipose tissue (VAT) are metabolically different and have differences in their gene expression profile. Our study evaluated the expression of adiponectin, FOXO1, PPARγ, and SIRT1 in VAT and SAT of non-obese and class III obese subjects. Methods: The adipose tissue samples were obtained by surgery. Reverse transcripts of studied genes were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Comparing the different lipid depots, adiponectin expression was lower only in VAT of obese individuals (p = 0.043); FOXO1 and PPARγ levels were decreased in VAT of both groups. When non-obese and obese were compared, only adiponectin expression was lower in SAT and in VAT of obese subjects (p = 0.004 and p = 0.002, respectively). No difference was found with regard to SIRT1 levels in VAT or SAT in both groups. FOXO1 expression in SAT of obese subjects had a negative correlation with age (r = –0.683; p = 0.029) and triglyceride serum levels (r = –0.794; p = 0.006). Conclusion: The decrease mRNA expression of this genes in VAT, responsible for central adiposity, may be associated with an increased risk of obesity and co-morbidities.
Prevalence, Distribution, Predictors, and Outcomes of Patients With Calcified Nodules in Native Coronary Arteries
Authors: Xu Yingjia , Mintz Gary S. , Tam Anthony , McPherson John A. , Iñiguez Andrés , Fajadet Jean , Fahy Martin , Weisz Giora , De Bruyne Bernard , Serruys Patrick W. , Stone Gregg W. , Maehara Akiko
Published: June 2012

Background—

Pathological studies suggest that calcified coronary nodules are a rare cause of thrombotic events. The frequency, distribution, predictors, and outcomes of calcified nodules have never been described.

Methods and Results—

After successful stenting in 697 patients (167 female; median age, 58.1 years) with acute coronary syndromes, 3-vessel gray-scale and virtual histology intravascular ultrasound was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective, multicenter study. On the basis of recent histological validation, an independent core laboratory identified calcified nodules as distinct calcification with an irregular, protruding, and convex luminal surface. Patients were followed up for 3 years (median). Overall, 314 calcified nodules were detected in 250 of 1573 analyzable arteries (185 of 623 patients). Thus, the prevalence of calcified nodules was 17% per artery and 30% per patient. Two or more calcified nodules were detected in 48 coronary arteries (3%) in 76 patients (12%). The calcified nodules were located <40 mm from the ostium of the coronary artery in 85% of left anterior descending arteries and 86% of left circumflex arteries, whereas calcified nodules within the right coronary arteries were evenly and more distally distributed. Patients with calcified nodules were significantly older and had more plaque volume, more thick-cap fibroatheroma, but fewer nonculprit lesion major adverse events on follow-up.

Conclusions—

Calcified nodules in untreated nonculprit coronary segments in patients with acute coronary syndromes were more prevalent than previously recognized. Although their distribution mirrored the origin of most thrombotic events, calcified nodules caused fewer major adverse events during 3 years of follow-up.
Noninvasive Magnetic Resonance Imaging Evaluation of Endothelial Permeability in Murine Atherosclerosis Using an Albumin-Binding Contrast Agent
Authors: Phinikaridou Alkystis , Andia Marcelo E. , Protti Andrea , Indermuehle Andreas , Shah Ajay , Smith Alberto , Warley Alice , Botnar René M.
Published: June 2012

Background—

Endothelial dysfunction promotes atherosclerosis and precedes acute cardiovascular events. We investigated whether in vivo magnetic resonance imaging with the use of an albumin-binding contrast agent, gadofosveset, could detect endothelial damage associated with atherosclerosis in apolipoprotein E–deficient (ApoE
−/−
) mice. Furthermore, we tested whether magnetic resonance imaging could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine.

Methods and Results—

ApoE
−/−
mice were imaged at 4, 8, and 12 weeks after commencement of a high-fat diet. Statin-treated ApoE
−/−
mice were scanned after 12 weeks of a high-fat diet. Wild-type mice were imaged before and 48 hours after injection of Russell's viper venom, an endothelial toxin. Delayed enhancement magnetic resonance imaging and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R
1
) with progression of atherosclerosis in ApoE
−/−
(R
1
[s
−1
]: R
4 weeks
2.42±0.35, R
8 weeks
3.45±0.54, R
12 weeks
3.83±0.52) and Russell's viper venom–injected wild-type mice (R
1
=4.57±0.86). Conversely, wild-type (R
1
=2.15±0.34) and statin-treated ApoE
−/−
(R
1
=3.0±0.65) mice showed less enhancement. Uptake of gadofosveset correlated with Evans blue staining, morphological changes of endothelial cells, and widening of the cell-cell junctions, suggesting that uptake occurs in regions of increased vascular permeability. Endothelial-dependent vasomotor responses showed vasoconstriction of the arteries of the ApoE
−/−
(−22.22±7.95%) and Russell's viper venom–injected (−10.37±17.60%) mice compared with wild-type mice (32.45±12.35%). Statin treatment improved endothelium morphology and function (−8.12±8.22%).

Conclusions—

We demonstrate the noninvasive assessment of endothelial permeability and function with the use of an albumin-binding magnetic resonance contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim to restore the endothelium.
Cyclin-Dependent Kinase 5–Mediated Hyperphosphorylation of Sirtuin-1 Contributes to the Development of Endothelial Senescence and Atherosclerosis
Authors: Bai Bo , Liang Yan , Xu Cheng , Lee Mary Y.K. , Xu Aimin , Wu Donghai , Vanhoutte Paul M. , Wang Yu
Published: June 2012

Background—

Endothelial senescence represents one of the major characteristics of vascular aging and promotes the development of atherosclerosis. Sirtuin-1 (SIRT1) is an NAD-dependent deacetylase possessing antiaging activities. During the occurrence of endothelial senescence, both the expression and activity of SIRT1 are downregulated. The present study was designed to investigate the molecular mechanisms contributing to the loss-of-SIRT1 function in senescent endothelial cells.

Methods and Results—

After repetitive passages, primary cultures of porcine aortic endothelial cells exhibited a severe senescence phenotype. Western blotting revealed that phosphorylation of SIRT1 at serine 47 (S47) was significantly enhanced in senescent endothelial cells. S47 phosphorylation was stimulated by agents promoting senescence and attenuated by drugs with antisenescence properties. Mutation of S47 to nonphosphorable alanine (S47A) enhanced whereas replacing S47 with phospho-mimicking aspartic acid (S47D) abolished the antisenescent, growth-promoting, and LKB1-downregulating actions of SIRT1. Phosphorylation at S47 was critically involved in the nuclear retention of SIRT1 but abolished its association with the telomeric repeat-binding factor 2–interacting protein 1. Cyclin-dependent kinase 5 (CDK5) was identified as an SIRT1 kinase modulating S47 phosphorylation. Knockdown or inhibition of CDK5 reduced the number of senescent endothelial cells, promoted nuclear exportation of SIRT1, and attenuated the expression of inflammatory genes in porcine aortic endothelial cells. The truncated regulatory subunit of CDK5, P25, accumulated in senescent porcine aortic endothelial cells and atherosclerotic aortas. Long-term treatment with roscovitine, a CDK5 inhibitor, blocked the development of cellular senescence and atherosclerosis in aortas of hypercholesterolemic apolipoprotein E–deficient mice.

Conclusion—

CDK5-mediated hyperphosphorylation of SIRT1 facilitates the development of endothelial senescence and atherosclerosis.
Circulation: Cardiovascular Genetics
' Editors' Picks
Authors:   The Editors
Published: July 2012

The following articles are being highlighted as part of
Circulation's
Topic Review series. This series summarizes the most important manuscripts, as selected by the editors, published in
Circulation
and the
Circulation
subspecialty journals. The studies included in this article represent the Editors' Picks for each
Circulation: Cardiovascular Genetics'
issue published in 2011.
A Latent Heat Retrieval and Its Effects on the Intensity and Structure Change of Hurricane Guillermo (1997). Part II: Numerical Simulations
Authors: Guimond Stephen R. , Reisner Jon M.
Published: June 2012

In Part I of this study, a new algorithm for retrieving the latent heat field in tropical cyclones from airborne Doppler radar was presented and fields from rapidly intensifying Hurricane Guillermo (1997) were shown. In Part II, the usefulness and relative accuracy of the retrievals is assessed by inserting the heating into realistic numerical simulations at 2-km resolution and comparing the generated wind structure to the radar analyses of Guillermo. Results show that using the latent heat retrievals as forcing produces very low intensity and structure errors (in terms of tangential wind speed errors and explained wind variance) and significantly improves simulations relative to a predictive run that is highly calibrated to the latent heat retrievals by using an ensemble Kalman filter procedure to estimate values of key model parameters.

Releasing all the heating/cooling in the latent heat retrieval results in a simulation with a large positive bias in Guillermo’s intensity that motivates the need to determine the saturation state in the hurricane inner-core retrieval through a procedure similar to that described in Part I of this study. The heating retrievals accomplish high-quality structure statistics by forcing asymmetries in the wind field with the generally correct amplitude, placement, and timing. In contrast, the latent heating fields generated in the predictive simulation contain a significant bias toward large values and are concentrated in bands (rather than discrete cells) stretched around the vortex. The Doppler radar–based latent heat retrievals presented in this series of papers should prove useful for convection initialization and data assimilation to reduce errors in numerical simulations of tropical cyclones.
Determining Key Model Parameters of Rapidly Intensifying Hurricane Guillermo (1997) Using the Ensemble Kalman Filter
Authors: Godinez Humberto C. , Reisner Jon M. , Fierro Alexandre O. , Guimond Stephen R. , Kao Jim
Published: June 2012

In this work the authors determine key model parameters for rapidly intensifying Hurricane Guillermo (1997) using the ensemble Kalman filter (EnKF). The approach is to utilize the EnKF as a tool only to estimate the parameter values of the model for a particular dataset. The assimilation is performed using dual-Doppler radar observations obtained during the period of rapid intensification of Hurricane Guillermo. A unique aspect of Guillermo was that during the period of radar observations strong convective bursts, attributable to wind shear, formed primarily within the eastern semicircle of the eyewall. To reproduce this observed structure within a hurricane model, background wind shear of some magnitude must be specified and turbulence and surface parameters appropriately specified so that the impact of the shear on the simulated hurricane vortex can be realized. To identify the complex nonlinear interactions induced by changes in these parameters, an ensemble of model simulations have been conducted in which individual members were formulated by sampling the parameters within a certain range via a Latin hypercube approach. The ensemble and the data, derived latent heat and horizontal winds from the dual-Doppler radar observations, are utilized in the EnKF to obtain varying estimates of the model parameters. The parameters are estimated at each time instance, and a final parameter value is obtained by computing the average over time. Individual simulations were conducted using the estimates, with the simulation using latent heat parameter estimates producing the lowest overall model forecast error.
Understanding the ENSO–CO2 Link Using Stabilized Climate Simulations
Authors: Stevenson Samantha , Fox-Kemper Baylor , Jochum Markus
Published: June 2012

The influence of atmospheric CO2 concentration on the El Niño–Southern Oscillation (ENSO) is explored using 800-yr integrations of the NCAR Community Climate System Model, version 3.5 (CCSM3.5), with CO2 stabilized at the a.d. 1850, 1990, and 2050 levels. Model mean state changes with increased CO2 include preferential SST warming in the eastern equatorial Pacific, a weakening of the equatorial trade winds, increased vertical ocean stratification, and a reduction in the atmospheric Hadley and oceanic subtropical overturning circulations. The annual cycle of SST strengthens with CO2, likely related to unstable air–sea interactions triggered by an increased Northern Hemisphere land–sea temperature contrast. The mean trade wind structure changes asymmetrically about the equator, with increased convergence in the Northern Hemisphere and divergence in the Southern Hemisphere leading to corresponding deepening and shoaling of the thermocline. The proportion of eastern versus central Pacific–type El Niño events increases with CO2, but the significance of the changes is relatively low; ENSO amplitude also increases with CO2, although the change is insignificant at periods longer than 4 yr. The 2–4-yr ENSO response shows an enhancement in equatorial Kelvin wave variability, suggesting that stochastic triggering of El Niño events may be favored with higher CO2. However, the seasonal cycle–ENSO interaction is also modified by the asymmetric climatological changes, and forcing by the Southern Hemisphere becomes more important with higher CO2. Finally, higher-resolution CCSM4 control simulations show that ENSO weakens with CO2 given a sufficiently long integration time. The cause for the difference in ENSO climate sensitivity is not immediately obvious but may potentially be related to changes in westerly wind bursts or other sources of high-frequency wind stress variability.