bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA16: Reconstructing compartment−specific regulatory programs in pancreatic cancer
Authors: Maurer H. Carlo , He Jing , Alvarez Mariano J. , Giorgi Federico , Holmstrom Sam , Califano Andrea , Olive Kenneth P.
Published: December 2016

Pancreatic cancer is characterized by an expansive, desmoplastic stroma that responds to neoplastic signals from the malignant epithelium while also instigating a cacophony of signals from diverse stromal cell types that in turn modulate the malignant process. Several published efforts have reported the global signaling profiles of bulk pancreatic tumors, which have proven useful for defining different molecular subtypes of the disease. However, in order to facilitate the precise assessment of both neoplastic and stromal signaling profiles, we developed a robust pipeline to perform RNA-sequencing from laser-capture microdissected tissues. We applied this technique to a collection of 200+ frozen primary pancreatic ductal adenocarcinomas, deriving both malignant epithelial and stromal gene expression profiles from each. These compartment-specific profiles may serve to define novel molecular subtypes grounded in the biology of the distinct compartments. This technique also enabled profiling of the epithelium and stromal from microscopic PanIN-1 proliferations, facilitating the precise delineation of changes arising during malignant progression. Using computational modelling of paired epithelial and stromal samples, we developed a novel digital deconvolution model that generates virtual compartment-specific gene expression signatures from bulk pancreatic tumor profiles. Thus, findings from our experimentally dissected sample set can be leveraged to analyze multiple publically-available gene expression datasets.

In order to learn more about the regulatory processes that drive malignancy in both the epithelial and stromal compartments, we used a systems biology approach to reconstruct their global regulatory networks in pancreatic cancer. Briefly, regulatory models comprising ~700,000 interactions were computationally reconstructed for each compartment from the LCM-RNA-seq datasets using the ARACNe algorithm. These networks then served as a scaffold for the application of the MARINa and VIPER algorithms, which define master regulatory proteins whose activity drives (or restrains) the PanIN-1 to PDA progression. We will discuss early results of master regulator analyses that illuminate both oncogenic signaling in the epithelium, and large-scale changes in stromal microenvironment that occur during progression from PanIN-1 to PDA.

Citation Format: H. Carlo Maurer, Jing He, Mariano J. Alvarez, Federico Giorgi, Sam Holmstrom, Andrea Califano, Kenneth P. Olive.{Authors}. Reconstructing compartment−specific regulatory programs in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA16.
Abstract IA17: The global phospho-proteome of K-Ras mutant cells and tissues
Authors: Haigis Kevin
Published: December 2016

K-Ras is the most commonly mutated oncogene in cancer and it plays a predominant role in the pathogenesis of cancers of the pancreas, colon, and lung. Mutationally activated K-Ras influences cellular behaviors through broad and complex effects on downstream signal transduction pathways. In an effort to understand the molecular mechanisms underlying the oncogenic properties of mutant forms of K-Ras, we are using mass spectroscopy (MS) to quantify proteome-wide changes in protein phosphorylation in primary mouse tissues that are engineered to express mutant forms of K-Ras. In total, we have obtained relative quantification of 5,936 and 11,455 phospho-peptides from mouse pancreas and colon of varying K-Ras genotype. The dataset paints a complex picture of signaling downstream of K-Ras, as phosphorylation of many proteins in known Ras effector pathways (i.e. MAPK and PI3K) are unaffected or down-regulated by mutationally activated K-Ras. Moreover, we have found that different activating K-Ras alleles often have polar effects on the phosphorylation state of a given downstream protein. The biological significance of any given phosphorylation change in a large dataset such as this is often difficult to interpret, since the vast majority of quantified sites have no functional annotation. To combat this issue, we developed phospho-site set enrichment analysis (PSSEA), a computational tool that identifies kinases that are activated in a given sample based on the representation of known substrates in the phospho-MS dataset. PSSEA revealed, for example, that casein kinase 2 (Csnk2a1) is selectively activated by K-RasG12D in the pancreas, but not in the colon. Overall, this study provides an unprecedented view of K-Ras signaling on a global scale and reveals a variety of novel insights into the signal transduction properties of different K-Ras alleles. Ultimately, systems-level and bioinformatic analyses of these data will reveal new therapeutic targets for cancers expressing mutant forms of K-Ras.

Citation Format: Kevin Haigis.{Authors}. The global phospho-proteome of K-Ras mutant cells and tissues. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA17.
Abstract IA22: Reprograming the tumor microenvironment to facilitate responses to immunotherapy
Authors: DeNardo David Glenn
Published: December 2016

Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells.

We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy. The results of these pre-clinical studies have led to the development of a new clinical trial (NCT02546531) testing the combination of FAK inhibition (Defactinib) with Pembrolizumab and Gemcitabine in advanced PDAC Patients.

Citation Format: David Glenn DeNardo.{Authors}. Reprograming the tumor microenvironment to facilitate responses to immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA22.
Abstract IA23: Immune landscape of human pancreatic cancer
Authors: Balli David , Rech Andrew J. , Stanger Ben Z. , Vonderheide Robert H.
Published: December 2016

Survival rates for pancreatic ductal adenocarcinoma (PDA) remain dismal. Immunotherapy has the potential to improve outcomes, but clinical trial results – particularly those employing single-agent CTLA4 or PD1/PD-L1 inhibition – have thus far been disappointing. We stratified human PDA based on a signature of cytolytic T-cell activity. Differences in cytolytic index correlated with defined PDA subtypes and distinct mutational events. Specifically, PDA tumors with low cytolytic activity exhibited increased genomic structural variation, including reproducible copy number alterations in MYC, FGFR1, NOTCH2, and CDKN2. In contrast to other tumors such as kidney cancer or melanoma, PDA tumors with a high cytolytic index lacked an increased mutation or neo-epitope load. Tumors with high cytolytic activity exhibited increased expression of several immune checkpoint genes, but PD-L1 expression was uniformly low. These data establish a link between genomic alterations and immune activation in PDA and suggest that immune checkpoints other than PD-L1/PD-1 may be attractive therapeutic targets in this lethal disease.

Citation Format: David Balli, Andrew J. Rech, Ben Z. Stanger, Robert H. Vonderheide.{Authors}. Immune landscape of human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA23.
Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Authors: Olsen Sarah Naomi , Wronski Ania , Castaño Zafira , Dake Benjamin , Malone Clare , De Raedt Thomas , Enos Miriam , DeRose Yoko S. , Zhou Wenhui , Guerra Stephanie , Loda Massimo , Welm Alana , Partridge Ann H. , McAllister Sandra S. , Kuperwasser Charlotte , Cichowski Karen
Published: December 2016

Luminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR.

See related commentary by Sears and Gray, p. 131.

This article is highlighted in the In This Issue feature, p. 115
The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis
Authors: Goddard Erica T. , Hill Ryan C. , Nemkov Travis , D'Alessandro Angelo , Hansen Kirk C. , Maller Ori , Mongoue-Tchokote Solange , Mori Motomi , Partridge Ann H. , Borges Virginia F. , Schedin Pepper
Published: December 2016

Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ∼3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer.

Significance: We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177–87. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 115
Aquaporin Water Channels and Hydrocephalus
Authors: Verkman Alan S. , Tradtrantip Lukmanee , Smith Alex J. , Yao Xiaoming
Published: December 2016

The aquaporins (AQPs) are a family of water-transporting proteins that are broadly expressed in mammalian cells. Two AQPs in the central nervous system, AQP1 and AQP4, might play a role in hydrocephalus and are thus potential drug targets. AQP1 is expressed in the ventricular-facing membrane of choroid plexus epithelial cells, where it facilitates the secretion of cerebrospinal fluid (CSF). AQP4 is expressed in astrocyte foot processes and ependymal cells lining ventricles, where it appears to facilitate the transport of excess water out of the brain. Altered expression of these AQPs in experimental animal models of hydrocephalus and limited human specimens suggests their involvement in the pathophysiology of hydrocephalus, as do data in knockout mice demonstrating a protective effect of AQP1 deletion and a deleterious effect of AQP4 deletion in hydrocephalus. Though significant questions remain, including the precise contribution of AQP1 to CSF secretion in humans and the mechanisms by which AQP4 facilitates clearance of excess brain water, AQP1 and AQP4 have been proposed as potential drug targets to reduce ventricular enlargement in hydrocephalus.
High Dialysate Calcium Concentration May Cause More Sympathetic Stimulus During Hemodialysis
Authors: Jimenez Zaida N. C. , Silva Bruno C. , Reis Luciene dos , Castro Manuel C. M. , Ramos Camila D. , Costa-Hong Valeria , Bortolotto Luiz A. , Consolim-Colombo Fernanda , Dominguez Wagner V. , Oliveira Ivone B. , Moysés Rosa M. A. , Elias Rosilene M.
Published: December 2016

Background/Aims: Acute activation of sympathetic activation during hemodialysis is essential to maintain blood pressure (BP), albeit long-term overactivity contributes to higher mortality. Low heart rate variability (HRV), a measure of autonomic nervous system activity, and abnormal ankle-brachial index (ABI) are associated with higher mortality in patients on hemodialysis. In this study, we assessed HRV and ABI pre and post dialysis in incident patients on hemodialysis using high (1.75mmol/l) and low (1.25mmol/l) dialysate calcium concentration (DCa). Methods: HRV was measured as the ratio between low frequency and high frequency power (LF/HF). Thirty patients (age 47±16 years, 67% men) were studied in two consecutive mid-week hemodialysis sessions. Results: Mean BP variation was positive with DCa 1.75 and negative with DCa 1.25 [4.0 (-6.0, 12.2 mmHg) vs. -3.2 (-9.8, 1.3 mmHg); p=0.050]. Reduction of ABI from pre to post HD was related to higher sympathetic activity (p=0.031). The increase in LF/HF ratio was higher with DCa 1.75 (58.3% vs. 41.7% in DCa 1.75 and 1.25, respectively, RR 2.8; p=0.026). Conclusion: Although higher DCa is associated with better hemodynamic tolerability during hemodialysis, this occurs at the expense of increased sympathetic activity. Higher sympathetic activity was associated with a decrease of ABI during hemodialysis.
Management of Fetal and Neonatal Graves' Disease
Authors: Léger Juliane
Published: December 2016

Fetal and neonatal autoimmune hyperthyroidism is a rare, serious but transient disorder. Early diagnosis and treatment are key objectives for an optimal prognosis and the well-being of the child. This review focuses on the management of these patients during the fetal and neonatal periods. We propose a diagnostic algorithm for high-risk pregnancies in mothers with current or past hyperthyroidism related to Graves' disease, involving repeated fetal thyroid gland assessments from 20 weeks of gestation onwards and maternal serum thyroid-stimulating hormone receptor antibody (TRAb) determination, with close monitoring if TRAb levels exceed 2 to 3 times the upper limit of the normal range. In fetuses with goiter, the main clinical issue is determining whether the cause is (1) maternal antithyroid drug (ATD) treatment that is appropriate for achieving normal maternal thyroid function but inappropriate and excessive for the fetus, resulting in hypothyroidism and necessitating a decrease in the ATD dose during pregnancy, or (2) the presence of TRAbs resulting in fetal thyroid stimulation and hyperthyroidism, requiring an increase in the maternal ATD dose. Methimazole/carbimazole treatment should be initiated as soon as possible during the neonatal period, carefully managed and maintained over a period of 1-3 months and then stopped when TRAb is no longer detectable in serum.
Successful Therapy of Severe Pseudomembranous Clostridium difficile Colitis Using a Combination of Fecal Microbiota Therapy and Fidaxomicin
Authors: Konturek Peter C. , Haziri Drilon , Helfritzsch Harry , Hess Thomas , Harsch Igor A.
Published: December 2016

Objective: The aim of this work was to describe the use of a combination of fidaxomicin and fecal microbiota therapy (FMT) in Clostridium difficile infection (CDI). Clinical Presentation and Intervention: A 78-year-old female, who was admitted for surgery due to acute diverticulitis caused by postoperative complications and broad antibiotic therapy, developed CDI-induced colitis. Despite the introduction of metronidazole and vancomycin therapy, her clinical condition continued to deteriorate. She was transferred to the intensive care unit where FMT followed by fidaxomicin were performed because her C-reactive protein and leucocyte levels remained elevated. Further clinical improvement and the resolution of colitis was observed. Conclusion: In this case, severe CDI colitis was successfully treated with the combination of FMT and fidaxomicin.
Reasons for the persistent incidence of venous thromboembolism
Authors: Heit John A. , Ashrani Aneel A. , Crusan Daniel J. , McBane Robert D. , Petterson Tanya M. , Bailey Kent R.
Published: December 2016

Reasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981–2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981–2010, did not change significantly. Over the time period, 1988–2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981–2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one-third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Paradoxical bleeding and thrombotic episodes of dysprothrombinaemia due to a homozygous Arg382His mutation
Authors: Ding Qiulan , Yang Likui , Zhao Xiaoqing , Wu Wenman , Wang Xuefeng , Rezaie Alireza R.
Published: December 2016

We have characterised the pathogenic basis of dysprothrombinaemia in a patient exhibiting paradoxical bleeding and thrombotic defects during pregnancy and postpartum. Genetic analysis revealed that the proband is homozygous for the prothrombin Arg382His mutation, possessing only ~1 % clotting activity. The proband experienced severe bleeding episodes during her pregnancy, which required treatment with prothrombin complex concentrates, and then pulmonary embolism and deep-vein thrombosis at 28 days postpartum, which required treatment with LMWH and fresh frozen plasma. Analysis of haemostatic parameters revealed that the subject had elevated FDP and DD and decreased fibrinogen levels, indicating the presence of hyperfibrinolysis. Thrombin generation and clotting assays with the proband’s plasma in the presence of soluble thrombomodulin and tissue-type plasminogen activator indicated a defect in activation of both protein C and thrombin activatable fibrinolysis inhibitor (TAFI). Unlike normal plasma, no TAFI activation could be detected in the patient’s plasma. The expression and characterisation of recombinant prothrombin Arg382His indicated that zymogen activation by prothrombinase was markedly impaired and the activation of protein C and TAFI by thrombin-Arg382His was impaired 600-fold and 2500-fold, respectively. The recombinant thrombin mutant exhibited impaired catalytic activity toward both fibrinogen and PAR1 as determined by clotting and signalling assays. However, the mutant activated factor XI normally in both the absence and presence of polyphosphates. Arg382 is a key residue on (pro)exosite-1 of prothrombin and kinetic analysis of substrate activation suggested that the poor zymogenic activity of the mutant is due to its inability to bind factor Va in the prothrombinase complex.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Institutional Resilience, Deterrence and the Transition to Zero Nuclear Weapons
Authors: Kühn Ulrich
Published: December 2016

The goal of a world free from nuclear weapons is directly related to the issues of international institutions and deterrence. Assuming that it would be possible, first, to move to significantly lower numbers of nuclear weapons and then to zero nuclear weapons, governing institutions would have to be resilient enough to respond in a timely manner and to uphold the bargain. But what factors determine and influence institutional resilience? And what would be the likely role of deterrence? This article first assesses what the general ir narratives tell us about determining factors. It then examines two empirical cases from the realm of arms control institutions (the cfe and the npt treaties) and asks why these agreements are not as effective as intended. The next section discusses three additional factors of influence and identifies a shared interest in overcoming the deterrence principle as a key variable for institutional cooperation and as a factor that continues to influence resilience and effectiveness. The last section presents the conclusions.
The 22nd osce Ministerial Council Meeting in Belgrade
Authors: Liechtenstein Stephanie
Published: December 2016

This article analyses the outcome of the 22nd
osce Ministerial Council (mc) meeting, held in Belgrade on 3 and 4 December 2015, the year that the osce celebrated the 40th anniversary of the Helsinki Final Act, its founding document. The article argues that the mc meeting was characterized by entrenched positions and that it illustrated the distrust and deep divides among the 57 osce participating States. The article explains that the negotiation process was overshadowed by the ongoing Ukraine crisis and by a number of bilateral conflicts between states. The author specifies some of the bilateral conflicts and shows how they took direct influence on the negotiation process and how they led to the fall of important draft documents. As a result, the Belgrade mc adopted only 5 declarations, among them on combating violent extremism and radicalization and on combating illicit drug trafficking.
Insecurity and Common Interests in Security in the osce Area
Authors: Voorhoeve Joris
Published: December 2016

How can we improve security in the immense area of the fifty-seven participating states of the Organization for Security and Co-operation in Europe (osce)? The author addresses this question by appealing to the Final Report and Recommendations of the Panel of Eminent Persons on European Security as a Common Project. This Report is full of insights, and much of it is seen by the author as an honest account of the events and policies that divide osce countries. On the basis of the final report, the author offers twelve concrete recommendations that may promote trust in the osce area.
Looking North of Vienna: The Organization for Security and Co-operation in Europe as a Facilitator of Arctic Security
Authors: Narvestad Paul André
Published: December 2016

Though the Arctic is known as a region of peace, military activity and militarization continue to influence it. The literature on Arctic security asserts that no international organization exists that can deal with military issues in the region. This article challenges this assertion by arguing that the osce is the perfect organization to coordinate Arctic security because of its initial purpose of facilitating nato-Russia relations in Europe, which is precisely the same relationship that requires coordination in the Arctic today. Given that all eight Arctic states are members, the osce is almost a pre-existing security organization for the Arctic. The article examines the security environment in the Arctic, the current institutional regime and the origins of the osce. Furthermore, it explores osce csbms as empirical examples of how the osce already builds military predictability in the Arctic.
Peace, Terrorism, Armed Conflict and War Crimes
Authors: Zuijdewijn Jeanine de Roy van
Published: December 2016

Terrorism has often been associated with armed conflict. The so-called Islamic State is the most prominent example of a group that rose to power amidst armed conflict. Against this backdrop, it sounds rather strange to associate terrorism with peace. Terrorism, however, has also been called, “the peacetime equivalent of war crimes”. This raises the question how the concepts of terrorism, peace, armed conflict and war crimes relate. This article defines these concepts and applies them in the context of International Humanitarian Law, which is also known as the law of armed conflict. It also discusses today’s fight against is in light of the November 2015 Paris Attacks, thereby questioning the consequences and desirability of a war paradigm.
Preventing Terrorism in the Courtroom – The Criminalisation of Preparatory Acts of Terrorism in the Netherlands
Authors: van der Heide Liesbeth , Geenen Jip
Published: December 2016

The shift towards preventism in security refers to the process in which national security becomes the focal point of policymaking. Within this preventative shift, more and more policy instruments, including criminal law, are being drawn into the realm of national security. The determining argument in this debate is the idea that we are faced with wicked problems, unknown threats and unpredictable risks that we must somehow control. Potentially catastrophic consequences demand exceptional measures here and now to control the risks and govern the future. In recent years, there has been a growing trend in Europe to criminalise preparatory acts related to terrorism. This article examines this trend in The Netherlands and analyses how it plays out in the courtroom and to what extent the preventative logic has permeated the legal sphere.
A new Philippine endemic species and new records of Lasianthus (Lasiantheae, Rubiaceae)
Authors: ARSHED MUHAMMAD JEFTE C. , ALEJANDRO GRECEBIO JONATHAN D.
Published: December 2016

A new species named as Lasianthus halconensis from Mt. Halcon, Mindoro, Philippines is described and illustrated. This species is easily distinguished from the other Lasianthus by having strigose indumentum on branches, abaxial leaf surface, petioles and calyx; lanceolate leaves, cuneate at base; obconical calyx and drupes with 8 pyrenes. This species is allied to L. obliquinervis and L. chrysoneurus but differs in stem, leaf and calyx indumentum, leaf and calyx shape and the absence of bracts. Moreover, three new records of Lasianthus in the country are reported including their diagnosis.
A new species of Pleroma (Melastomataceae) endemic to Chapada Diamantina, Bahia, Brazil
Authors: FREITAS JULIANA GOMES , BERG CÁSSIO VAN DEN
Published: December 2016

Pleroma rubrum (Melastomataceae, Melastomeae), a new shrubby species endemic to rocky outcrops of Chapada Diamantina, northeastern Brazil, is here described, illustrated and compared with closely related taxa. The new taxon is easily distinguished, within the Tibouchina pereirae species complex, by its quadrangular distal branches with a crown of long hirsute trichomes around nodes, leaves elliptic-lanceolate with reddish margins and petioles, reddish inflorescence and bracteoles, colored stipitate glands on all reproductive structures, except the pedoconnectives, involucral bracteoles, and urceolate capsules.
Monophyly, review, six new species and DNA barcode of micropterous Afromontane Afropictinus (Heteroptera: Aradidae)
Authors: HEISS ERNST , GREBENNIKOV VASILY
Published: December 2016

The micropterous East African flat bug genus Afropictinus Heiss, 1986 (Heteroptera: Aradidae: Mezirinae) is revised. In addition to the type and only known species A. congoensis (Hoberlandt, 1956) from Rwanda, four new species from Tanzania (A. castor sp. nov., A. hylas sp. nov., A. idas sp. nov., A. nauplius sp. nov.), one new species from the Democratic Republic of the Congo (A. kahuzianus sp. nov.), and one new species from Ethiopia (A. nabu sp. nov.) are described and illustrated. An identification key is presented to all seven nominal species of Afropictinus. DNA barcodes of 28 individuals of Afropictinus species were newly generated and together with 12 sequences of other Aradidae were made publicly available at dx.doi.org/10.5883/DS-AFROPICT. These mtDNA sequences were analyzed phylogenetically using Maximum Likelihood approach with 500 bootstraps. Obtained topology reveals a monophyletic Afropictinus with high statistical support (84%), although its sister group remains elusive. Both specimens of non-Tanzanian Afropictinus species included in the study (A. kahuzianus and A. nabu) were nested among Tanzanian congeners. The internal clades within Afropictinus, except for those at species and population level, had lesser statistical support. Despite of intense sampling, no Afropictinus species was found in mountain forests of geologically young (<2 Ma) volcanic highlands of the Ngorongoro-Kilimanjaro Volcanic Belt, which suggest reduced dispersal capacities.
Positive Trend in the Antarctic Sea Ice Cover and Associated Changes in Surface Temperature
Authors: Comiso Josefino C. , Gersten Robert A. , Stock Larry V. , Turner John , Perez Gay J. , Cho Kohei
Published: December 2016

The Antarctic sea ice extent has been slowly increasing contrary to expected trends due to global warming and results from coupled climate models. After a record high extent in 2012 the extent was even higher in 2014 when the magnitude exceeded 20 × 106 km2 for the first time during the satellite era. The positive trend is confirmed with newly reprocessed sea ice data that addressed inconsistency issues in the time series. The variability in sea ice extent and ice area was studied alongside surface ice temperature for the 34-yr period starting in 1981, and the results of the analysis show a strong correlation of −0.94 during the growth season and −0.86 during the melt season. The correlation coefficients are even stronger with a one-month lag in surface temperature at −0.96 during the growth season and −0.98 during the melt season, suggesting that the trend in sea ice cover is strongly influenced by the trend in surface temperature. The correlation with atmospheric circulation as represented by the southern annular mode (SAM) index appears to be relatively weak. A case study comparing the record high in 2014 with a relatively low ice extent in 2015 also shows strong sensitivity to changes in surface temperature. The results suggest that the positive trend is a consequence of the spatial variability of global trends in surface temperature and that the ability of current climate models to forecast sea ice trend can be improved through better performance in reproducing observed surface temperatures in the Antarctic region.
Evaluation of Statistical Downscaling of North American Multimodel Ensemble Forecasts over the Western United States
Authors: Barbero Renaud , Abatzoglou John T. , Hegewisch Katherine C.
Published: December 2016

The skill of two statistical downscaled seasonal temperature and precipitation forecasts from the North American Multimodel Ensemble (NMME) was evaluated across the western United States at spatial scales relevant to local decision-making. Both statistical downscaling approaches, spatial disaggregation (SD) and bias correction spatial disaggregation (BCSD), exhibited similar correlative skill measures; however, the BCSD method showed superior tercile-based skill measures since it corrects for variance deflation in NMME ensemble averages. Geographic and seasonal variations in downscaled forecast skill revealed patterns across the complex topography of the western United States not evident using coarse-scale skill assessments, particularly in regions subject to inversions and variability in orographic precipitation ratios. Similarly, differences in the skill of cool-season temperature and precipitation forecasts issued when the fall El Niño–Southern Oscillation (ENSO) signal was strong versus ENSO-neutral years were evident across topographic gradients in the northwestern United States.
Experiencing and Responding to Everyday Weather in Darwin, Australia: The Important Role of Tolerance
Authors: de Vet Eliza
Published: December 2016

Climates are changing, yet the everyday implications for societies and cultures are unclear. Until recently, weather and climate (change) have been largely represented quantitatively and discussed at broad spatial and social scales. Qualitative weather research is helping to reconnect weather with its diverse local meanings and to explain how climate change may alter future representational and behavioral understands of weather (herein called “weather-relations”) in the hope of furthering climate change action. Responding to the need for greater research into weather-relations, particularly in industrialized urban areas, this paper examines the role of weather in everyday life in tropical Darwin, Australia. It identifies a willingness among participants to stay “weather-connected” despite challenging weather conditions and access to air conditioning. This willingness is driven by desires to remain acclimatized in order to enhance positive weather sensations, retain outdoor lifestyles, and reduce financial and environmental costs associated with resource-intensive technologies. In delving into weather adjustment strategies that facilitate weather-connectedness along with possible climate change implications, greater potential for weather-relations research is recognized. By drawing attention to weather experiences and understandings alongside resource efficient weather responses, this paper uncovered a substantial capacity among participants to respond sustainably to environmental change. These capacities are the outcome of adjustment practices relating to food, clothing, laundering, physical and outdoor activities, and domestic comfort and a previously unrecognized coping strategy—expressions of tolerance. Findings suggest that by recognizing and fostering existing adjustment capabilities of societies and cultures and the local values that afford their reproduction, communities would be better placed to adapt to future climate change.
SwitchFinder – a novel method and query facility for discovering dynamic gene expression patterns
Authors: Bulashevska Svetlana , Priest Colin , Speicher Daniel , Zimmermann Jörg , Westermann Frank , Cremers Armin B.
Published: December 2016

Background

Biological systems and processes are highly dynamic. To gain insights into their functioning time-resolved measurements are necessary. Time-resolved gene expression data captures temporal behaviour of the genes genome-wide under various biological conditions: in response to stimuli, during cell cycle, differentiation or developmental programs. Dissecting dynamic gene expression patterns from this data may shed light on the functioning of the gene regulatory system. The present approach facilitates this discovery. The fundamental idea behind it is the following: there are change-points (switches) in the gene behaviour separating intervals of increasing and decreasing activity, whereas the intervals may have different durations. Elucidating the switch-points is important for the identification of biologically meanigfull features and patterns of the gene dynamics.

Results

We developed a statistical method, called SwitchFinder, for the analysis of time-series data, in particular gene expression data, based on a change-point model. Fitting the model to the gene expression time-courses indicates switch-points between increasing and decreasing activities of each gene. Two types of the model - based on linear and on generalized logistic function - were used to capture the data between the switch-points. Model inference was facilitated with the Bayesian methodology using Markov chain Monte Carlo (MCMC) technique Gibbs sampling. Further on, we introduced features of the switch-points:growth,decay,spikeandcleft, which reflect important dynamic aspects. With this, the gene expression profiles are represented in a qualitative manner - as sets of the dynamic features at their onset-times. We developed a Web application of the approach, enabling to put queries to the gene expression time-courses and to deduce groups of genes with common dynamic patterns.

SwitchFinder was applied to our original data - the gene expression time-series measured in neuroblastoma cell line upon treatment with all-transretinoic acid (ATRA). The analysis revealed eight patterns of the gene expression responses to ATRA, indicating the induction of the BMP, WNT, Notch, FGF and NTRK-receptor signaling pathways involved in cell differentiation, as well as the repression of the cell-cycle related genes.

Conclusions

SwitchFinder is a novel approach to the analysis of biological time-series data, supporting inference and interactive exploration of its inherent dynamic patterns, hence facilitating biological discovery process. SwitchFinder is freely available at https://newbioinformatics.eu/switchfinder.
Interrelation between Laplace constants and the gradient distortion effect in Laplace-domain waveform inversion
Authors: Kwon Jungmin , Jin Hyojoon , Calandra Henri , Shin Changsoo
Published: December 2016

Laplace-domain waveform inversion (WI) is generally used to generate smooth initial velocity models for frequency- or time-domain full-waveform inversion. However, in the inversion results of Laplace-domain WI, anomalies such as salt domes are sometimes shifted. We evaluate the “gradient-distortion effect” that causes undesirable changes in parameter updates and found that this is caused by the relationship between the partial derivatives of Laplace wavefields with respect to two different parameters. By analyzing the gradient of the Laplace-domain misfit function, we found that the gradient distortion effect increases as the Laplace constants used in the Laplace-domain WI decrease. The velocity model inverted in the Laplace domain is generally blurred from shallower parameters to deeper parameters because the partial derivatives of the Laplace wavefields with respect to shallower parameters tend to be larger than those of deeper parameters. We found two solutions for suppressing the gradient distortion effect. The first one is the sequentially ordered Laplace constant approach with multiple Laplace constants. We discover that a dense, broad set of Laplace constants should be sequentially used in this approach. The second solution is the Gauss-Newton method, in which the Hessian matrix is considered. Numerical tests performed using a four-layer model and the BP benchmark model show the gradient distortion effect appeared in the inversion results and the effectiveness of the sequentially ordered Laplace constant approach. In addition, tests using an inverted BP benchmark model determine that the inversion results can be improved by applying a broad, dense set of Laplace constants to synthetic data. Finally, we verify the effectiveness of the Gauss-Newton method at suppressing the gradient distortion effect using the BP benchmark model.
A retrospective analysis of personality disorder presentations in a Canadian university-affiliated hospital's emergency department
Authors: Penfold Sarah , Groll Dianne , Mauer-Vakil Dane , Pikard Jennifer , Yang Megan , Mazhar Mir Nadeem
Published: December 2016

Background

Individuals with personality disorders often have extensive involvement with healthcare services including frequent utilisation of emergency departments.

Aims

The aim of this study was to identify factors associated with emergency department presentations by individuals with personality disorders.

Method

A 12-month retrospective data analysis of all mental-health-related emergency department visits was performed. Age, gender, time and season of presentation, length of stay, mode of arrival and discharge arrangements for individuals with personality disorders were compared to individuals with other psychiatric diagnoses.

Results

There were 336 visits by individuals with personality disorders and 5290 visits by individuals with other psychiatric diagnoses.

Individuals with personality disorders were significantly more likely to be female, young adults, brought in by police, arrive in the evening, discharged home and have a longer median length of stay.

Conclusion

Knowing what factors are associated with emergency department presentations by individuals with personality disorders can help ensure that appropriately trained support staff are available.
A Randomized Controlled Trial of Music Use During Epidural Catheter Placement on Laboring Parturient Anxiety, Pain, and Satisfaction
Authors: Drzymalski Dan M. , Tsen Lawrence C. , Palanisamy Arvind , Zhou Jie , Huang Chuan-Chin , Kodali Bhavani S.
Published: December 2016

BACKGROUND:

Although music is frequently used to promote a relaxing environment during labor and delivery, the effect of its use during the placement of neuraxial techniques is unknown. Our study sought to determine the effects of music use on laboring parturients during epidural catheter placement, with the hypothesis that music use would result in lower anxiety, lower pain, and greater patient satisfaction.

METHODS:

We conducted a prospective, randomized, controlled trial of laboring parturients undergoing epidural catheter placement with or without music. The music group listened to the patient’s preferred music on a Pandora® station broadcast through an external amplified speaker; the control group listened to no music. All women received a standardized epidural technique and local anesthetic dose. The primary outcomes were 3 measures of anxiety. Secondary outcomes included pain, patient satisfaction, hemodynamic parameters, obstetric parameters, neonatal outcomes, and anesthesia provider anxiety. Intention-to-treat analysis with Bonferroni correction was used for the primary outcomes. For secondary outcomes, a P value of <.001 was considered statistically significant.

RESULTS:

A total of 100 parturients were randomly assigned, with 99 included in the intention-to-treat analysis. Patient characteristics were similar in both groups; in the music group, the duration of music use was 31.1 ± 7.7 minutes (mean ± SD). The music group experienced higher anxiety as measured by Numeric Rating Scale scores immediately after epidural catheter placement (2.9 ± 3.3 vs 1.4 ± 1.7, mean difference 1.5 [95% confidence interval {CI} 0.2–2.7], P = .02), and as measured by fewer parturients being “very much relaxed” 1 hour after epidural catheter placement (51% vs 78%, odds ratio {OR} 0.3 [95% CI 0.1–0.9], P = .02). No differences in mean pain scores immediately after placement or patient satisfaction with the overall epidural placement experience were observed; however, the desire for music use with future epidural catheter placements was higher in the music group (84% vs 45%, OR 6.4 [95% CI 2.5–16.5], P < .0001). No differences in the difficulty with the epidural catheter placement or in the rate of cesarean delivery were observed.

CONCLUSIONS:

Music use during epidural catheter placement in laboring parturients is associated with higher postprocedure anxiety and no improvement in pain or satisfaction; however, a stronger desire for music with future epidural catheter placements was observed. Further investigation is needed to determine the effect of music use in parturients requesting and using epidural labor analgesia.