bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐Fidelity Reprogrammed Human IPSCs Have a High Efficacy of DNA Repair and Resemble hESCs in Their MYC Transcriptional Signature
Authors: Nagaria Pratik K. , Robert Carine , Park Tea Soon , Huo Jeffrey S. , Zambidis Elias T. , Rassool Feyruz V.
Published: September 2016

Human induced pluripotent stem cells (hiPSCs) are reprogrammed from adult or progenitor somatic cells and must make substantial adaptations to ensure genomic stability in order to become “embryonic stem cell‐ (ESC‐) like.” The DNA damage response (DDR) is critical for maintenance of such genomic integrity. Herein, we determined whether cell of origin and reprogramming method influence the DDR of hiPSCs. We demonstrate that hiPSCs derived from cord blood (CB) myeloid progenitors (i.e., CB‐iPSC) via an efficient high‐fidelity stromal‐activated (sa) method closely resembled hESCs in DNA repair gene expression signature and irradiation‐induced DDR, relative to hiPSCs generated from CB or fibroblasts via standard methods. Furthermore, sa‐CB‐iPSCs also more closely resembled hESCs in accuracy of nonhomologous end joining (NHEJ), DNA double‐strand break (DSB) repair, and C‐MYC transcriptional signatures, relative to standard hiPSCs. Our data suggests that hiPSCs derived via more efficient reprogramming methods possess more hESC‐like activated MYC signatures and DDR signaling. Thus, an authentic MYC molecular signature may serve as an important biomarker in characterizing the genomic integrity in hiPSCs.
Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis?
Authors: Martinez-Useros Javier , Garcia-Foncillas Jesus
Published: September 2016

Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status ofP53,KRAS, orBRCA2are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
Existence of Solutions for Some Nonlinear Problems with Boundary Value Conditions
Authors: Dallos Santos Dionicio Pastor
Published: September 2016

We study the existence of solutions for nonlinear boundary value problemsφu′′=ft,u,u′,  lu,u′=0, wherel(u,u′)=0denotes the boundary conditions on a compact interval0,T,φis a homeomorphism such thatφ(0)=0, andf:0,T×R×R→Ris a continuous function. All the contemplated boundary value problems are reduced to finding a fixed point for one operator defined on a space of functions, and Schauder fixed point theorem or Leray-Schauder degree is used.
Reactive-Diffusive-Advective Traveling Waves in a Family of Degenerate Nonlinear Equations
Authors: Sánchez-Garduño Faustino , Pérez-Velázquez Judith
Published: September 2016

This paper deals with the analysis of existence of traveling wave solutions (TWS) for a diffusion-degenerate (atD(0)=0) and advection-degenerate (ath′(0)=0) reaction-diffusion-advection (RDA) equation. Diffusion is a strictly increasing function and the reaction term generalizes the kinetic part of the Fisher-KPP equation. We consider different forms of the convection termh(u):(1)  h′(u)is constantk,(2)  h′(u)=kuwithk>0, and(3)it is a quite general form which guarantees the degeneracy in the advective term. In Case 1, we prove that the task can be reduced to that for the corresponding equation, wherek=0, and then previous results reported from the authors can be extended. For the other two cases, we use both analytical and numerical tools. The analysis we carried out is based on the restatement of searching TWS for the full RDA equation into a two-dimensional dynamical problem. This consists of searching for the conditions on the parameter values for which there exist heteroclinic trajectories of the ordinary differential equations (ODE) system in the traveling wave coordinates. Throughout the paper we obtain the dynamics by using tools coming from qualitative theory of ODE.
TaqI, FokI, and ApaI Polymorphisms in the Vitamin D Receptor in Behçet’s Disease in Turkish Population
Authors: Erten Gaye , Kalkan Muhammed , Bilgiç Gazioğlu Sema , Akdeniz Nilgun , Ozkok Elif , Vural Burcak
Published: September 2016

Objectives. In our study we aimed to determine VDR gene polymorphisms in patients with Behçet’s disease (BD) and neuro-Behçet’s disease (NBD) in Turkish population.Methods.PBL obtained from 37 patients with BD, 21 patients with NB, and 30 healthy controls were investigated. Genomic DNA was extracted from whole blood using the QIAamp Blood Kit. VDR ApaI (rs7975232), VDR FokI (rs2228570), and VDR TaqI (rs731236) genotyping was performed by real-time polymerase chain reaction with SimpleProbe melting-curve analysis.Results.The allelic and genotype distributions of FokI and TaqI polymorphisms were not different among Behçet’s disease, neuro-Behçet’s disease, and control subjects in Turkish population (p>0.05). Only the frequency of ApaI A allele in control is higher than that in BD (60% versus 38.5%), and thepvalue is 0.014, but the power is not enough to conclude that ApaI A allele is protective in BD in our study. Taken together, we found no significant differences between the BD, NBD, and control groups regarding the distribution of ApaI, TaqI, and FokI genotype and alleles frequencies.Conclusions.Future studies with larger patients’ numbers may show differences between VDR polymorphisms and Behçet’s disease.
Transmission Dynamics and Optimal Control of Malaria in Kenya
Authors: Otieno Gabriel , Koske Joseph K. , Mutiso John M.
Published: September 2016

This paper proposes and analyses a mathematical model for the transmission dynamics of malaria with four-time dependent control measures in Kenya: insecticide treated bed nets (ITNs), treatment, indoor residual spray (IRS), and intermittent preventive treatment of malaria in pregnancy (IPTp). We first considered constant control parameters and calculate the basic reproduction number and investigate existence and stability of equilibria as well as stability analysis. We proved that ifR0≤1, the disease-free equilibrium is globally asymptotically stable inD. IfR0>1, the unique endemic equilibrium exists and is globally asymptotically stable. The model also exhibits backward bifurcation atR0=1. IfR0>1, the model admits a unique endemic equilibrium which is globally asymptotically stable in the interior of feasible regionD. The sensitivity results showed that the most sensitive parameters are mosquito death rate and mosquito biting rates. We then consider the time-dependent control case and use Pontryagin’s Maximum Principle to derive the necessary conditions for the optimal control of the disease using the proposed model. The existence of optimal control problem is proved. Numerical simulations of the optimal control problem using a set of reasonable parameter values suggest that the optimal control strategy for malaria control in endemic areas is the combined use of treatment and IRS; for epidemic prone areas is the use of treatment and IRS; for seasonal areas is the use of treatment; and for low risk areas is the use of ITNs and treatment. Control programs that follow these strategies can effectively reduce the spread of malaria disease in different malaria transmission settings in Kenya.
Israel-Stewart Approach to Viscous Dissipative Extended Holographic Ricci Dark Energy Dominated Universe
Authors: Chattopadhyay Surajit
Published: September 2016

This paper reports a study on the truncated Israel-Stewart formalism for bulk viscosity using the extended holographic Ricci dark energy (EHRDE). Under the consideration that the universe is dominated by EHRDE, the evolution equation for the bulk viscous pressureΠin the framework of the truncated Israel-Stewart theory has been taken asτΠ˙+Π=-3ξH, whereτis the relaxation time andξis the bulk viscosity coefficient. Considering effective pressure as a sum of thermodynamic pressure of EHRDE and bulk viscous pressure, it has been observed that under the influence of bulk viscosity the EoS parameterwDEis behaving like phantom, that is,wDE≤-1. It has been observed that the magnitude of the effective pressurepeff=p+Πis decaying with time. We also investigated the case for a specific choice of scale factor; namely,a(t)=(t-t0)β/(1-α). For this choice we have observed that a transition from quintessence to phantom is possible for the equation of state parameter. However, theΛCDM phase is not attainable by the state-finder trajectories for this choice. Finally it has been observed that in both of the cases the generalized second law of thermodynamics is valid for the viscous EHRDE dominated universe enveloped by the apparent horizon.
Security Situation Assessment of All-Optical Network Based on Evidential Reasoning Rule
Authors: Zhao Zhong-Nan , Qiao Pei-Li , Wang Jian , Hu Guan-Yu
Published: September 2016

It is important to determine the security situations of the all-optical network (AON), which is more vulnerable to hacker attacks and faults than other networks in some cases. A new approach of the security situation assessment to the all-optical network is developed in this paper. In the new assessment approach, the evidential reasoning (ER) rule is used to integrate various evidences of the security factors including the optical faults and the special attacks in the AON. Furthermore, a new quantification method of the security situation is also proposed. A case study of an all-optical network is conducted to demonstrate the effectiveness and the practicability of the new proposed approach.
Commentary on “Proteasome Inhibitors: A Novel Class of Potent and Effective Antitumor Agents”
Authors: Tew Kenneth D.
Published: September 2016

The relatively recent clinical success of bortezomib, particularly in multiple myeloma, has established the validity of the proteasome as a viable target for anticancer drug development. This highly cited 1999 Cancer Research article from Adams and colleagues was published during the period when this drug was transitioning from preclinical studies to phase I clinical trial status. Their results detail structure–activity analyses using a series of boronic acid proteasome inhibitors and correlate cytotoxicity with inhibition of proteasome activity. In and of itself, the recognition that interference with proteasome functions represented a novel therapeutic approach likely underlies the popularity of this article. In addition, the provision of in vitro (at that time using the NCI 60 cell line panel) and in vivo antitumor activity, toxicology, and mouse pharmacokinetic and pharmacodynamic data provided a solid basis for establishing the future credentials for bortezomib to gain initial FDA approval in 2003. Cancer Res; 76(17); 4916–7. ©2016 AACR.

See related article by Adams et al., Cancer Res 1999;59:2615–22.

Visit the Cancer Research 75th Anniversary timeline.
Developing EZH2-Targeted Therapy for Lung Cancer
Authors: Frankel Arthur E. , Liu Xin , Minna John D.
Published: September 2016

Summary: Epigenetic targets are exciting new avenues for cancer drug discovery. Zhang and colleagues have designed the open-source EZH2 inhibitor JQEZ5 and shown antitumor efficacy in vitro and in vivo in preclinical studies in murine and human lung adenocarcinoma models expressing high levels of EZH2. Cancer Discov; 6(9); 949–52. ©2016 AACR.

See related article by Zhang and colleagues, p. 1006.
Voice Range Profiles of Singing Students: The Effects of Training Duration and Institution
Authors: Lycke Hugo , Siupsinskiene Nora
Published: September 2016

Objective: The aim of the study was to assess differences in voice parameters measured by the physiological voice range profile (VRP) in groups of vocally healthy subjects differentiated by the duration of vocal training and the training institution. Patients and Methods: Six basic frequency- and intensity-related VRP parameters and the frequency dip of the register transition zone were determined from VRP recordings of 162 females studying in individual singing lessons (1st-5th level) in Dutch, Belgian, English, and French public or private training facilities. Sixty-seven nonsinging female students served as controls. Results: Singing students in more advanced singing classes demonstrated a significantly greater frequency range, particularly at high frequencies, than did first-year students. Students with private training showed a significantly increased mean intensity range in comparison to those in group classes, while students with musical theater training exhibited significantly increased frequency- and intensity-related VRP parameters in comparison to the students with classical training. When compared to nonsingers, all singing student subgroups showed significant increases in all basic VRP parameters. However, the register transition parameter was not influenced by training duration or institution. Conclusion: Our study suggests that the extension of physiological vocal limits might depend on training duration and institution.
Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes
Authors: Izumi Kosuke
Published: September 2016

Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability. As a basis for some shared phenotypic characteristics in these syndromes, a similar transcriptome disturbance, characterized by global transcriptional dysregulation, is believed to play a major role. In this review article, a general overview of gene transcription is provided, and the current knowledge of the mechanisms underlying some disorders of transcriptional regulation, such as Rubinstein- Taybi, Coffin-Siris, Cornelia de Lange, and CHOPS syndromes, are discussed.
Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis
Authors: Middeldorp Saskia , Prins Martin H. , Pap Akos F. , Lensing Anthonie W. A. , ten Cate-Hoek Arina J. , Villalta Sabina , Milan Marta , Beyer-Westendorf Jan , Verhamme Peter , Bauersachs Rupert M. , Prandoni Paolo , Cheung Y. Whitney ,   on behalf of the Einstein PTS Investigators Group
Published: September 2016

Post-thrombotic syndrome (PTS) is a common complication of deepvein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48–64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51–1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.

Supplementary Material to this article is available online at www.thrombosis-online.com.
COMUNICA(C)CIÓN. La comunicación en la acción colectiva juvenil: dos experiencias organizativas en la ciudad de Bogotá
Authors: Aguilar-Forero Nicolás J. C.
Published: September 2016

(analítico): En esta investigación el objetivo principal fue comprender el lugar que ocupa la comunicación en las formas de acción colectiva juvenil de dos experiencias organizativas que trabajan por la memoria y contra la impunidad: H.I.J.O.S. (Hijos e Hijas por la Identidad y la Justicia, contra el Olvido y el Silencio) y Contagio comunicación multimedia. La propuesta metodológica se basó en un enfoque de investigación colaborativa y militante, y en la combinación de distintas técnicas: "participación observanteâ€, conversatorios, entrevistas semiestructuradas y análisis de contenidos radiales, textuales y audiovisuales. Se logró identificar que ambas experiencias construyen la relación entre comunicación y acción colectiva a través de prácticas y dinámicas diversas, que en su conjunto agencian políticas de la memoria contrahegemónicas y promueven iniciativas movilizadoras en términos de construcción de paz.
Estilos parentales y consumo de sustancias psicoactivas en estudiantes de 8° a 10°
Authors: Prieto-Montoya José Alejandro , Cardona-Castañeda Lina María , Vélez-Álvarez Consuelo
Published: September 2016

(analítico): Esta investigación buscó establecer la relación entre los estilos parentales y consumo de sustancias psicoactivas en 13029 estudiantes de 8° a 10° de Manizales. Es un estudio descriptivo, transversal, que utilizó como instrumentos la escala de estilos de socialización parental de adolescentes (Espa29) y un instrumento basado en el del Sistema Interamericano de Datos Uniformes sobre Consumo de la Organización de Estados Americanos. Los resultados evidenciaron según los valores p del estadístico X2, que existe una asociación estadísticamente significativa p<0,05 entre las variables estudiadas. Los estilos autoritario y negligente indicaron en general ser un factor de riesgo y el indulgente y autorizativo un factor protector. Poseer padres con estilo negligente, eleva el riesgo en un 34% de consumir cocaína, 31% marihuana, 23% cigarrillo, 39% pegantes y 26% dick.
Factores de riesgo y protección de las trayectorias académicas: Voces y miradas del alumnado inmigrante en el contexto del área metropolitana de Barcelona, España
Authors: Cano-Hila Ana Belén , Sánchez-Martí Angelina , Massot-Lafón María Inés
Published: September 2016

(analítico): Este artículo analiza la atribución percibida del alumnado de familias inmigrantes sobre los factores de riesgo y los factores protectores que favorecen la continuidad académica en la transición de riesgo de la educación secundaria obligatoria (ESO) a la postobligatoria (PO). Dicho análisis es parte de un estudio longitudinal más amplio y se ubica en su última fase en la que se llevaron a cabo grupos de discusión y entrevistas semiestructuradas a los jóvenes que lograron persistir. Los resultados encuentran que los jóvenes que desarrollan trayectorias exitosas llevan a cabo estrategias de acomodación multicultural que han sido fruto de la conjugación de varios factores de protección claves: el apoyo familiar, de pares e institucional; referentes familiares que motiven la continuidad (en especial la figura materna); la capacidad de superación; y, que las familias y el profesorado comprendan las dificultades que conllevan las transiciones simultáneas que viven los estudiantes de familias inmigrantes.
Um problema da administração municipal: das fontes textuais à cartografia de síntese (Lyon do século XVI ao XVIII)
Authors: Zeller Olivier
Published: September 2016

O estudo de Lyon nos tempos mo­dernos mostra que é impossível compreender a ação da administração municipal somente a partir das fontes escritas. Isso porque elas se referem geralmente a endereços difíceis de lo­calizar com precisão, e porque parecem refletir apenas ações isoladas. Somente uma narrativa geral é possível trabalhando-se dessa maneira. A cartografia de precisão faz surgir as lógicas de funcionamento implícitas por trás das deci­sões aparentemente isoladas, localizando cada casa, associando-se casas e nomes, informando as transformações das ruas. Os agrupamentos de eventos espaciais sobre o mapa associaram as decisões antes impossíveis de visualizar: séries de reconstruções ao longo de novos alinhamen­tos, pavimentação de trechos de ruas, adução de água, localização da riqueza e pobreza, ligações políticas. Assim, as lógicas de planificação não mencionadas nas fontes escritas tornam-se evi­dentes. A geografia ajuda a fazer uma história que seja também uma história sobre o espaço e entrelaçada ao tecido urbano.
Saúde urbana e higienismo, o exemplo da França
Authors: Chasles Virginie
Published: September 2016

A saúde é um bom indicador de qua­lidade territorial e nos informa sobre a quali­dade do ambiente vivido. A saúde na cidade foi compreendida, por um longo tempo, através das topografias médicas, que puderam eviden­ciar os riscos de saúde ligados à concepção das cidades. Este artigo visa ilustrar as interações antigas entre cidade e saúde. Num primeiro momento, tratar-se-á da apresentação histó­rica de alguns indicadores de morbidade e de mortalidade, além de alguns fatores de risco. Veremos, em seguida, como a conscientização em relação aos desafios sanitários na cidade pôde influenciar o urbanismo e, através da incorporação do higienismo, como se pôde pensar em preservar a saúde das populações, transformando o seu espaço. Este texto eviden­ciará o caso da França e da cidade de Lyon.
Established and Emerging Roles of Biomarkers in Heart Failure Clinical Trials
Authors: Ibrahim Nasrien E. , Gaggin Hanna K. , Konstam Marvin A. , Januzzi James L.
Published: September 2016

The role of circulating biomarkers in heart failure clinical trials has evolved in recent decades. Increasing evidence behind the use of natriuretic peptides, emergence of novel biomarkers, and increased emphasis on targeting therapies toward physiological basis of disease (so-called precision medicine) have all contributed to the continued expansion of biomarker use in heart failure clinical trials. We will explore the advantages and pitfalls encountered through the use of biomarkers in clinical trials as an inclusion criterion, toxicity marker, and end point. We will also review their role in providing insights into the mechanism of action of therapeutics and guiding therapy in the management of patients with heart failure.
Impact of Pulmonary Hemodynamics and Ventricular Interdependence on Left Ventricular Diastolic Function in Children With Pulmonary Hypertension
Authors: Burkett Dale A. , Slorach Cameron , Patel Sonali S. , Redington Andrew N. , Ivy D. Dunbar , Mertens Luc , Younoszai Adel K. , Friedberg Mark K.
Published: September 2016

Background—

Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that pediatric PH patients have LV diastolic dysfunction, related to adverse pulmonary hemodynamics, leftward septal shift, and prolonged right ventricular systole.

Methods and Results—

Echocardiography was prospectively performed at 2 institutions in 54 pediatric PH patients during cardiac catheterization and in 54 matched controls. Diastolic LV measures including myocardial deformation were assessed by echocardiography. PH patients had evidence of LV diastolic dysfunction, most consistent with impaired LV relaxation, though some features of reduced ventricular compliance were present. PH patients demonstrated the following: reduced mitral
E
velocity and inflow duration, mitral
E′
and
E′
/
A′
, septal
E′
and
A′
, pulmonary vein S and D wave velocities, and LV basal global early diastolic circumferential strain rate and increased mitral
E
deceleration time, LV isovolumic relaxation time, mitral
E
/
E′
, and pulmonary vein A wave duration. PH patients demonstrated leftward septal shift and prolonged right ventricular systole, both known to affect LV diastole. These changes were exacerbated in severe PH. There were no statistically significant differences in diastolic measures between patients with and without a shunt and minimal differences between patients with and without congenital heart disease. Multiple echocardiographic LV diastolic parameters demonstrated weak-to-moderate correlations with invasively determined PH severity, leftward septal shift, and prolonged right ventricular systole.

Conclusions—

Pediatric PH patients exhibit LV diastolic dysfunction most consistent with impaired relaxation and reduced myocardial deformation, related to invasive hemodynamics, leftward septal shift, and prolonged right ventricular systole.
Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock
Authors: Gazit Salomé L. , Mariko Boubacar , Thérond Patrice , Decouture Benoit , Xiong Yuquan , Couty Ludovic , Bonnin Philippe , Baudrie Véronique , Le Gall Sylvain M. , Dizier Blandine , Zoghdani Nesrine , Ransinan Jessica , Hamilton Justin R. , Gaussem Pascale , Tharaux Pierre-Louis , Chun Jerold , Coughlin Shaun R. , Bachelot-Loza Christilla , Hla Timothy , Ho-Tin-Noé Benoit , Camerer Eric
Published: September 2016

Rationale:

Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear.

Objective:

To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature.

Methods and Results:

S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus–response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P
2
receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P
1
receptor was dispensable for survival despite its importance for maintaining vascular integrity.

Conclusions:

Although source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock.
Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction
Authors: Beer Lynn A. , Kossenkov Andrew V. , Liu Qin , Luning Prak Eline , Domchek Susan , Speicher David W. , Ky Bonnie
Published: September 2016

Rationale:

There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics–related cardiac dysfunction (CTRCD).

Objective:

We aimed to discover new biomarkers associated with doxorubicin- and trastuzumab-induced CTRCD using high-throughput proteomic profiling.

Methods and Results:

Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from 3 cases with CTRCD and 4 age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography–mass spectrometry. From these analyses, 862 proteins were identified from case/control pairs 1 and 2 and 1360 proteins from case/control pair 3. Proteins with a >1.5-fold change in cases compared with controls with a
P
<0.05 either at the time of CTRCD diagnosis or across all time points were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E, with higher levels detected at baseline and across all time points in controls without CTRCD as compared with matched CTRCD cases (
P
<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline immunoglobulin E levels were associated with a significantly lower risk of CTRCD (
P
=0.018).

Conclusions:

In patients receiving doxorubicin and trastuzumab, high baseline immunoglobulin E levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin- and trastuzumab-induced cardiac dysfunction.
In Vivo Post–Cardiac Arrest Myocardial Dysfunction Is Supported by Ca
2+
/Calmodulin-Dependent Protein Kinase II–Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2
Authors: Woods Christopher E. , Shang Ching , Taghavi Fouad , Downey Peter , Zalewski Adrian , Rubio Gabriel R. , Liu Jing , Homburger Julian R. , Grunwald Zachary , Qi Wei , Bollensdorff Christian , Thanaporn Porama , Ali Ayyaz , Riemer R. Kirk , Kohl Peter , Mochly-Rosen Daria , Gerstenfeld Edward , Large Stephen , Ali Ziad A. , Ashley Euan A.
Published: September 2016

Background:

Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies.

Methods:

We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca
2
+
-induced Ca
2+
release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo.

Results:

We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca
2+
/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca
2+
potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo.

Conclusions:

Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.
Preliminary Studies on the Growth and Movements of the Yellow-bellied Toad, Bombina variegata (Anura: Discoglossidae)
Authors: Płytycz Barbara , Bigaj Janusz
Published: September 2016

Yellow-bellied toads were studied in their natural environment in a mountain locality in south-eastern Poland. In June 1981, 353 specimens were captured in a small area, marked by yellow skin autografts, and released. 49 individuals were recaptured in July 1982 in the same area, and 17 animals were recaptured at other places 200-1200 m away. Movements were carried out mainly by juveniles. Large increases in body length of young individuals, probably yearlings, and small growth rates in older individuals, were generally found.
The Systematic Status of Adenomera griseigularis Henle, with Comments on Systematic Problems in the Genus Adenomera (Amphibia: Leptodactylidae)
Authors: Heyer W. Ronald
Published: September 2016

Adenomera griseigularis Henle is a junior synonym of Leptodactylus wagneri (Peters). Systematic problems and opportunities are discussed for certain members of the genus Adenomera. Researchers are cautioned that resolution of certain taxa will require non-morphological data.
An investigation of egg laying in Phelsuma (Reptilia: Sauria: Gekkonidae)
Authors: Osadnik Gerhard
Published: September 2016

Egg-laying behaviour of 15 species and 5 subspecies of the diurnal gecko genus Phelsuma was investigated in captivity. Specific behaviour patterns associated with egg-laying ("site cleaning", "egg patting" and defense of the clutch) are described and their significance is discussed.

This work is the first to distinguish two groups within the genus Phelsuma according to the m ode of oviposition: "gluers" which glue their eggs to a substrate and "non-gluers". Gluers include all species from the Mascarene Islands and P. dubia from Madagascar; non-gluers include species from the Seychelles, Comores and Madagascar.

The relationship between m ode of oviposition and habitat of related South African geckos together with the present-day distribution of gluing and non-gluing species of Phelsuma lead to certain conclusions concerning the evolution of this genus.
Evolutionary Divergences in the Smooth Newt, Triturus vulgaris (Urodela, Salamandridae) : Electrophoretic Evidence
Authors: Kalezić Miloš L.
Published: September 2016

An electrophoretic survey of proteins from 27 populations examines the level of genetic differentiation among four subspecies of T. vulgaris in Yugoslavia. Populations of T. v. vulgaris, T. v. meridionalis and T. v. graecus are genetically the most similar to each other, while T. v. dalmaticus is substantially different from these subspecies. This pattern , which is not in accordance with the pattern of morphological similarities, is discussed with special reference to Pleistocene glaciation periods.
Relationships among Discoglossid Frogs : An Albumin Perspective
Authors: Maxson Linda R. , Szymura Jacek M.
Published: September 2016

Relationships among frogs of the genera Alytes, Bombina, Discoglossus, and Baleaphryne were studied using the quantitative immunological micro-complement fixation technique. Albumins were compared among these genera as well as among several species of each genus. Our results indicate that the closest genetic relative of Baleaphryne muletensis is Alytes obstetricians. Moreover, the albumins of Baleaphryne and A. obstetricians are as similar or more similar to each other than the albumins of all four species of Bom bina, both species of Discoglossus, or the two species of Alytes available for study are to each other. We conclude that Baleaphryne is congeneric with Alytes. The distances measured among Alytes, Bombina, and Discoglossus suggest a Cretaceous (85-92 MYBP) divergence of Alytes from the lineage that later gave rise to Bombina and Discoglossus. These latter two genera appear to have diverged in the late Cretaceous, roughly 69-75 MYBP. Extant species of Bombina began diverging in the mid- to late-Miocene, as did Alytes obstetricans and A. cistemasii.

Discoglossus pictus and D. sardus in Europe last shared a common gene pool in the Pliocene. Albumins of individuals of D. pictus from Spain compared with northwestern African D. pictus suggest that these populations have been separated for some 9-10 million years, and are probably not conspecific. Our findings do not support Lanza et al.’s (1975, 1976) suggestions that Bombina and Alytes belong in the separate family Bombinidae.
Are the Ranidae (Anura, Amphibia) known prior to the Oligocene?
Authors: Rage Jean-Claude
Published: September 2016

Up to the present, early records of supposed Ranidae have been reported from the ante-Oligocene and even as early as the middle Jurassic. These anurans should be either rejected from the Ranidae (most of them) or considered only as possible ranids. On the other hand, some authors have indicated that ranids are known only since the Oligocene . It is demonstrated here that true ante-Oligocene ranids occur in Europe (in the upper Eocene) . They predate an important paleobiological event: the "Grande Coupure". These eocene ranids could be autochthonous, thus conveying the suggestion that Europe is the center of origin of the family, but this seems very unlikely. An alternative hypothesis is that these ranids are immigrants from Asia.
Cycles Journaliers d’Activité chez deux Espèces Sympatriques de Sceloporus (Iguanidae), S. grammicus et S. scalaris
Authors: Ortega Alfredo , Rodriguez Ricardo , Hernandez Lucina , Barbault Robert
Published: September 2016

The activity cycles of Sceloporus grammicus and Sceloporus scalaris were studied from transect census data during several months of the year in two sympatric mountain populations (2480 m) of Mexico. The two species exhibit very similar cycles, resulting from the harshness of the weather. Using at the best their thermic environment these lizards are able to maintain a mean cloacal temperature around 30°C, even in winter. The potential competition between these two species seems to be highly reduced by habitat segregation, S. grammicus being mainly a trunk-dwelling species while S. scalaris is a ground-dwelling one.

Les cycles journaliers d'activité de Sceloporus grammicus et de Sceloporus scalaris ont été étudiés a différentes saisons dans deux populations d'altitude (2480 m) du nord du Mexique. Les deux espèces présentent des cycles très similaires, qui résultent des fortes contraintes climatiques qu'elles subissent. Exploitant au mieux leur environnement thermique, ces lézards parviennent a conserver, pendant leurs phases d'activité, une température interne proche de 30°C, même en hiver. La coexi¬stence de ces deux espèces potentiellement compétitives est facilitée par une ségrégation spatiale, S. grammicus étant principalement inféodé aux troncs d'arbres tandis que S. scalaris est terricole.
Systems of Legal Defence Used by Latin American Countries in Investment Disputes
Authors: Polanco Lazo Rodrigo
Published: September 2016

This article describes the main features of the systems of legal defence that Latin American countries have been using when facing investment arbitration. It focuses on Argentina, Venezuela, Ecuador, Mexico, Peru, Bolivia, and Costa Rica, as a group of countries representative of the region and examines their strategies of internalisation or externalisation of the State’s legal defence and briefly addresses whether a policy to prevent investment disputes is in place. The article concludes that there is no uniform strategy of Latin American countries for the legal defence of investment disputes, but the large majority of States follow a mixed approach employing in-house lawyers and external counsel. With respect to the prevention of investment disputes, only some countries in the region have considered a preventive approach, or foster the use of alternative dispute resolution (ADR).
The Rise of Common Principles for Investment in Latin America: Proposing a Methodological Shift for Investor-State Dispute Settlement
Authors: Prieto Muñoz José Gustavo
Published: September 2016

The present article argues for the need of an alternative way of thinking about international investment law and investor-State disputes in Latin America. The article explains how the current critical approach to foreign investment comes from a conceptual trajectory that originated in the 19th century with the work of Carlos Calvo, inspired in turn by Emer De Vattel’s conceptual model for international law, and how a principles discourse would be a viable alternative for enhancing the legitimacy of investment arbitration. The article further structures such a principles discourse in three clusters: general principles recognised by Latin American nations; principles compatible with concepts developed by investment arbitrators, and regional principles not yet recognised by international investment arbitrators. The last cluster contains in particular principles such as transparency and inclusion that ought to be the core of a Latin American discourse as the limit of the authority granted to investment arbitrators.
Inter-State Investment Dispute Settlement in Latin America: Is There Space for Transparency?
Authors: Luque Macías María José
Published: September 2016

Reinforcing inter-State dispute settlement gradually constitutes an attractive alternative in Latin America to overcome the lack of predictability in the interpretation and application of international investment agreements (IIA). Procedural transparency should certainly be part of this development. An initial question is whether, and if so to which extent, this approach serves reform. The next question is whether relying on the practice of the World Trade Organization (WTO) is appropriate to enhance transparency, considering that the WTO dispute settlement system has served as a model for introducing reforms in inter-State and investor-State dispute settlement (ISDS). This article shows that resorting to inter-State mechanisms may not remedy deficits of treaty interpretation or application. Furthermore, the WTO experience on procedural transparency reveals that transparency has not become an essential standard, so that other means shall be devised for ensuring, in inter-State dispute settlement, the degree of transparency attained so far in ISDS.
Preparation and Characterization of Polyacrylamide/Silk Fibroin/Graphene Oxide Composite Hydrogel for Peripheral Nerve Regeneration
Authors: Kong Yan , Zhao Yinxin , Ji Bing , Shi Beibei , Wei Siying , Chen Guanyi , Zhang Luzhong , Li Guicai , Yang Yumin
Published: September 2016

The hydrogels have been widely used in various tissue engineering fields. Its excellent threedimension network structure and hydrophilicity could be used as cell culture scaffold for tissue regeneration. Graphene oxide (GO) related hydrogels have attracted more and more attention in
recent years. However, rare report referring to the application of GO related hydrogel in peripheral nerve regeneration. In this study a composite hydrogel consisting of polyacrylamide, silk fibroin and graphene oxide was prepared. The materials properties were characterized and Schwann cells
were cultured onto hydrogels in vitro to evaluate the influence on cell growth. The results showed that the composite hydrogel possessed excellent three-dimensional network structure, the hydrophilicity, wettability and porosity. Moreover, the mechanical strength of the hydrogels could
be obviously enhanced. The morphological characterization of Schwann cells cultured on the composite hydrogels showed mononeuritis than single polyacrylamide hydrogel, indicating a better growth environment for cells. The results indicated that the polyacrylamide/silk fibroin/graphene oxide
composite hydrogel with suitable content of each component could significantly affect the mechanical properties of the hydrogel and further the morphology of Schwann cells. The study provides a theoretical basis for design and potential application of hydrogels in regenerative medicine and
tissue engineering.
Modified with Pigment Epithelium-Derived Factor Enhances Cardiospheres Properties to Improve Cardiac Repair in Rats
Authors: Li Lei , Zhang Hao , Yuan Xulong , Liu Zhiwei , Pan Jiajun , Hui Hongliang , Lu Peng , Sun Teng , Yuan Honghua , Zhang Zhongming , Dong Hongyan
Published: September 2016

Cardiospheres is one of the best candidate progenitor cells for cell therapy. However, poor cell engraftment after implantation still remains to be solved. Pigment epithelium-derived factor was demonstrated to have a range of functions in different cells. However, the effects of pigment
epithelium-derived factor on the property of cardiospheres in vitro and cardiospheres overexpressing pigment epithelium-derived factor on the protection of cardiac function is better than the simple cardiospheres transplantation remain unknown. In this study, we expanded cardiospheres
from neonatal rat hearts and confirmed that pigment epithelium-derived factor could improve the survival, migration and stemness of the cardiospheres. In rat model of myocardial infarction, survival of cardiospheres transfected lentiviral pigment epithelium-derived factor after intramyocardial
injection was higher than that of the control and local micro-environment had been improved. Finally, cardiac function was protected more effectively in cardiospheres transfected lentiviral pigment epitheliumderived factor. These findings suggest that modified cardiospheres has stronger cell
properties and ability to protect myocardial function.
Electrospun Poly(lactic-co-glycolic acid)/Multiwalled Carbon Nanotube Nanofibers for Cardiac Tissue Engineering
Authors: Liu Yaowen , Liang Xue , Wang Shuyao , Hu Ke
Published: September 2016

Many conductive scaffolds were fabricated to mimic the topography of the cardiac microenvironment in vitro in order to improve the performance of engineered cardiac tissues. This study fabricated aligned poly(lactic-co-glycolic acid)/multiwalled carbon nanotube fibers by electrospinning.
The Young's modulus and conductivity were significantly greater on poly(lactic-co-glycolic acid) fibers with 3% multiwalled carbon nanotubes compared to others. Topographical cues and conductivity were applied to investigate the combined effect on cardiomyocyte behavior. Neonatal rat cardiomyocytes
cultured on the conductive fibers maintained their viability, induced cell elongation, and enhanced sarcomeric α-actinin and troponin I production in cardiomyocytes. The results indicate that poly(lactic-co-glycolic acid)/multiwalled carbon nanotube composite fibers have great
potential for cardiac tissue engineering.