bluuebunny/crossref_metadata_2025 huggingface dataset:
From Genomics to Gene Therapy: Induced Pluripotent Stem Cells Meet Genome Editing
Authors: Hotta Akitsu , Yamanaka Shinya
Published: September 2015

The advent of induced pluripotent stem (iPS) cells has opened up numerous avenues of opportunity for cell therapy, including the initiation in September 2014 of the first human clinical trial to treat dry age-related macular degeneration. In parallel, advances in genome-editing technologies by site-specific nucleases have dramatically improved our ability to edit endogenous genomic sequences at targeted sites of interest. In fact, clinical trials have already begun to implement this technology to control HIV infection. Genome editing in iPS cells is a powerful tool and enables researchers to investigate the intricacies of the human genome in a dish. In the near future, the groundwork laid by such an approach may expand the possibilities of gene therapy for treating congenital disorders. In this review, we summarize the exciting progress being made in the utilization of genomic editing technologies in pluripotent stem cells and discuss remaining challenges toward gene therapy applications.
Mangrove Sedimentation and Response to Relative Sea-Level Rise
Authors: Woodroffe C.D. , Rogers K. , McKee K.L. , Lovelock C.E. , Mendelssohn I.A. , Saintilan N.
Published: September 2015

Mangroves occur on upper intertidal shorelines in the tropics and subtropics. Complex hydrodynamic and salinity conditions, related primarily to elevation and hydroperiod, influence mangrove distributions; this review considers how these distributions change over time. Accumulation rates of allochthonous and autochthonous sediment, both inorganic and organic, vary between and within different settings. Abundant terrigenous sediment can form dynamic mudbanks, and tides redistribute sediment, contrasting with mangrove peat in sediment-starved carbonate settings. Sediments underlying mangroves sequester carbon but also contain paleoenvironmental records of adjustments to past sea-level changes. Radiometric dating indicates long-term sedimentation, whereas measurements made using surface elevation tables and marker horizons provide shorter perspectives, indicating shallow subsurface processes of root growth and substrate autocompaction. Many tropical deltas also experience deep subsidence, which augments relative sea-level rise. The persistence of mangroves implies an ability to cope with moderately high rates of relative sea-level rise. However, many human pressures threaten mangroves, resulting in a continuing decline in their extent throughout the tropics. *
Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking
Authors: Andersen Martin N. , Hefting Louise L. , Steffensen Annette B. , Schmitt Nicole , Olesen Søren-Peter , Olsen Jesper V. , Lundby Alicia , Rasmussen Hanne B.
Published: September 2015

The potassium channel Kv7.1 plays critical physiological roles in both heart and epithelial tissues. In heart, Kv7.1 and the accessory subunit KCNE1 forms the slowly activating delayed-rectifier potassium current current, which is enhanced by protein kinase A (PKA)-mediated phosphorylation. The observed current increase requires both phosphorylation of Kv7.1 and the presence of KCNE1. However, PKA also stimulates Kv7.1 currents in epithelial tissues, such as colon, where the channel does not coassemble with KCNE1. Here, we demonstrate that PKA activity significantly impacts the subcellular localization of Kv7.1 in Madin-Darby canine kidney cells. While PKA inhibition reduced the fraction of channels at the cell surface, PKA activation increased it. We show that PKA inhibition led to intracellular accumulation of Kv7.1 in late endosomes/lysosomes. By mass spectroscopy we identified eight phosphorylated residues on Kv7.1, however, none appeared to play a role in the observed response. Instead, we found that PKA acted by regulating endocytic trafficking involving the ubiquitin ligase Nedd4-2. We show that a Nedd4-2-resistant Kv7.1-mutant displayed significantly reduced intracellular accumulation upon PKA inhibition. Similar effects were observed upon siRNA knockdown of Nedd4-2. However, although Nedd4-2 is known to regulate Kv7.1 by ubiquitylation, biochemical analyses demonstrated that PKA did not influence the amount of Nedd4-2 bound to Kv7.1 or the ubiquitylation level of the channel. This suggests that PKA influences Nedd4-2-dependent Kv7.1 transport though a different molecular mechanism. In summary, we identify a novel mechanism whereby PKA can increase Kv7.1 current levels, namely by regulating Nedd4-2-dependent Kv7.1 transport.
Automated quantitative assessment of cardiovascular magnetic resonance-derived atrioventricular junction velocities
Authors: Leng Shuang , Zhao Xiao-Dan , Huang Fei-Qiong , Wong Jia-Ing , Su Bo-Yang , Allen John Carson , Kassab Ghassan S. , Tan Ru-San , Zhong Liang
Published: September 2015

The assessment of atrioventricular junction (AVJ) deformation plays an important role in evaluating left ventricular systolic and diastolic function in clinical practice. This study aims to demonstrate the effectiveness and consistency of cardiovascular magnetic resonance (CMR) for quantitative assessment of AVJ velocity compared with tissue Doppler echocardiography (TDE). A group of 145 human subjects comprising 21 healthy volunteers, 8 patients with heart failure, 17 patients with hypertrophic cardiomyopathy, 52 patients with myocardial infarction, and 47 patients with repaired Tetralogy of Fallot were prospectively enrolled and underwent TDE and CMR scan. Six AVJ points were tracked with three CMR views. The peak systolic velocity (Sm1), diastolic velocity during early diastolic filling (Em), and late diastolic velocity during atrial contraction (Am) were extracted and analyzed. All CMR-derived septal and lateral AVJ velocities correlated well with TDE measurements (Sm1: r = 0.736; Em: r = 0.835; Am: r = 0.701; Em/Am: r = 0.691; all p < 0.001) and demonstrated excellent reproducibility [intrastudy: r = 0.921–0.991, intraclass correlation coefficient (ICC): 0.918–0.991; interstudy: r = 0.900–0.970, ICC: 0.887–0.957; all p < 0.001]. The evaluation of three-dimensional AVJ motion incorporating measurements from all views better differentiated normal and diseased states [area under the curve (AUC) = 0.918] and provided further insights into mechanical dyssynchrony diagnosis in HF patients (AUC = 0.987). These findings suggest that the CMR-based method is feasible, accurate, and consistent in quantifying the AVJ deformation, and subsequently in diagnosing systolic and diastolic cardiac dysfunction.
Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats
Authors: Yoshioka Kei , Otani Hajime , Shimazu Takayuki , Fujita Masanori , Iwasaka Toshiji , Shiojima Ichiro
Published: September 2015

Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.
Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy
Authors: Mata Karina M. , Li Wei , Reslan Ossama M. , Siddiqui Waleed T. , Opsasnick Lauren A. , Khalil Raouf A.
Published: September 2015

Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E2) may promote vasodilation during pregnancy; however, the specific E2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E2 were measured in virgin and pregnant ( day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ERα, ERβ, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E2 (all ERs) and the specific ER agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERα), diarylpropionitrile (DPN; ERβ), and G1 (GPER). BP was slightly lower and plasma E2 was higher in pregnant versus virgin rats. Western blots revealed increased ERα and ERβ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrine-precontracted vessels, E2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN- and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E2, PPT, DPN, and G1 caused relaxation of Ca2+ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ERα expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ERα-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca2+ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ERα in pregnancy-associated vasodilation. GPER may contribute to aortic relaxation while enhanced ERβ expression could mediate other genomic vascular effects during pregnancy.
Regulation of cardiac microRNAs induced by aerobic exercise training during heart failure
Authors: Souza Rodrigo W. A. , Fernandez Geysson J. , Cunha João P. Q. , Piedade Warlen P. , Soares Luana C. , Souza Paula A. T. , de Campos Dijon H. S. , Okoshi Katashi , Cicogna Antonio C. , Dal-Pai-Silva Maeli , Carvalho Robson F.
Published: September 2015

Exercise training (ET) has beneficial effects on the myocardium in heart failure (HF) patients and in animal models of induced cardiac hypertrophy and failure. We hypothesized that if microRNAs (miRNAs) respond to changes following cardiac stress, then myocardial profiling of these miRNAs may reveal cardio-protective mechanisms of aerobic ET in HF. We used ascending aortic stenosis (AS) inducing HF in Wistar rats. Controls were sham-operated animals. At 18 wk after surgery, rats with cardiac dysfunction were randomized to 10 wk of aerobic ET (HF-ET) or to a heart failure sedentary group (HF-S). ET attenuated cardiac remodeling as well as clinical and pathological signs of HF with maintenance of systolic and diastolic function when compared with that of the HF-S. Global miRNA expression profiling of the cardiac tissue revealed 53 miRNAs exclusively dysregulated in animals in the HF-ET, but only 11 miRNAs were exclusively dysregulated in the HF-S. Out of 23 miRNAs that were differentially regulated in both groups, 17 miRNAs exhibited particularly high increases in expression, including miR-598, miR-429, miR-224, miR-425, and miR-221. From the initial set of deregulated miRNAs, 14 miRNAs with validated targets expressed in cardiac tissue that respond robustly to ET in HF were used to construct miRNA-mRNA regulatory networks that revealed a set of 203 miRNA-target genes involved in programmed cell death, TGF-β signaling, cellular metabolic processes, cytokine signaling, and cell morphogenesis. Our findings reveal that ET attenuates cardiac abnormalities during HF by regulating cardiac miRNAs with a potential role in cardio-protective mechanisms through multiple effects on gene expression.
Pharmacologic inhibition of lactate production prevents myofibroblast differentiation
Authors: Kottmann Robert Matthew , Trawick Emma , Judge Jennifer L. , Wahl Lindsay A. , Epa Amali P. , Owens Kristina M. , Thatcher Thomas H. , Phipps Richard P. , Sime Patricia J.
Published: September 2015

Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis.
Will chronic e-cigarette use cause lung disease?
Authors: Rowell Temperance R. , Tarran Robert
Published: September 2015

Chronic tobacco smoking is a major cause of preventable morbidity and mortality worldwide. In the lung, tobacco smoking increases the risk of lung cancer, and also causes chronic obstructive pulmonary disease (COPD), which encompasses both emphysema and chronic bronchitis. E-cigarettes (E-Cigs), or electronic nicotine delivery systems, were developed over a decade ago and are designed to deliver nicotine without combusting tobacco. Although tobacco smoking has declined since the 1950s, E-Cig usage has increased, attracting both former tobacco smokers and never smokers. E-Cig liquids (e-liquids) contain nicotine in a glycerol/propylene glycol vehicle with flavorings, which are vaporized and inhaled. To date, neither E-Cig devices, nor e-liquids, are regulated by the Food and Drug Administration (FDA). The FDA has proposed a deeming rule, which aims to initiate legislation to regulate E-Cigs, but the timeline to take effect is uncertain. Proponents of E-Cigs say that they are safe and should not be regulated. Opposition is varied, with some opponents proposing that E-Cig usage will introduce a new generation to nicotine addiction, reversing the decline seen with tobacco smoking, or that E-Cigs generally may not be safe and will trigger diseases like tobacco. In this review, we shall discuss what is known about the effects of E-Cigs on the mammalian lung and isolated lung cells in vitro. We hope that collating this data will help illustrate gaps in the knowledge of this burgeoning field, directing researchers toward answering whether or not E-Cigs are capable of causing disease.
Influenza lung injury: mechanisms and therapeutic opportunities
Authors: Gregory David J. , Kobzik Lester
Published: September 2015

In this Perspectives, we discuss some recent developments in the pathogenesis of acute lung injury following influenza infection, with an emphasis on promising therapeutic leads. Damage to the alveolar-capillary barrier has been quantified in mice, and agents have been identified that can help to preserve barrier integrity, such as vasculotide, angiopoietin-like 4 neutralization, and sphingosine 1-phosphate mimics. Results from studies using mesenchymal stem cells have been disappointing, despite promising data in other types of lung injury. The roles of fatty acid binding protein 5, prostaglandin E2, and the interplay between IFN-γ and STAT1 in epithelial signaling during infection have been addressed in vitro. Finally, we discuss the role of autophagy in inflammatory cytokine production and the viral life cycle and the opportunities this presents for intervention.
The proportion of common synaptic input to motor neurons increases with an increase in net excitatory input
Authors: Castronovo Anna Margherita , Negro Francesco , Conforto Silvia , Farina Dario
Published: September 2015

α-Motor neurons receive synaptic inputs from spinal and supraspinal centers that comprise components either common to the motor neuron pool or independent. The input shared by motor neurons—common input—determines force control. The aim of the study was to investigate the changes in the strength of common synaptic input delivered to motor neurons with changes in force and with fatigue, two conditions that underlie an increase in the net excitatory drive to the motor neurons. High-density surface electromyogram (EMG) signals were recorded from the tibialis anterior muscle during contractions at 20, 50, and 75% of the maximal voluntary contraction force (in 3 sessions separated by at least 2 days), all sustained until task failure. EMG signal decomposition identified the activity of a total of 1,245 motor units. The coherence values between cumulative motor unit spike trains increased with increasing force, especially for low frequencies. This increase in coherence was not observed when comparing two subsets of motor units having different recruitment thresholds, but detected at the same force level. Moreover, the coherence values for frequencies <5 Hz increased at task failure with respect to the beginning of the contractions for all force levels. In conclusion, the results indicated that the relative strength of common synaptic input to motor neurons increases with respect to independent input when the net excitatory drive to motor neurons increases as a consequence of a change in force and fatigue.
IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer
Authors: Loncle Celine , Bonjoch Laia , Folch-Puy Emma , Lopez-Millan Maria Belen , Lac Sophie , Molejon Maria Inés , Chuluyan Eduardo , Cordelier Pierre , Dubus Pierre , Lomberk Gwen , Urrutia Raul , Closa Daniel , Iovanna Juan L.
Published: September 2015

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering “druggable” molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation. Cancer Res; 75(22); 4852–62. ©2015 AACR.
Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma
Authors: Pham Christina D. , Flores Catherine , Yang Changlin , Pinheiro Elaine M. , Yearley Jennifer H. , Sayour Elias J. , Pei Yanxin , Moore Colin , McLendon Roger E. , Huang Jianping , Sampson John H. , Wechsler-Reya Robert , Mitchell Duane A.
Published: September 2015

Purpose: Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice.

Experimental Design and Results: Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment.

Conclusions: This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. Clin Cancer Res; 22(3); 582–95. ©2015 AACR.
Evaluation of PD-L1 Expression and Associated Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma
Authors: Vassilakopoulou Maria , Avgeris Margaritis , Velcheti Vamsidhar , Kotoula Vassiliki , Rampias Theodore , Chatzopoulos Kyriakos , Perisanidis Christos , Kontos Christos K. , Giotakis Aris I. , Scorilas Andreas , Rimm David , Sasaki Clarence , Fountzilas George , Psyrri Amanda
Published: September 2015

Purpose: Programmed death-ligand 1 (PD-L1; also known as CD274 or B7-H1) expression represents a mechanism of immune escape for cancer. Our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in primary laryngeal squamous cell carcinomas (SCC).

Experimental Design: A well-annotated cohort of 260 operable primary laryngeal SCCs [formalin-fixed paraffin-embedded (FFPE) specimens] was morphologically characterized for stromal tumor-infiltrating lymphocytes (TIL), on hematoxylin/eosin-stained whole sections and for PD-L1 mRNA expression by qRT-PCR in FFPE specimens. For PD-L1 protein expression, automated quantitative protein analysis (AQUA) was applied on tissue microarrays consisting of two cores from these tumors. In addition, PD-L1 mRNA expression in fresh-frozen tumors and normal adjacent tissue specimens was assessed in a second independent cohort of 89 patients with primary laryngeal SCC.

Results: PD-L1 mRNA levels were upregulated in tumors compared with surrounding normal tissue (P = 0.009). TILs density correlated with tumor PD-L1 AQUA levels (P = 0.021). Both high TILs density and high PD-L1 AQUA levels were significantly associated with superior disease-free survival (DFS; TILs: P = 0.009 and PD-L1: P = 0.044) and overall survival (OS; TILs: P = 0.015 and PD-L1: P = 0.059) of the patients and retained significance in multivariate analysis.

Conclusions: Increased TILs density and PD-L1 levels are associated with better outcome in laryngeal squamous cell cancer. Assessment of TILs and PD-L1 expression could be useful to predict response to immune checkpoint inhibitors. Clin Cancer Res; 22(3); 704–13. ©2015 AACR.
Association between Redox Status of Serum Albumin and Peritoneal Membrane Transport Properties in Patients on Peritoneal Dialysis
Authors: Lim Paik Seong , Chen Hung-Ping , Chen Chang-Hsu , Wu Ming Yin , Wu Chuen Yuh , Wu Tsai-Kun
Published: September 2015

Background: Albumin, the most abundant protein in the extracellular fluid, displays an important antioxidant activity. Increased levels of oxidized albumin levels (high human non-mercaptoalbumin (HNA) level) have been reported in the serum of patients with end-stage renal disease. In this study, we attempted to identify the albumin redox status in the serum of patients on peritoneal dialysis (PD) and examined the relationship between these proteins and the transport type of the peritoneal membrane and other clinical and laboratory variables. Methods: We performed a cross-sectional study of a cohort of 80 patients with end-stage renal disease receiving PD. Peritoneal transport characteristics were identified and after peritoneal equilibration test patients were grouped as high (high(H)/high-average (HA) group, n = 31) or low (low (L)/low-average (LA) group, n = 49) transporters. The redox state of human serum albumin was measured using high-performance liquid chromatography. Results: The fraction of human mercaptoalbumin (HMA) showed significantly higher values in patients with high transport status than those with low transport status (f(HMA) 64.0 ± 5.4 and 52.7 ± 10.4%, respectively). Our data showed that the H/HA transport characteristic was associated with lower albumin (3.76 ± 0.48 vs. 4.00 ± 0.35, p < 0.05), and lower levels of advanced oxidized protein product (p = 0.008) when compared with the L/LA type. A correlation analysis showed that there was a positive correlation between dialysate/plasma (D/P) creatinine and f(HMA) levels (r = 0.511, p < 0.0001), as well as hemoglobin levels r = 0.231, p = 0.044 and a negative correlation between D/P creatinine and serum albumin, cholesterol and LDL levels (r = -0.236, p = 0.039; r = -0.237, p = 0.038; r = -0.272, p = 0.018, respectively). Conclusions: This study showed that higher serum levels of reduced albumin f(HMA) appear to be associated with high/high average peritoneal membrane transport characteristics in the incident PD patients.
FOXA1 and SOX9 Expression in the Developing Urogenital Sinus of the Tammar Wallaby (Macropus eugenii)
Authors: Gamat Melissa , Chew Keng Yih , Shaw Geoffrey , Renfree Marilyn B.
Published: September 2015

The mammalian prostate is a compact structure in humans but multi-lobed in mice. In humans and mice, FOXA1 and SOX9 play pivotal roles in prostate morphogenesis, but few other species have been examined. We examined FOXA1 and SOX9 in the marsupial tammar wallaby, Macropus eugenii, which has a segmented prostate more similar to human than to mouse. In males, prostatic budding in the urogenital epithelium (UGE) was initiated by day 24 postpartum (pp), but in the female the UGE remained smooth and had begun forming the marsupial vaginal structures. FOXA1 was upregulated in the male urogenital sinus (UGS) by day 51 pp, whilst in the female UGS FOXA1 remained basal. FOXA1 was localised in the UGE in both sexes between day 20 and 80 pp. SOX9 was upregulated in the male UGS at day 21-30 pp and remained high until day 51-60 pp. SOX9 protein was localised in the distal tips of prostatic buds which were highly proliferative. The persistent upregulation of the transcription factors SOX9 and FOXA1 after the initial peak and fall of androgen levels suggest that in the tammar, as in other mammals, these factors are required to sustain prostate differentiation, development and proliferation as androgen levels return to basal levels.
Subthreshold Micropulse Laser (577 nm) Treatment in Chronic Central Serous Chorioretinopathy
Authors: Scholz Paula , Ersoy Lebriz , Boon Camiel J.F. , Fauser Sascha
Published: September 2015

Purpose: To assess treatment with a 577-nm subthreshold micropulse laser (SML) in patients with chronic central serous chorioretinopathy (cCSC). Methods: This retrospective study included 38 patients treated with a 577-nm SML (Supra Scan; Quantel Medical) for cCSC. We included a subgroup of 18 patients with persistent subretinal fluid (SRF) after photodynamic therapy (PDT). Assessment included visual acuity (VA), central retinal thickness (CRT) and resolution of SRF. Results: At the last follow-up (mean 5 months), 74% of patients responded to therapy. The CRT decreased after treatment (mean CRT -115 µm, p < 0.001) and VA improved (mean logMAR -0.06, p = 0.039). No laser burns were detected with any imaging modality. In the subgroup of patients resistant to PDT, 61% of patients responded to therapy with a decrease in CRT (mean CRT -75 µm, p = 0.019). Conclusions: The 577-nm SML is an effective treatment for cCSC even in patients without sufficient improvement after PDT.
Functional Characterization of c.870+3_6delGAGT Splice Site Mutation in NR5A1
Authors: Takagi Masaki , Nishina Noriko , Yagi Hiroko , Hasegawa Yukihiro
Published: September 2015

Background: To date, more than 100 mutations of NR5A1 have been reported; however, mutations affecting the splice site are rare, with only two reported mutations. Objective: To characterize the c.870+3_6delGAGT splice mutation of NR5A1 through molecular analyses. Results: The reverse transcription polymerase chain reaction (RT-PCR) study revealed that c.870+3_6delGAGT resulted in p.A82fs*95. Mutant NR5A1 showed a reduced transactivation on the CYP11A1 and STAR promoters without a dominant negative effect. Conclusion: To the best of our knowledge, this is the first report of the NR5A1 splice site mutation, which was proven to be deleterious by the RT-PCR method.
Distinct First Trimester Cytokine Profiles for Gestational Hypertension and Preeclampsia
Authors: Tangerås Line H. , Austdal Marie , Skråstad Ragnhild B. , Salvesen Kjell Å. , Austgulen Rigmor , Bathen Tone F. , Iversen Ann-Charlotte
Published: September 2015

Objective—

Gestational hypertension and preeclampsia involve dysregulated maternal inflammatory responses to pregnancy, but whether such responses differ between the disorders has not been determined. We aimed to investigate disease-specific early pregnancy serum cytokine profiles of women subsequently developing gestational hypertension or preeclampsia for new insight into the underlying pathogeneses and differences between the disorders.

Approach and Results—

The study cohort consisted of 548 pregnant Norwegian women who were either multiparous with previous gestational hypertension or preeclampsia or were nulliparous. Maternal sera at gestational weeks 11
0
–13
6
were assayed for 27 cytokines, C-reactive protein, total cholesterol, high-density lipoprotein, triglyceride, creatinine, calcium, uric acid, and placental growth factor. Compared with normotensive women, women with both hypertensive conditions presented an atherogenic lipid profile at early gestation, but only those later developing gestational hypertension had significantly higher serum levels of interleukin (IL)-5 and IL-12. Comparing the 2 hypertensive pregnancy disorders, women subsequently developing gestational hypertension had higher serum levels of IL-1β, IL-5, IL-7, IL-8, IL-13, basic fibroblast growth factor, and vascular endothelial growth factor than the women subsequently developing preeclampsia.

Conclusions—

This study identifies early pregnancy differences in serum cytokine profiles for gestational hypertension and preeclampsia.
Deficiency of HIF1α in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice
Authors: Chaudhari Sweena M. , Sluimer Judith C. , Koch Miriam , Theelen Thomas L. , Manthey Helga D. , Busch Martin , Caballero-Franco Celia , Vogel Frederick , Cochain Clément , Pelisek Jaroslav , Daemen Mat J. , Lutz Manfred B. , Görlach Agnes , Kissler Stephan , Hermanns Heike M. , Zernecke Alma
Published: September 2015

Objective—

Although immune responses drive the pathogenesis of atherosclerosis, mechanisms that control antigen-presenting cell (APC)–mediated immune activation in atherosclerosis remain elusive. We here investigated the function of hypoxia-inducible factor (HIF)-1α in APCs in atherosclerosis.

Approach and Results—

We found upregulated HIF1α expression in CD11c
+
APCs within atherosclerotic plaques of low-density lipoprotein receptor–deficient (
Ldlr
−/−
) mice. Conditional deletion of
Hif1a
in CD11c
+
APCs in high-fat diet–fed
Ldlr
−/−
mice accelerated atherosclerotic plaque formation and increased lesional T-cell infiltrates, revealing a protective role of this transcription factor. HIF1α directly controls Signal Transducers and Activators of Transcription 3 (
Stat3
), and a reduced STAT3 expression was found in HIF1α-deficient APCs and aortic tissue, together with an upregulated interleukin-12 expression and expansion of type 1 T-helper (Th1) cells. Overexpression of STAT3 in
Hif1a
-deficient APCs in bone marrow reversed enhanced atherosclerotic lesion formation and reduced Th1 cell expansion in chimeric
Ldlr
−/−
mice. Notably, deletion of
Hif1a
in LysM
+
bone marrow cells in
Ldlr
−/−
mice did not affect lesion formation or T-cell activation. In human atherosclerotic lesions, HIF1α, STAT3, and interleukin-12 protein were found to colocalize with APCs.

Conclusions—

Our findings identify HIF1α to antagonize APC activation and Th1 T cell polarization during atherogenesis in
Ldlr
−/−
mice and to attenuate the progression of atherosclerosis. These data substantiate the critical role of APCs in controlling immune mechanisms that drive atherosclerotic lesion development.
Slow [Na]
i
Changes and Positive Feedback Between Membrane Potential and [Ca]
i
Underlie Intermittent Early Afterdepolarizations and Arrhythmias
Authors: Xie Yuanfang , Liao Zhandi , Grandi Eleonora , Shiferaw Yohannes , Bers Donald M.
Published: September 2015

Background—

Most cardiac arrhythmias occur intermittently. As a cellular precursor of lethal cardiac arrhythmias, early afterdepolarizations (EADs) during action potentials(APs) have been extensively investigated, and mechanisms for the occurrence of EADs on a beat-to-beat basis have been proposed. However, no previous study explains slow fluctuations in EADs, which may underlie intermittency of EAD trains and consequent arrhythmias. We hypothesize that the feedback of intracellular calcium and sodium concentrations ([Na]
i
and [Ca]
i
) that influence membrane voltage (V) can explain EAD intermittency.

Methods and Results—

AP recordings in rabbit ventricular myocytes revealed intermittent EADs, with slow fluctuations between runs of APs with EADs present or absent. We then used dynamical systems analysis and detailed mathematical models of rabbit ventricular myocytes that replicate the observed behavior and investigated the underlying mechanism. We found that a dominance of inward Na–Ca exchanger current (I
NCX
) over Ca-dependent inactivation of L-type Ca current (I
CaL
) forms a positive feedback between [Ca]
i
and V, thus resulting in 2 stable AP states, with and without EADs (ie, bistability). Slow changes in [Na]
i
determine the transition between these 2 states, forming a bistable on–off switch of EADs. Tissue simulations showed that this bistable switch of cellular EADs provided both a trigger and a functional substrate for intermittent arrhythmias in homogeneous tissues.

Conclusions—

Our study demonstrates that the interaction among V, [Ca]
i
, and [Na]
i
causes slow on–off switching (or bistability) of AP duration in cardiac myocytes and EAD-mediated arrhythmias and suggests a novel possible mechanism for intermittency of cardiac arrhythmias.
Estimates of Global and Regional Premature Cardiovascular Mortality in 2025
Authors: Roth Gregory A. , Nguyen Grant , Forouzanfar Mohammad H. , Mokdad Ali H. , Naghavi Mohsen , Murray Christopher J.L.
Published: September 2015

Background—

United Nations member states have agreed to reduce premature cardiovascular disease (CVD) mortality 25% by 2025. Global CVD risk factor targets have been recommended. We produced estimates to show how selected risk factor reduction would affect CVD mortality for different regions and countries.

Methods and Results—

We used mortality, risk factor, and relative risk data from the Global Burden of Disease, Risk Factors, and Injuries (GBD) 2013 study to project CVD mortality for 188 countries up to the year 2025. We disaggregated observed CVD mortality in 1990 and 2013 into deaths attributable and unattributable to hypertension, tobacco smoking, diabetes mellitus, and obesity using an age- and sex-specific population-attributable fraction. Risk factors were projected to 2025 assuming that current trends continue. Counterfactual scenarios were then constructed reflecting CVD premature mortality if United Nations risk factor targets are achieved in the year 2025, adjusting for joint effects of risk factors. We estimate 7.8 million premature CVD deaths in 2025 if current risk factor trends continue. Premature CVD deaths would be reduced to 5.7 million if these risk factors targets are achieved as a result of a 26% reduction for men and a 23% reduction for women in the global risk of premature CVD death. Globally, decreasing the prevalence of hypertension accounted for the largest risk reduction, followed by a reduction in tobacco smoking for men and obesity for women, but these results varied by region. The impact of meeting all risk factor targets on CVD mortality varied widely by region and sex.

Conclusions—

The United Nations target of a 25% reduction in premature CVD mortality by the year 2025 appears achievable for some countries, but more aggressive risk factor targets may be required if all regions are to reach this goal. Without these reductions in CVD risk factors, many countries will see no change or even an increase in premature CVD mortality.
Sulodexide for the Prevention of Recurrent Venous Thromboembolism
Authors: Andreozzi Giuseppe M. , Bignamini Angelo A. , Davì Giovanni , Palareti Gualtiero , Matuška Jiří , Holý Martin , Pawlaczyk-Gabriel Katarzyna , Džupina Andrej , Sokurenko German Y. , Didenko Yury P. , Andrei Laurentia D. , Lessiani Gianfranco , Visonà Adriana
Published: September 2015

Background—

Patients with a first episode of unprovoked venous thromboembolism have a high risk of recurrence after discontinuation of anticoagulant therapy. Extending anticoagulation reduces the risk of recurrence but is associated with increased bleeding. Sulodexide, a glycosaminoglycan, exerts antithrombotic and profibrinolytic actions with a low bleeding risk when administered orally, but its benefit for preventing recurrent venous thromboembolism is not well known.

Methods and Results—

In this multicenter, double-blind study, 615 patients with first-ever unprovoked venous thromboembolism who had completed 3 to 12 months of oral anticoagulant treatment were randomly assigned to sulodexide 500 lipasemic units twice daily or placebo for 2 years, in addition to elastic stockings. The primary efficacy outcome was recurrence of venous thromboembolism. Major or clinically relevant bleeding was the primary safety outcome. Venous thromboembolism recurred in 15 of the 307 patients who received sulodexide and in 30 of the 308 patients who received placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.27–0.92;
P
=0.02). The analysis in which lost to follow-up was assigned to failure yielded a risk ratio among treated versus control subjects of 0.54 (95% confidence interval, 0.35–0.85;
P
=0.009). No major bleeding episodes occurred; 2 patients in each treatment group had a clinically relevant bleeding episode. Adverse events were similar in the 2 groups.

Conclusion—

Sulodexide given after discontinuation of anticoagulant treatment reduced the risk of recurrence in patients with unprovoked venous thromboembolism, with no apparent increase of bleeding risk.

Clinical Trial Registration—

URL:
https://www.clinicaltrialsregister.eu/
. Identifier: EudraCT number 2009-016923-77.
Extending XCS with Cyclic Graphs for Scalability on Complex Boolean Problems
Authors: Iqbal Muhammad , Browne Will N. , Zhang Mengjie
Published: September 2015

A main research direction in the field of evolutionary machine learning is to develop a scalable classifier system to solve high-dimensional problems. Recently work has begun on autonomously reusing learned building blocks of knowledge to scale from low-dimensional problems to high-dimensional ones. An XCS-based classifier system, known as XCSCFC, has been shown to be scalable, through the addition of expression tree–like code fragments, to a limit beyond standard learning classifier systems. XCSCFC is especially beneficial if the target problem can be divided into a hierarchy of subproblems and each of them is solvable in a bottom-up fashion. However, if the hierarchy of subproblems is too deep, then XCSCFC becomes impractical because of the needed computational time and thus eventually hits a limit in problem size. A limitation in this technique is the lack of a cyclic representation, which is inherent in finite state machines (FSMs). However, the evolution of FSMs is a hard task owing to the combinatorially large number of possible states, connections, and interaction. Usually this requires supervised learning to minimize inappropriate FSMs, which for high-dimensional problems necessitates subsampling or incremental testing. To avoid these constraints, this work introduces a state-machine-based encoding scheme into XCS for the first time, termed XCSSMA. The proposed system has been tested on six complex Boolean problem domains: multiplexer, majority-on, carry, even-parity, count ones, and digital design verification problems. The proposed approach outperforms XCSCFA (an XCS that computes actions) and XCSF (an XCS that computes predictions) in three of the six problem domains, while the performance in others is similar. In addition, XCSSMA evolved, for the first time, compact and human readable general classifiers (i.e., solving any n-bit problems) for the even-parity and carry problem domains, demonstrating its ability to produce scalable solutions using a cyclic representation.
A new species of the genus Alchemilla (Rosaceae) from Central Russia
Authors: Chkalov Andrey Vyacheslavovich
Published: September 2015

A new apomictic species of Alchemilla from several regions of Central Russia is here described as A. tzvelevii. Description and images of the principal morphological features of this species are provided. Alchemilla tzvelevii combines the features of quite distant groups (i.e. A. subsect. Pubescentes and A. subsect. Alchemilla ser. Alchemilla subser. Heptagonae). Its presumed hybridogenous origin is discussed.
Taxonomic revision of Phygopoda Thomson, 1864 and Pseudophygopoda Tavakilian & Peñaherrera-Leiva, 2007 (Insecta: Coleoptera: Cerambycidae: Cerambycinae)
Authors: CARELLI ALLAN , MONNÉ MARCELA L.
Published: September 2015

A taxonomic revision based on the study of the external morphology and the terminalia of Phygopoda Thomson, 1864 and Pseudophygopoda Tavakilian & Peñaherrera-Leiva, 2007 is presented. The genera and their species are redescribed. Five synonymies are proposed: Panamapoda Clarke, 2014 and Paraphygopoda Clarke, 2014 = Pseudophygopoda Tavakilian & Peñaherrera-Leiva, 2007; Paraphygopoda viridimicans (Fisher, 1952); Paraphygopoda nappae Clarke, 2014; and Paraphygopoda longipennis (Zajciw, 1963) = Pseudophygopoda albitarsis (Klug, 1825). The genus Phygopoda is composed of five species: Phygopoda fugax Thomson, 1864; Phygopoda fulvitarsis Gounelle, 1911; Phygopoda ingae Peñaherrera-Leiva & Tavakilian, 2004; Phygopoda jacobi Fuchs, 1961; and Phygopoda nigritarsis Gounelle, 1911. Pseudophygopoda is now composed of three species: Pseudophygopoda subvestita (White, 1855), Pseudophygopoda panamensis (Giesbert, 1996) comb. nov., and Pseudophygopoda albitarsis (Klug, 1825) comb. nov. New geographical records are reported for six species. A key to the species of Phygopoda and Pseudophygopoda, photographs, plates of drawings, and maps of the geographical distribution of the species are provided.
A review of the Munidopsidae Ortmann, 1898 (Decapoda, Galatheoidea) in Chilean waters, including new records for the Southeastern Pacific
Authors: GUZMAN GUILLERMO L. , SELLANES JAVIER
Published: September 2015

The information about the family Munidopsidae in Chile is scarce and sparse, making identification of new material. difficult. Due to this we lack precise information about the number and accurate distribution of Chilean species. Recent expeditions to Chile have collected specimens of this group, allowing an exhaustive review of the registers and collections in four museums in the country. A total of 93 specimens from six expeditions were analyzed, belonging to twelve species, of which five represent first records for the Chilean waters. The family in Chile is now composed by 19 bathyal and abyssal species; three belong to the genus Galacantha and 16 to Munidopsis. Only three species have distributions restricted to southeastern Pacific waters (M. cochlearis, M. follirostris and M. opalescens). Three other species are widely distributed along the eastern Pacific from Alaska or from Oregon to Chile (M. aspera, M. quadrata and M. verrucosus). No relationships were observed between the extensive geographical distribution of species and the bathymetric distribution.