bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots
Authors: Heinäniemi Merja , Vuorenmaa Tapio , Teppo Susanna , Kaikkonen Minna U , Bouvy-Liivrand Maria , Mehtonen Juha , Niskanen Henri , Zachariadis Vasilios , Laukkanen Saara , Liuksiala Thomas , Teittinen Kaisa , Lohi Olli
Published: July 2016

Progression of malignancy to overt disease requires multiple genetic hits. Activation-induced deaminase (AID) can drive lymphomagenesis by generating off-target DNA breaks at loci that harbor highly active enhancers and display convergent transcription. The first active transcriptional profiles from acute lymphoblastic leukemia (ALL) patients acquired here reveal striking similarity at structural variation (SV) sites. Specific transcriptional features, namely convergent transcription and Pol2 stalling, were detected at breakpoints. The overlap was most prominent at SV with recognition motifs for the recombination activating genes (RAG). We present signal feature analysis to detect vulnerable regions and quantified from human cells how convergent transcription contributes to R-loop generation and RNA polymerase stalling. Wide stalling regions were characterized by high DNAse hypersensitivity and unusually broad H3K4me3 signal. Based on 1382 pre-B-ALL patients, the ETV6-RUNX1 fusion positive patients had over ten-fold elevation in RAG1 while high expression of AID marked pre-B-ALL lacking common cytogenetic changes.
Improvement of light extraction for a target wavelength in InGaN/GaN LEDs with an indium tin oxide dual layer by oblique angle deposition
Authors: Seo Dong-Ju , Lee Dong-Seon
Published: July 2016

GaN-based blue LEDs were fabricated and studied with porous, dense, and dual-layer indium tin oxide (ITO) structures as transparent top electrodes to enhance light extraction. The electroluminescence intensity of the LED with a thickness-optimized and refractive-index-tuned ITO dual layer at I = 20 mA was higher by 19.7% than that of the conventional LED with a 200 nm planar ITO. This study confirmed that an ITO dual layer can be made with a single material by optimizing the thickness and tuning the refractive index, which improves the power output without any electrical property degradation.
Effect of an intersection of carbon nanotubes on the carrier accumulation under an external electric field
Authors: Kochi Taketo , Okada Susumu
Published: July 2016

We studied the electronic structure of semiconducting carbon nanotube (CNT) thin films, in which CNTs intersect each other, under an external electric field, using first-principles total-energy calculations within the framework of the density functional theory. Our calculations show that the distribution of accumulated carriers strongly depends on the CNT species, their mutual arrangement with respect to the electrode, and carrier concentrations. Under particular conditions, an induced electric field between the CNTs is opposite to the applied field. We also showed that the quantum capacitance of the CNT thin films depends on the arrangement of the CNTs relative to the electrode.
Temperature dependence of spin Hall magnetoresistance in W/CoFeB bilayer
Authors: Okuno Takaya , Taniguchi Takuya , Kim Sanghoon , Baek Seung-heon Chris , Park Byong-Guk , Moriyama Takahiro , Kim Kab-Jin , Ono Teruo
Published: July 2016

We investigate the temperature dependence of the spin Hall magnetoresistance (SMR) in a W/CoFeB bilayer. The SMR is found to increase with decreasing temperature. An analysis based on the SMR theory suggests that the spin Hall angle of W and/or the spin polarization of CoFeB can be the origin of the temperature dependence of the SMR. We also find that the spin diffusion length and the resistivity of W do not significantly vary with temperature, which indicates the necessity of further study on the electron transport mechanism in W films to reveal the origin of the spin Hall effect in W.
Observation of adsorption behavior of biomolecules on ferroelectric crystal surfaces with polarization domain patterns
Authors: Nakayama Tomoaki , Isobe Akiko , Ogino Toshio
Published: July 2016

Lithium tantalate (LiTaO3) is one of the ferroelectric crystals that exhibit spontaneous polarization domain patterns on its surface. We observed the polarization-dependent adsorption of avidin molecules, which are positively charged in a buffer solution at pH 7.0, on LiTaO3 surfaces caused by electrostatic interaction at an electrostatic double layer using atomic force microscopy (AFM). Avidin adsorption in the buffer solution was confirmed by scratching the substrate surfaces using the AFM cantilever, and the adsorption patterns were found to depend on the avidin concentration. When KCl was added to the buffer solution to weaken the electrostatic double layer interaction between avidin molecules and LiTaO3 surfaces, adsorption domain patterns disappeared. From the comparison between the adsorption and chemically etched domain patterns, it was found that avidin molecule adsorption is enhanced on negatively polarized domains, indicating that surface polarization should be taken into account in observing biomolecule behaviors on ferroelectric crystals.
Dimensional comparison between amplitude-modulation atomic force microscopy and scanning ion conductance microscopy of biological samples
Authors: Kim Joonhui , Choi MyungHoon , Jung Goo-Eun , Ferhan Abdul Rahim , Cho Nam-Joon , Cho Sang-Joon
Published: July 2016

The range of scanning probe microscopy (SPM) applications for atomic force microscopy (AFM) is expanding in the biological sciences field, reflecting an increasing demand for tools that can improve our fundamental understanding of the physics behind biological systems. However, the complexity associated with applying SPM techniques in biomedical research hampers the full exploitation of its capabilities. Recently, the development of scanning ion conductance microscopy (SICM) has overcome these limitations and enabled contact-free, high resolution imaging of live biological specimens. In this work, we demonstrate the limitation of AFM for imaging biological samples in liquid due to artifacts arising from AFM tip–sample interaction, and how SICM imaging is able to overcome those limitations with contact-free scanning. We also demonstrate that SICM measurements, when compared to AFM, show better fit to the actual dimensions of the biological samples. Our results highlight the superiority of SICM imaging, enabling it to be widely adopted as a general and versatile research tool for biological studies in the nanoscale.
Research on Heritage Spanish Phonetics and Phonology: Pedagogical and Curricular Implications
Authors: Rao Rajiv , Kuder Emily
Published: July 2016

This paper creates a novel link between research on linguistics and education by discussing what we know about the sound system of heritage language users of Spanish and how these findings can inform practices implemented in heritage Spanish courses in the USA. First, we provide an overview of terminology associated with heritage language research, situating heritage Spanish programs within the educational context of the USA, and explaining why heritage Spanish phonetics and phonology remain relatively unexplored. Next, we delve into previous linguistic research on the heritage Spanish sound system in terms of individual vowels and consonants, as well as at the level of intonation, rhythm, and stress, while highlighting any observed differences between the system of heritage Spanish and those of Spanish speakers of other backgrounds. Finally, motivated by the phonetic/phonological insight of previous work, in addition to existing pedagogical and curricular research on heritage Spanish, we consider how and why the inclusion of specific types of sound-system-based commentary and practice in the educational experience of heritage users of Spanish could be beneficial.
Challenges in the analysis of long noncoding RNA functionality
Authors: Leone Sergio , Santoro Raffaella
Published: July 2016

Long noncoding RNA (lncRNA) are emerging as important regulators of diverse biological functions. Although mechanistic models are starting to emerge, it is also clear that the lncRNA field needs appropriate model systems in order to better elucidate the functions of lncRNA and their roles in both physiological and pathological conditions. The field of lncRNA is new, and the biochemical and genetic methods used to address function and mechanisms of lncRNA have only recently been developed or adapted from techniques used to investigate protein‐coding genes. In this review, we discuss the strengths and weaknesses of available techniques for the analysis of chromatin‐associated lncRNA and emerging models for the recruitment to specific genomic sites such as triple‐helix, RNA–protein–DNA recognition and proximity‐guided search models.
A three‐dimensional analysis on the role of atmospheric waves in the climatology and interannual variability of stratospheric final warming in the Southern Hemisphere
Authors: Hirano Soichiro , Kohma Masashi , Sato Kaoru
Published: July 2016

Stratospheric final warming (SFW) in the Southern Hemisphere is examined in terms of their interannual variability and climatology using reanalysis data from January 1979 to March 2014. First, it is shown from a two‐dimensional transformed Eulerian mean (TEM) analysis that a time‐integrated vertical component of Eliassen‐Palm flux during the spring is significantly related with SFW date. To clarify the role of residual mean flow in the interannual variability of the SFW date, SFWs are categorized into early and late groups according to the SFW date and their differences are examined. Significant difference in potential temperature tendency is observed in the middle and lower stratosphere in early October. Their structure in the meridional cross section accords well with that of vertical potential temperature advection by the residual mean flow. Difference in heating rate by shortwave radiation is minor. These results suggest that the adiabatic heating associated with the residual mean flow largely affects polar stratospheric temperature during austral spring and SFW date. The analysis is extended to investigate the longitudinal structure by using a three‐dimensional (3‐D) TEM theory. The significant difference in potential temperature tendency is mainly observed around the Weddell Sea at 10 hPa. Next, climatological 3‐D structure of a vertical component of the residual mean flow in association with SFW is examined in terms of the effect on the troposphere. The results suggest that a downward residual mean flow from the stratosphere penetrates into underlying troposphere over East Antarctica and partly influences tropospheric temperature there.
Persistent longitudinal variations in 8 years of CIPS/AIM polar mesospheric clouds
Authors: Liu Xiao , Yue Jia , Xu Jiyao , Yuan Wei , Russell James M. , Hervig M. E. , Nakamura Takuji
Published: July 2016

The Cloud Imaging and Particle Size (CIPS) instrument on the Aeronomy of Ice in the Mesosphere (AIM) satellite provides an opportunity to study the longitudinal variation in polar mesospheric cloud (PMC). We examined the longitudinal variation in PMC albedo using 8 years (2007–2014) of observations from the CIPS instrument. The results show that the PMC albedo in the Southern Hemisphere (SH), especially in the latitude band of 80°S–85°S, is persistently low (~65% relative to the rest of the hemisphere) within 60°W to 150°W longitude. In the Northern Hemisphere (NH), however, PMC albedo is found to be relatively zonally asymmetry. Harmonic analyses show that the persistent longitudinal variation in the SH PMC albedo is due to zonal wave numbers 1 through 4 (WN1–WN4) processes with minima in the longitude range of 60°W–150°W. The influence of temperature and H2O on the longitudinal variation of the PMC albedo is discussed based on results obtained using a simple 0‐D PMC model and temperature from the Microwave Limb Sounder (MLS) and the Sounding of the Atmosphere with Broadband Emission Radiometry (SABER) and H2O from MLS. The modeled region of low ice mass in the SH is generally consistent with that of low PMC albedo seen in CIPS. Tidal analyses using the SABER temperatures indicate that the nonmigrating semidiurnal tides with modes of S0, W1, and E1 might be the main drivers of the persistent longitudinal variations of PMC albedo in the SH. Nonmigrating tides are much weaker in the NH and consistent with the observed lack of longitudinal variability in PMC albedo.
Integrated surface/subsurface permafrost thermal hydrology: Model formulation and proof‐of‐concept simulations
Authors: Painter Scott L. , Coon Ethan T. , Atchley Adam L. , Berndt Markus , Garimella Rao , Moulton J. David , Svyatskiy Daniil , Wilson Cathy J.
Published: July 2016

The need to understand potential climate impacts and feedbacks in Arctic regions has prompted recent interest in modeling of permafrost dynamics in a warming climate. A new fine‐scale integrated surface/subsurface thermal hydrology modeling capability is described and demonstrated in proof‐of‐concept simulations. The new modeling capability combines a surface energy balance model with recently developed three‐dimensional subsurface thermal hydrology models and new models for nonisothermal surface water flows and snow distribution in the microtopography. Surface water flows are modeled using the diffusion wave equation extended to include energy transport and phase change of ponded water. Variation of snow depth in the microtopography, physically the result of wind scour, is modeled phenomenologically with a diffusion wave equation. The multiple surface and subsurface processes are implemented by leveraging highly parallel community software. Fully integrated thermal hydrology simulations on the tilted open book catchment, an important test case for integrated surface/subsurface flow modeling, are presented. Fine‐scale 100 year projections of the integrated permafrost thermal hydrological system on an ice wedge polygon at Barrow Alaska in a warming climate are also presented. These simulations demonstrate the feasibility of microtopography‐resolving, process‐rich simulations as a tool to help understand possible future evolution of the carbon‐rich Arctic tundra in a warming climate.
A mitigation strategy for commercial aviation impact on NOx‐related O3 change
Authors: Wasiuk D. K. , Khan M. A. H. , Shallcross D. E. , Derwent R. G. , Lowenberg M. H.
Published: July 2016

An operational mitigation strategy for commercial aircraft impact on atmospheric composition, referred to as the turboprop replacement strategy (TRS), is described in this paper. The global air traffic between 2005 and 2011 was modeled with the TRS in which turbofan powered aircraft were replaced with nine chosen turboprop powered aircraft on all routes up to 1700 nautical miles (NM) in range. The results of this TRS double the global number of departures, as well as global mission distance, while global mission time grows by nearly a factor of 3. However, the global mission fuel and the emissions of aviation CO2, H2O, and SOx remain approximately unchanged, and the total global aviation CO, hydrocarbons (HC), and NOx emissions are reduced by 79%, 21%, and 11% on average between 2005 and 2011. The TRS lowers the global mean cruise altitude of flights up to 1700 NM by ~2.7 km which leads to a significant decrease in global mission fuel burn, mission time, distance flown, and the aircraft emissions of CO2, CO, H2O, NOx, SOx, and HC above 9.2 km. The replacement of turbofans with turboprops in regional fleets on a global scale leads to an overall reduction in levels of tropospheric O3 at the current estimated mean cruise altitude near the tropopause where the radiative forcing of O3 is strongest. Further, the replacement strategy results in a reduction of ground‐level aviation CO and NOx emissions by 33 and 29%, respectively, between 2005 and 2011.
Correlation between the spectral features and electric field changes for natural lightning return stroke followed by continuing current with M‐components
Authors: Wang Xuejuan , Yuan Ping , Cen Jianyong , Xue Simin
Published: July 2016

According to the high time‐resolved spectra of two first and a subsequent return strokes and the following continuing current processes overlapped with M‐components in three natural cloud‐to‐ground lightning, the correlation between the total intensity of ionic lines in the spectra and the corresponding amplitude of electric field change and that between the total intensity of the spectra and the apparent diameter of the discharge channel have been investigated. Linear correlations have been found for the above two sets of parameters. The luminous properties along the channel show that the total intensity of ionic lines in the spectra for both the return stroke and M‐components decreases with increasing height along the channel. The total intensity of the spectra and the apparent diameter for the return stroke also go down with increase of the height, while those for M‐components do the reverse.
Porous Bioceramics Produced by Impregnation of 3D‐Printed Wax Mold: Ceramic Architectural Control and Process Limitations
Authors: Charbonnier Baptiste , Laurent Coralie , Blanc Gilles , Valfort Olivier , Marchat David
Published: July 2016

Current architectural and production limitations prevent the manufacturing standardization and design of bioceramics. Such limitations have hindered advances in bone tissue engineering and regeneration. In this context, we propose a bioceramic manufacturing process based on the impregnation of wax molds produced by additive manufacturing. Hydroxyapatite bioceramics with custom architectures were fabricated to evaluate the reliability, robustness, and limitations of this process. Results indicate that this process preserves phase biocompatibility, permits homogeneous shrinkage of the biomaterial during heat treatment, and allows reproducible and precise manufacturing of custom architectures.
The immunophenotypic spectrum of primary mediastinal large B‐cell lymphoma reveals prognostic biomarkers associated with outcome
Authors: Bledsoe Jacob R. , Redd Robert A. , Hasserjian Robert P. , Soumerai Jacob D. , Nishino Ha T. , Boyer Daniel F. , Ferry Judith A. , Zukerberg Lawrence R. , Harris Nancy Lee , Abramson Jeremy S. , Sohani Aliyah R.
Published: July 2016

Primary mediastinal large B‐cell lymphoma (PMBL) is a distinct subtype of diffuse large B‐cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray‐zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow‐up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5‐year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell‐of‐origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 (P = 0.011) and high MUM1 (P = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS (P = 0.001) and OS (P = 0.032). On separate multivariate models, low PDL1 was independent of R‐IPI risk group for PFS (HR 6.0, P = 0.023), as was a biologic risk score of 2 (HR 5.6, P = 0.011). Incorporation of the biologic risk score sub‐stratified patients within R‐IPI groups for both PFS (P < 0.001) and OS (P < 0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high‐risk disease. Am. J. Hematol. 91:E436–E441, 2016. © 2016 Wiley Periodicals, Inc.
A Rechargeable Al/S Battery with an Ionic‐Liquid Electrolyte
Authors: Gao Tao , Li Xiaogang , Wang Xiwen , Hu Junkai , Han Fudong , Fan Xiulin , Suo Liumin , Pearse Alex J , Lee Sang Bok , Rubloff Gary W. , Gaskell Karen J , Noked Malachi , Wang Chunsheng
Published: July 2016

Aluminum metal is a promising anode material for next generation rechargeable batteries owing to its abundance, potentially dendrite‐free deposition, and high capacity. The rechargeable aluminum/sulfur (Al/S) battery is of great interest owing to its high energy density (1340 Wh kg−1) and low cost. However, Al/S chemistry suffers poor reversibility owing to the difficulty of oxidizing AlSx. Herein, we demonstrate the first reversible Al/S battery in ionic‐liquid electrolyte with an activated carbon cloth/sulfur composite cathode. Electrochemical, spectroscopic, and microscopic results suggest that sulfur undergoes a solid‐state conversion reaction in the electrolyte. Kinetics analysis identifies that the slow solid‐state sulfur conversion reaction causes large voltage hysteresis and limits the energy efficiency of the system.
A Family of Chiral Ferrocenyl Diols: Modular Synthesis, Solid‐State Characterization, and Application in Asymmetric Organocatalysis
Authors: Nottingham Chris , Müller‐Bunz Helge , Guiry Patrick J.
Published: July 2016

Readily available chiral diol scaffolds are useful as sources of chirality for asymmetric synthesis, however, few such scaffolds are readily available in enantiopure form. Reported herein is a cheap and modular synthesis of a novel family of chiral ferrocenyl diols in excellent yields with excellent enantio‐ and diastereoselectivity (>99 % ee and 99 % de). These diols possess not only planar and central chirality, but also axial chirality around the central iron atom. Characterization of these diols by X‐ray crystallography revealed intra‐ and intermolecular hydrogen‐bond networks depending on substitution at the carbinol positions. The potential of these diols as catalysts was subsequently demonstrated in an asymmetric hetero‐Diels–Alder reaction which provided cycloadducts in up to 84 % yield with ee values ranging from −92 to +72 %.
Immobilization of lipase from Candida rugosa and its application for the synthesis of biodiesel in a two‐step process
Authors: Xu Ming‐Hong , Kuan I‐Ching , Deng Fu‐Yin , Lee Shiow‐Ling , Kao Wei‐Chen , Yu Chi‐Yang
Published: July 2016

Lipase from Candida rugosa was immobilized onto polystyrene‐divinylbenzene support for converting waste cooking oil to biodiesel using a two‐step process. The immobilization improved the thermal stability and stability at acidic pH. The adsorbed lipase was applied to the hydrolysis of waste cooking oil to fatty acids, and the effects of temperature, pH, shaking speed and isooctane/waste cooking oil ratio were evaluated using response surface methodology combined with central composite design. The optimal conditions for the lipase‐catalyzed hydrolysis were 35.3 °C, pH 5.5, shaking speed of 222 rpm, and isooctane/waste cooking oil ratio of 0.34; the predicted and experimental conversions were 100 and 99.7%, respectively. The conversion of waste cooking oil to fatty acids remained the same after reuse for seven reaction cycles. The hydrolysis of waste cooking oil was also performed in recycled‐batch mode with a packed‐bed reactor; the maximal conversion of 93% was observed after reaction with 490 mg of immobilized lipase for 2 h. The fatty acids separated were further converted to biodiesel by Amberlyst 15‐catalyzed esterification; 99.9% conversion was obtained after 2 h incubation. © 2016 Curtin University of Technology and John Wiley & Sons, Ltd.
Characteristics of murta bast fiber reinforced epoxy composites
Authors: Hussain Barbhuiya Ajmal , Uddin Choudhury Saad , Ismail Kochi
Published: July 2016

The growing global concern over environment protection has led to the application of natural fiber reinforced polymer composites as alternative materials in manufacturing sectors. Various natural fibers are therefore being explored for reinforcement of polymer matrices. In the present work, murta bast fibers of varying length and weight percent are mixed randomly with the epoxy matrix and the composites are prepared from these mixtures by using the hand lay‐up method. The composites are characterized on the basis of density, thermal gravimetric analysis, infrared spectroscopy, scanning electron microscopy, tensile strength, flexural strength, compressive strength, impact strength, and Rockwell hardness studies. Tensile, flexural, and compressive moduli of the composites are also determined. The tensile strength of the composite was analyzed in the light of the different analytical models. Composites containing 30 weight % fibers of length 25 or 35 mm have the optimum mechanical properties. Murta bast fiber has the characteristics to become a good natural material for reinforcement. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 44142.
Economic implications of incorporating emission controls to mitigate air pollutants emitted from a modeled hydrocarbon‐fuel biorefinery in the United States
Authors: Bhatt Arpit , Zhang Yimin , Davis Ryan , Eberle Annika , Heath Garvin
Published: July 2016

The implementation of the US Renewable Fuel Standard is expected to increase the construction and operation of new biofuel facilities. Allowing this industry to grow without adversely affecting air quality is an important sustainability goal sought by multiple stakeholders. However, little is known about how the emission controls potentially required to comply with air quality regulations might impact biorefinery cost and deployment strategies such as siting and sizing. In this study, we use a baseline design for a lignocellulosic hydrocarbon biofuel production process to assess how the integration of emission controls impacts the minimum fuel selling price (MFSP) of the biofuel produced. We evaluate the change in MFSP for two cases as compared to the baseline design by incorporating (i) emission controls that ensure compliance with applicable federal air regulations and (ii) advanced control options that could be used to achieve potential best available control technology (BACT) emission limits. Our results indicate that compliance with federal air regulations can be achieved with minimal impact on biofuel cost (~$0.02 per gasoline gallon equivalent (GGE) higher than the baseline price of $5.10 GGE−1). However, if air emissions must be further reduced to meet potential BACT emission limits, the cost could increase nontrivially. For example, the MFSP could increase to $5.50 GGE−1 by adopting advanced emission controls to meet potential boiler BACT limits. Given tradeoffs among emission control costs, permitting requirements, and economies of scale, these results could help inform decisions about biorefinery siting and sizing and mitigate risks associated with air permitting. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Biofuels, Bioproducts and Biorefining published by Society of Industrial Chemistry and John Wiley & Sons Ltd.
To clear, or not to clear (senescent cells)? That is the question
Authors: Lujambio Amaia
Published: July 2016

Cellular senescence is an anti‐proliferative program that restricts the propagation of cells subjected to different kinds of stress. Cellular senescence was initially described as a cell‐autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a non‐cell‐autonomous manner. These non‐cell‐autonomous activities are, in part, mediated by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence‐associated secretory phenotype. One of the key functions of the senescence‐associated secretory phenotype is to attract immune cells, which in turn can orchestrate the elimination of senescent cells. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti‐cancer and anti‐aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential.
P‐TEFb goes viral
Authors: Zaborowska Justyna , Isa Nur F. , Murphy Shona
Published: July 2016

Positive transcription elongation factor b (P‐TEFb), which comprises cyclin‐dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P‐TEFb is required for productive elongation of transcription of protein‐coding genes by RNA polymerase II (pol II). In addition, P‐TEFb‐mediated phosphorylation of the carboxyl‐terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P‐TEFb could be effective anti‐viral agents.
Arf6 and the 5'phosphatase of synaptojanin 1 regulate autophagy in cone photoreceptors
Authors: George Ashley A. , Hayden Sara , Stanton Gail R. , Brockerhoff Susan E.
Published: July 2016

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1‐deficient zebrafish mutant, nrca14. We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type.
In EXOG‐depleted cardiomyocytes cell death is marked by a decreased mitochondrial reserve capacity of the electron transport chain
Authors: Tigchelaar Wardit , De Jong Anne Margreet , van Gilst Wiek H. , De Boer Rudolf A. , Silljé Herman H. W.
Published: July 2016

Depletion of mitochondrial endo/exonuclease G‐like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G‐like‐depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G‐like depletion. Interestingly, PE‐induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease G‐like‐depleted cells, suggesting a reverse signaling function of endo/exonuclease G‐like. Endo/exonuclease G‐like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G‐like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G‐like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G‐like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death.
The tumorigenic potential of pluripotent stem cells: What can we do to minimize it?
Authors: Peterson Suzanne E. , Garitaonandia Ibon , Loring Jeanne F.
Published: July 2016

Human pluripotent stem cells (hPSCs) have the potential to fundamentally change the way that we go about treating and understanding human disease. Despite this extraordinary potential, these cells also have an innate capability to form tumors in immunocompromised individuals when they are introduced in their pluripotent state. Although current therapeutic strategies involve transplantation of only differentiated hPSC derivatives, there is still a concern that transplanted cell populations could contain a small percentage of cells that are not fully differentiated. In addition, these cells have been frequently reported to acquire genetic alterations that, in some cases, are associated with certain types of human cancers. Here, we try to separate the panic from reality and rationally evaluate the true tumorigenic potential of these cells. We also discuss a recent study examining the effect of culture conditions on the genetic integrity of hPSCs. Finally, we present a set of sensible guidelines for minimizing the tumorigenic potential of hPSC‐derived cells. © 2016 The Authors. Inside the Cell published by Wiley Periodicals, Inc.
Association of TIP30 expression and prognosis of hepatocellular carcinoma in patients with HBV infection
Authors: Zhang Xia , Lv Lizhi , Ouyang Xuenong , Zhang Shi'an , Fang Jian , Cai Lirong , Li Dongliang
Published: July 2016

Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high‐density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha‐fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC (P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect (P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30++/+++) had a better 5‐year overall survival rate than those with low/negative (TIP30+/−) expression (P < 0.001). TIP30+/−/HBV+ patients had the worst 5‐year overall survival rate, whereas TIP30++/+++/HBV− patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV+ hepatoblastoma cell‐line HepG2 2.2.15 and HCC cell‐line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC.
New schedule of bevacizumab/paclitaxel as first‐line therapy for metastatic HER2‐negative breast cancer in a real‐life setting
Authors: Cannita Katia , Paradisi Stefania , Cocciolone Valentina , Bafile Alberto , Rinaldi Lucia , Irelli Azzurra , Lanfiuti Baldi Paola , Zugaro Luigi , Manetta Rosa , Alesse Edoardo , Ricevuto Enrico , Ficorella Corrado
Published: July 2016

Angiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first‐line treatment of unselected, HER2‐negative, metastatic breast cancer (MBC) patients, in a real‐life setting. Thirty‐five patients (median age 56 years, range 40–81) with HER2‐negative MBC were treated with paclitaxel (70 mg/m2) dd 1,8,15 q21 (60 mg/m2 if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty‐two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple‐negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow‐up of 13 months (range 1–79 months), the median progression‐free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real‐life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.
Mechanisms of immune evasion and current status of checkpoint inhibitors in non‐small cell lung cancer
Authors: Qin Angel , Coffey David G. , Warren Edus H. , Ramnath Nithya
Published: July 2016

In the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non‐small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti‐program death‐1 (PD‐1) and anti‐program death‐ligand 1(PD‐L1) pathway (4) outline determinants of response to PD‐1/PD‐L1 therapy and (5) discuss potential future areas for research.
Monitoring and delinquency
Authors: Weintraub Karen J. , Gold Martin
Published: July 2016

This study examined the effects of parental monitoring in order to discover specific ways that their relationships with their parents affect adolescents’ delinquent behaviour. Data were taken from the National Survey of Youth 1972, a survey of a representative sample of 1395 Americans in the age range 11‐18 years. Conditions such as the age and sex of the respondents, their affectional relationships with their parents, the composition of their families and their estimates of the delinquency of their friends all qualified the relationship between parental monitoring and their self‐reported delinquency. In one condition, the generally negative relationship was reversed.
Managing difficult behaviour in a long‐term prison
Authors: STAPLES JOHN
Published: July 2016

Use of the term psychopathic disorder, or some related diagnostic concept, is avoided in this paper, as it is written from the perspective of a prison governor who has to manage difficult behaviour in a long‐term prison. The context in which difficult behaviour is handled is vital, and this paper addresses some of the management aspects of the issues raised in the previous paper. It determines the nature of the behaviour and the options for responding to it: difficult behaviours rather than difficult individuals are the chief focus. The formal options for managers in the Prison Service are not always as effective as the informal controls exercised by staff and prisoners: indeed, the formal sanctions tend to be punitive in practice if not in theory. The special units in prisons have tried to develop a response which is therapeutic, not punitive. Access to these units is not easy and they have not been used by the Prison Service as much as was expected when they were set up. The special hospitals provide another opportunity to break the cycle of punishment and I believe there is a case for close cooperation between at least one special hospital and at least one unit as a half‐way house facilitating the change of role from prisoner to patient and back to prisoner in a way that is helpful to the individual.
DSM‐III diagnosis in criminal psychopaths: a way forward
Authors: COID JEREMY W.
Published: July 2016

Research diagnostic instruments were administered to 243 subjects, consisting of three subsamples. These included men detained under the English legal category of psychopathic disorder from one special hospital, female ‘psychopaths’ from three special hospitals, and male prisoners from three special units developed in prisons for the containment and control of highly dangerous and disruptive inmates. Using the DSM‐III classification, subjects were found to have multiple Axis‐II personality disorder categories and multiple Axis‐I clinical syndromes over their lifetime. Borderline and antisocial personality disorder were the most prevalent diagnoses, often in combination. The remaining subjects comprised subgroups with schizoid personality disorder and ‘pseudopsychopaths’, who were later recognised as suffering from slowly developing chronic schizophrenia or organic psychoses. Problems of treatability of these subjects relate to the ‘severity’ of their personality disorder. This in turn is reflected in the multiple Axis‐II diagnoses which are required to encompass the sheer range of their psychopathology. Multiple recurring Axis‐I conditions, which are amenable to conventional psychiatric treatment, indicate a need for specialist medical services for these patients, irrespective of arguments over the treatability of their Axis‐II conditions.
Towards a new methodology for making sense of case material: an illustrative case involving attempted multiple murder
Authors: GRESSWELL DAVID M. , HOLLIN CLIVE R.
Published: July 2016

Functional analysis provides a method of understanding behaviour in terms of its consequences for the individual concerned. The suggestion is made here that the application of this method to past behaviour will be useful to both practitioners and researchers. It offers benefits in terms of organising case material, understanding the aetiology of the behaviour, planning interventions and predicting dangerousness. It should be noted, however, that this is not an exercise in developing causal models of specific offences. In this paper multiple sequential functional analysis methodology is described and the problems of applying it retrospectively to criminal behaviours discussed. The methodology is illustrated with the case of a man who formulated a plan to kill 20 people and was convicted of two counts of attempted murder.
Memory disorder in offenders and victims
Authors: STONE I.H.
Published: July 2016

Historically, amnesia has occupied an important place in the development of the principle of acquittal on the grounds of insanity. Recently the main area of legal controversy has been to do with fitness to plead. Following the Podola case in 1959, the direction of research on this topic was towards an assessment of the genuineness of an amnesia. Now it appears that such an assessment offers little insight into the understanding of the causes and mechanisms of both organic and psychogenic amnesia, the aetiology of which is discussed. Amnesia in subjects accused of crime is most often found in crimes of violence, especially homicide, and may have an organic cause such as a head injury, or a psychogenic cause due to the psychological trauma associated with the violence. Some cases may have a combination of organic and psychogenic causes. Recently there has been greater recognition that victims of crime, and especially of violent crime, can suffer from a memory loss similar to that seen in the perpetrators. It is perhaps in this direction that the way forward lies in understanding the causes of psychogenic amnesia without the hindrance of having to decide whether the amnesia is genuine or not, a task that is fruitless.
The crime of passion and the changing cultural construction of jealousy
Authors: MULLEN PAUL E.
Published: July 2016

Killings motivated by jealousy are, on occasion, glorified by the term ‘crime of passion’. The response to such crimes depends on the prevailing attitudes to jealousy and the legal practices current at the time. The cultural construction of jealousy has undergone radical changes in emphasis over the history of Western society, and legal systems have altered in response to changing cultural and social contexts. It is argued that the generosity accorded to the jealous killer has survived these changes. In our current emotionology jealousy is increasingly regarded as psychopathological and as such ceases to be the responsibility of the jealous individual. Although pathological jealousies do exist, the vast majority of jealous reactions are not usefully regarded as pathological. If jealousy is to be translated from a vengeful cry of rage into a disappointed hope, it is essential to recognise that most jealous reactions fall within the scope of normal human experience. When violence emerges from such jealousy, appeals by mental health professionals to psychopathology to explain and mitigate are misguided.
Forensic mental hospitals according to Dutch standards
Authors: KOENRAADT FRANS
Published: July 2016

This paper briefly examines the forensic mental health system in The Netherlands. A description of the criminal law sanction TBS is given. This is a therapeutically oriented sanction in the Dutch criminal code. In 15 items the Dutch forensic mental health system is typified and characterised. The hospital as a therapeutic instrument and the necessity for diversion from the hospital is dealt with in this contribution.