bluuebunny/crossref_metadata_2025 huggingface dataset:
Ring Imaging Cherenkov Detector Technologies for Particle Identification in the Electron-Ion Collider Experiments
Authors: He X.
Published: May 2018

In the proposed Electron-Ion Collider (EIC) experiments, particle identification (PID) of the final state hadrons in the semi-inclusive deep inelastic scattering allows the measurement of flavor-dependent gluon and quark distributions inside nucleons and nuclei. The EIC PID consortium (eRD14 Collaboration) has been formed for identifying and developing PID detectors using Ring Imaging Cherenkov (RICH) techniques for the EIC experiments. A modular Ring Imaging Cherenkov (mRICH) detector has been designed for particle identification in the momentum coverage from 3 GeV/c to 10 GeV/c. The mRICH detector consists of an aerogel radiator block, a Fresnel lens, a mirror-wall and a photosensor plane. The first prototype of this detector was successfully tested at Fermi National Accelerator Laboratory in April 2016 for verifying the detector working principles. This talk will highlight the mRICH beam test results and their comparison with GEANT4-based detector simulations. An implementation of the mRICH detector concept in the Forward Angle sPHENIX spectrometer at BNL will also be mentioned in this talk.
Petroleum reservoir quality prediction: overview and contrasting approaches from sandstone and carbonate communities
Authors: Worden R. H. , Armitage P. J. , Butcher A. R. , Churchill J. M. , Csoma A. E. , Hollis C. , Lander R. H. , Omma J. E.
Published: May 2018

The porosity and permeability of sandstone and carbonate reservoirs (known as reservoir quality) are essential inputs for successful oil and gas resource exploration and exploitation. This chapter introduces basic concepts, analytical and modelling techniques and some of the key controversies to be discussed in 20 research papers that were initially presented at a Geological Society conference in 2014 titled ‘Reservoir Quality of Clastic and Carbonate Rocks: Analysis, Modelling and Prediction’. Reservoir quality in both sandstones and carbonates is studied using a wide range of techniques: log analysis and petrophysical core analysis, core description, routine petrographic tools and, ideally, less routine techniques such as stable isotope analysis, fluid inclusion analysis and other geochemical approaches. Sandstone and carbonate reservoirs both benefit from the study of modern analogues to constrain the primary character of sediment before they become a hydrocarbon reservoir. Prediction of sandstone and carbonate reservoir properties also benefits from running constrained experiments to simulate diagenetic processes during burial, compaction and heating. There are many common controls on sandstone and carbonate reservoir quality, including environment of deposition, rate of deposition and rate and magnitude of sea-level change, and many eogenetic processes. Compactional and mesogenetic processes tend to affect sandstone and carbonate somewhat differently but are both influenced by rate of burial, and the thermal and pressure history of a basin. Key differences in sandstone and carbonate reservoir quality include the specific influence of stratigraphic age on seawater composition (calcite v. aragonite oceans), the greater role of compaction in sandstones and the greater reactivity and geochemical openness of carbonate systems. Some of the key controversies in sandstone and carbonate reservoir quality focus on the role of petroleum emplacement on diagenesis and porosity loss, the role of effective stress in chemical compaction (pressure solution) and the degree of geochemical openness of reservoirs during diagenesis and cementation. This collection of papers contains case study-based examples of sandstone and carbonate reservoir quality prediction as well as modern analogue, outcrop analogue, modelling and advanced analytical approaches.
Quality of Experience-Centric Management of Adaptive Video Streaming Services
Authors: Petrangeli Stefano , Hooft Jeroen Van Der , Wauters Tim , Turck Filip De
Published: May 2018

Video streaming applications currently dominate Internet traffic. Particularly, HTTP Adaptive Streaming (HAS) has emerged as the dominant standard for streaming videos over the best-effort Internet, thanks to its capability of matching the video quality to the available network resources. In HAS, the video client is equipped with a heuristic that dynamically decides the most suitable quality to stream the content, based on information such as the perceived network bandwidth or the video player buffer status. The goal of this heuristic is to optimize the quality as perceived by the user, the so-called Quality of Experience (QoE). Despite the many advantages brought by the adaptive streaming principle, optimizing users’ QoE is far from trivial. Current heuristics are still suboptimal when sudden bandwidth drops occur, especially in wireless environments, thus leading to freezes in the video playout, the main factor influencing users’ QoE. This issue is aggravated in case of live events, where the player buffer has to be kept as small as possible in order to reduce the playout delay between the user and the live signal. In light of the above, in recent years, several works have been proposed with the aim of extending the classical purely client-based structure of adaptive video streaming, in order to fully optimize users’ QoE. In this article, a survey is presented of research works on this topic together with a classification based on where the optimization takes place. This classification goes beyond client-based heuristics to investigate the usage of server- and network-assisted architectures and of new application and transport layer protocols. In addition, we outline the major challenges currently arising in the field of multimedia delivery, which are going to be of extreme relevance in future years.
DarkCache
Authors: Zoni Davide , Colombo Luca , Fornaciari William
Published: May 2018

The Last Level Cache (LLC) is a key element to improve application performance in multi-cores. To handle the worst case, the main design trend employs tiled architectures with a large LLC organized in banks, which goes underutilized in several realistic scenarios. Our proposal, named
DarkCache
, aims at properly powering off such unused banks to optimize the Energy-Delay Product (EDP) through an adaptive cache reconfiguration, thus aggressively reducing the leakage energy. The implemented solution is general and it can recognize and skip the activation of the
DarkCache
policy for the few strong memory intensive applications that actually require the use of the entire LLC. The validation has been carried out on 16- and 64-core architectures also accounting for two state-of-the-art methodologies. Compared to the baseline solution,
DarkCache
exhibits a performance overhead within 2% and an average EDP improvement of 32.58% and 36.41% considering 16 and 64 cores, respectively. Moreover,
DarkCache
shows an average EDP gain between 16.15% (16 cores) and 21.05% (64 cores) compared to the best state-of-the-art we evaluated, and it confirms a good scalability since the gain improves with the size of the architecture.
Cross-Layer Memory Management to Improve DRAM Energy Efficiency
Authors: Olson Matthew Benjamin , Teague Joseph T. , Rao Divyani , JANTZ Michael R. , Doshi Kshitij A. , Kulkarni Prasad A.
Published: May 2018

Controlling the distribution and usage of memory power is often difficult, because these effects typically depend on activity across multiple layers of the vertical execution stack. To address this challenge, we construct a novel and collaborative framework that employs object placement, cross-layer communication, and page-level management to effectively distribute application objects in the DRAM hardware to achieve desired power/performance goals. This work describes the design and implementation of our framework, which is the first to integrate automatic object profiling and analysis at the application layer with fine-grained management of memory hardware resources in the operating system. We demonstrate the utility of this framework by employing it to control memory power consumption more effectively. First, we design a custom memory-intensive workload to show the potential of this approach to reduce DRAM energy consumption. Next, we develop sampling and profiling-based analyses and modify the code generator in the HotSpot VM to understand object usage patterns and
automatically
control the placement of hot and cold objects in a partitioned VM heap. This information is communicated to the operating system, which uses it to map the logical application pages to the appropriate DRAM modules according to user-defined provisioning goals. The evaluation shows that our Java VM-based framework achieves our goal of significant DRAM energy savings across a variety of workloads, without any source code modifications or recompilations.
Ensemble of Deep Models for Event Recognition
Authors: Ahmad Kashif , Mekhalfi Mohamed Lamine , Conci Nicola , Melgani Farid , Natale Francesco De
Published: May 2018

In this article, we address the problem of recognizing an event from a single related picture. Given the large number of event classes and the limited information contained in a single shot, the problem is known to be particularly hard. To achieve a reliable detection, we propose a combination of multiple classifiers, and we compare three alternative strategies to fuse the results of each classifier, namely: (i) induced order weighted averaging operators, (ii) genetic algorithms, and (iii) particle swarm optimization. Each method is aimed at determining the optimal weights to be assigned to the decision scores yielded by different deep models, according to the relevant optimization strategy. Experimental tests have been performed on three event recognition datasets, evaluating the performance of various deep models, both alone and selectively combined. Experimental results demonstrate that the proposed approach outperforms traditional multiple classifier solutions based on uniform weighting, and outperforms recent state-of-the-art approaches.
AAAI/ACM SIGAI job fair 2018
Authors: Dickerson John P , Mattei Nicholas
Published: May 2018

The 2018 AAAI/ACM SIGAI Job fair marked the third installment of the popular event for both recruiters and students. As we have seen steady growth in the attendance at AAAI over the last several years we have seen similar growth in the number of companies and students who are actively participating in the job fair. This year, twenty-one companies attended---typically with a team of recruiters and other representatives---and hundreds of students and other job seekers either uploaded their resumes to a public book before the event or came through the event space during the event. Those resumes were then shared with participating companies.
Artificial intelligence in 2027
Authors: Gini Maria , Agmon Noa , Giunchiglia Fausto , Koenig Sven , Leyton-Brown Kevin
Published: May 2018

Every day we read in the scientific and popular press about advances in AI and how AI is changing our lives. Things are moving at a fast pace, with no obvious end in sight.
A pipeline-based heterogeneous framework for efficient synthetic light field rendering
Authors: Kao Chih-Chen , Tseng Liang-Chi , Hsu Wei-Chung
Published: May 2018

The research interest of real-time global illumination has increased due to the growing demand of graphics applications such as virtual reality. Recently, the design that combines Image-Based Rendering (IBR) and Ray-Tracing to create Synthetic Light Field (SLF) has been widely adopted to provide delicate visual experience for multiple viewpoints at an acceptable frame rate. However, despite its parallel characteristic, constructing a SLF is still inefficient on modern Graphics Processing Unit (GPU) due to the irregularities. For instance, the issues caused by branch divergence, early-termination and irregular memory access prolong the execution time that cannot be simply resolved by workload merging. In this paper, we proposed a Runtime framework that reorganizes the execution into a pipeline-based pattern with grouping of primary rays. The workloads are later distributed to all heterogeneous cores to increase the efficiency of the execution. With this approach, the number of valid rays can be maintained at a high level with less divergence of paths. Based on the experiment on a heterogeneous system, the maximum throughput for a single GPU becomes 3.12 times higher than the original on average and becomes even higher on systems with multiple heterogeneous cores.
Member spotlight
Authors: Doyle Maureen
Published: May 2018

In this feature of the Bulletin, we highlight members of the SIGCSE community. In this issue, Bulletin co-editor Maureen Doyle interviewed Jane Prey. Jane is retired and still very active in the CS Education community.
Broadening participation
Authors: Russell Erik , Hirschberg Julia , Martonosi Margaret
Published: May 2018

The Computing Research Association's Committee on the Status of Women in Computing Research (CRA-W) was established in 1991 to increase the participation and success of women in computing research. CRA-W is currently co-chaired by Julia Hirschberg (Columbia University) and Margaret Martonosi (Princeton University) who lead an active volunteer board of 26 successful researchers from academia, government labs, and industry. Increasingly, CRA-W's portfolio has broadened to include under-represented minority men in many programs as well. Visit CRA-W.org to learn more about our many programs for undergraduate and graduate students, early- and mid-career faculty, and researchers in government labs and industry.
C Is Not a Low-level Language
Authors: Chisnall David
Published: May 2018

In the wake of the recent Meltdown and Spectre vulnerabilities, it’s worth spending some time looking at root causes. Both of these vulnerabilities involved processors speculatively executing instructions past some kind of access check and allowing the attacker to observe the results via a side channel. The features that led to these vulnerabilities, along with several others, were added to let C programmers continue to believe they were programming in a low-level language, when this hasn’t been the case for decades.
The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair
Authors: Syed Aleem , Tainer John A.
Published: May 2018

Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and enabling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.
Defining Phenotypes from Clinical Data to Drive Genomic Research
Authors: Robinson Jamie R. , Wei Wei-Qi , Roden Dan M. , Denny Joshua C.
Published: May 2018

The rise in available longitudinal patient information in electronic health records (EHRs) and their coupling to DNA biobanks have resulted in a dramatic increase in genomic research using EHR data for phenotypic information. EHRs have the benefit of providing a deep and broad data source of health-related phenotypes, including drug response traits, expanding the phenomes available to researchers for discovery. The earliest efforts at repurposing EHR data for research involved manual chart review of limited numbers of patients but now typically involve applications of rule-based and machine learning algorithms operating on sometimes huge corpora for both genome-wide and phenome-wide approaches. In this review, we highlight the current methods, impact, challenges, and opportunities for repurposing clinical data to define patient phenotypes for genomic discovery. Use of EHR data has proven a powerful method for elucidating genomic influences on diseases, traits, and drug-response phenotypes and will continue to have increasing applications in large cohort studies.
Deep Learning in Biomedical Data Science
Authors: Baldi Pierre
Published: May 2018

Since the 1980s, deep learning and biomedical data have been coevolving and feeding each other. The breadth, complexity, and rapidly expanding size of biomedical data have stimulated the development of novel deep learning methods, and application of these methods to biomedical data have led to scientific discoveries and practical solutions. This overview provides technical and historical pointers to the field, and surveys current applications of deep learning to biomedical data organized around five subareas, roughly of increasing spatial scale: chemoinformatics, proteomics, genomics and transcriptomics, biomedical imaging, and health care. The black box problem of deep learning methods is also briefly discussed.
Big Data Approaches for Modeling Response and Resistance to Cancer Drugs
Authors: Jiang Peng , Sellers William R. , Liu X. Shirley
Published: May 2018

Despite significant progress in cancer research, current standard-of-care drugs fail to cure many types of cancers. Hence, there is an urgent need to identify better predictive biomarkers and treatment regimes. Conventionally, insights from hypothesis-driven studies are the primary force for cancer biology and therapeutic discoveries. Recently, the rapid growth of big data resources, catalyzed by breakthroughs in high-throughput technologies, has resulted in a paradigm shift in cancer therapeutic research. The combination of computational methods and genomics data has led to several successful clinical applications. In this review, we focus on recent advances in data-driven methods to model anticancer drug efficacy, and we present the challenges and opportunities for data science in cancer therapeutic research.
Alignment-Free Sequence Analysis and Applications
Authors: Ren Jie , Bai Xin , Lu Yang Young , Tang Kujin , Wang Ying , Reinert Gesine , Sun Fengzhu
Published: May 2018

Genome and metagenome comparisons based on large amounts of next-generation sequencing (NGS) data pose significant challenges for alignment-based approaches due to the huge data size and the relatively short length of the reads. Alignment-free approaches based on the counts of word patterns in NGS data do not depend on the complete genome and are generally computationally efficient. Thus, they contribute significantly to genome and metagenome comparison. Recently, novel statistical approaches have been developed for the comparison of both long and shotgun sequences. These approaches have been applied to many problems, including the comparison of gene regulatory regions, genome sequences, metagenomes, binning contigs in metagenomic data, identification of virus–host interactions, and detection of horizontal gene transfers. We provide an updated review of these applications and other related developments of word count–based approaches for alignment-free sequence analysis.
Radical Decentralization: Does Community-Driven Development Work?
Authors: Casey Katherine
Published: May 2018

Classic arguments for decentralization, augmented by ideas about how participation empowers the poor, motivate the widely used approach in foreign aid called community-driven development (CDD). CDD devolves control over the selection, implementation, and financial management of public goods to communities. Until recently, policy enthusiasm has outstripped the evidence. I synthesize findings from randomized controlled trials and find that CDD effectively delivers public goods and modest economic returns at low cost in difficult environments. There is little evidence, however, that CDD transforms local decision making or empowers the poor in any enduring way. Part of this failure may be because some constraints believed to be important—like insufficient social capital—appear not to bind. Others, like exclusive local institutions, are a problem, although not one that CDD remedies. These results present a conundrum: How much participation is enough to safeguard the gains of such extreme decentralization while minimizing the opportunity costs imposed on poor people's time?
Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data
Authors: Burgess Stephen , Foley Christopher N. , Zuber Verena
Published: May 2018

An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences?
The Use of Amicus Briefs
Authors: Collins Paul M.
Published: May 2018

Judicial decisions play an important role in shaping public policy. Recognizing this, interest groups and other entities lobby judges in an attempt to translate their policy preferences into law. One of the primary vehicles for doing so is the amicus curiae brief. Through these legal briefs, amici can attempt to influence judicial outcomes while attending to organizational maintenance concerns. This article examines scholarship on the use of amicus briefs pertaining to five main areas: ( a) why amicus briefs are filed, ( b) who files amicus briefs and in what venues, ( c) the content of amicus briefs, ( d) the influence of amicus briefs, and ( e) normative issues implicated in the amicus practice. In addition to presenting a critical review of the scholarship in these areas, this article also provides suggestions for future research on amicus briefs.
The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time
Authors: Ramirez Jan-Marino , Baertsch Nathan A.
Published: May 2018

Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time.
Memory Allocation: Mechanisms and Function
Authors: Josselyn Sheena A. , Frankland Paul W.
Published: May 2018

Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry.
Viral Strategies for Targeting the Central and Peripheral Nervous Systems
Authors: Bedbrook Claire N. , Deverman Benjamin E. , Gradinaru Viviana
Published: May 2018

Recombinant viruses allow for targeted transgene expression in specific cell populations throughout the nervous system. The adeno-associated virus (AAV) is among the most commonly used viruses for neuroscience research. Recombinant AAVs (rAAVs) are highly versatile and can package most cargo composed of desired genes within the capsid's ∼5-kb carrying capacity. Numerous regulatory elements and intersectional strategies have been validated in rAAVs to enable cell type–specific expression. rAAVs can be delivered to specific neuronal populations or globally throughout the animal. The AAV capsids have natural cell type or tissue tropism and trafficking that can be modified for increased specificity. Here, we describe recently engineered AAV capsids and associated cargo that have extended the utility of AAVs in targeting molecularly defined neurons throughout the nervous system, which will further facilitate neuronal circuit interrogation and discovery.
International Climate Change Policy
Authors: Chan Gabriel , Stavins Robert , Ji Zou
Published: May 2018

International cooperation to address the threat of climate change has become more institutionally diverse over the past decade, reflecting multiple scales of governance and the growing inclusion of climate change issues in other policy arenas. Cooperation under the United Nations Framework Convention on Climate Change has continued to evolve from the 1997 Kyoto Protocol to the 2015 Paris Agreement, while other governmental and private sector international fora for cooperation have arisen. As the level of activity in international cooperation on climate change mitigation has increased, so too has the related scholarly literature. In this review, we synthesize the literature on international climate change cooperation and identify key policy implications, as well as those findings most relevant for the research community. Our scope includes critical evaluation of the organization and implementation of agreements and instruments, retrospective analysis of cooperative efforts, and explanations of successes and failures.
Consumer Credit in Comparative Perspective
Authors: Rona-Tas Akos , Guseva Alya
Published: May 2018

We review the literature in sociology and related fields on the fast global growth of consumer credit and debt and the possible explanations for this expansion. We describe the ways people interact with the strongly segmented consumer credit system around the world—more specifically, the way they access credit and the way they are held accountable for their debt. We then report on research on two areas in which consumer credit is consequential: its effects on social relations and on physical and mental health. Throughout the article, we point out national variations and discuss explanations for these differences. We conclude with a brief discussion of the future tasks and challenges of comparative research on consumer credit.
Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non–Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab
Authors: Higgs Brandon W. , Morehouse Christopher A. , Streicher Katie , Brohawn Philip Z. , Pilataxi Fernanda , Gupta Ashok , Ranade Koustubh
Published: May 2018

Purpose: To identify a predictive biomarker for durvalumab, an anti–programmed death ligand 1 (PD-L1) mAb.

Experimental Design: RNA sequencing of 97 advanced-stage non–small cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with ≥25% tumor cells and urothelial cancer with ≥25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD-L1+). Kaplan–Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG status, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA).

Results: In the NSCLC discovery set, a four-gene IFNγ-positive (IFNγ+) signature comprising IFNγ, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFNγ+-signature NSCLC patients had improved survival regardless of IHC PD-L1 status. These associations were replicated in a urothelial cancer cohort. The IFNγ+ signature was induced 2-fold (P = 0.003) by durvalumab after 8 weeks of therapy in patients with NSCLC, and baseline signature was associated with TMB but not survival in TCGA data.

Conclusions: The IFNγ+ mRNA signature may assist in identifying patients with improved outcomes with durvalumab, independent of PD-L1 assessed by IHC. Clin Cancer Res; 24(16); 3857–66. ©2018 AACR.
CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies
Authors: Bacac Marina , Colombetti Sara , Herter Sylvia , Sam Johannes , Perro Mario , Chen Stanford , Bianchi Roberta , Richard Marine , Schoenle Anne , Nicolini Valeria , Diggelmann Sarah , Limani Florian , Schlenker Ramona , Hüsser Tamara , Richter Wolfgang , Bray-French Katharine , Hinton Heather , Giusti Anna Maria , Freimoser-Grundschober Anne , Lariviere Laurent , Neumann Christiane , Klein Christian , Umaña Pablo
Published: May 2018

Purpose: Despite promising clinical activity, T-cell–engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug.

Experimental Design: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug.

Results: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell–binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD.

Conclusions: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). Clin Cancer Res; 24(19); 4785–97. ©2018 AACR.

See related commentary by Prakash and Diefenbach, p. 4631
Prospective Randomized Biomarker Study of Metformin and Lifestyle Intervention for Prevention in Obese Women at Increased Risk for Endometrial Cancer
Authors: Yates Melinda S. , Coletta Adriana M. , Zhang Qian , Schmandt Rosemarie E. , Medepalli Meena , Nebgen Denise , Soletsky Beth , Milbourne Andrea , Levy Erma , Fellman Bryan , Urbauer Diana , Yuan Ying , Broaddus Russell R. , Basen-Engquist Karen , Lu Karen
Published: May 2018

Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) × 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (−4.23 kg, P = 0.006) and total fat mass (−3.23 kg, P < 0.001). Participants receiving metformin lost 3.43 kg of weight (P = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Cancer Prev Res; 11(8); 477–90. ©2018 AACR.
Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy
Authors: Trembley Michael A. , Quijada Pearl , Agullo-Pascual Esperanza , Tylock Kevin M. , Colpan Mert , Dirkx Ronald A. , Myers Jason R. , Mickelsen Deanne M. , de Mesy Bentley Karen , Rothenberg Eli , Moravec Christine S. , Alexis Jeffrey D. , Gregorio Carol C. , Dirksen Robert T. , Delmar Mario , Small Eric M.
Published: May 2018

Background:

Hypertrophic cardiomyocyte growth and dysfunction accompany various forms of heart disease. The mechanisms responsible for transcriptional changes that affect cardiac physiology and the transition to heart failure are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling cardiomyocyte force transmission and propagation of electrical activity. The ID is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy.

Methods:

Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor (MRTF)-A and MRTF-B specifically in adult cardiomyocytes to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling.

Results:

We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure. Although mice lacking MRTFs in adult cardiomyocytes display normal cardiac physiology at baseline, pressure overload leads to rapid heart failure characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and cardiomyocyte adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by single-molecule localization microscopy may partially stem from a reduction in
Mapre1
expression, which we show is a direct mechanosensitive MRTF target.

Conclusions:

Our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates cross-talk between the actin and microtubule cytoskeleton and maintains ID integrity and cardiomyocyte homeostasis in heart disease.
Public Theology and the Present Debate on Whiteness in the Democratic South Africa
Authors: de Villiers D. Etienne
Published: May 2018

During the last decade there has been an intense public debate in the South African society on the issue of ‘whiteness’ or ‘whiteliness’. In this article the challenges whiteness and the debate surrounding it pose for practitioners of public theology in South Africa are explored. In the first part some of the origins of the debate on whiteness, as well as some of the main features of whiteness researchers identify, are traced. In the second part a brief sketch is provided of two different kinds of critical response to whiteness in the present South African society, namely critical responses to structural whiteness and critical responses of a more personal nature. In the third part the challenges the present debate on whiteness pose to public theology in South Africa are identified and discussed.
Economic Inequality: Economics and Theology in Dialogue
Authors: Naudé Piet J. , du Plessis Stan
Published: May 2018

This essay is a bi-disciplinary effort in applied ethics by a theologian and an economist who both share the convictions of the Christian faith and wish to demonstrate the significance of this faith for the vexing question of economic inequality. Following the see- judge- act- model often used in public theology, it examines first conceptual matters in order to define economic inequality and undertake a limited descriptive task to get a clearer empirical picture of what economic inequality entails. There is then a moral assessment of economic inequalities (“judge”) where ethically acceptable and objectionable aspects of inequality from the economic and theological perspectives are distinguished. From these perspectives, this essay concludes with possible interventions and actions (“act”) to reduce morally unacceptable forms of economic inequality and scope for co-operative efforts between economics and public theology in this area.
Who Are “the People”? Populism, the “Othered”, and the Public Identity of a Minority Church in Europe
Authors: Field David N.
Published: May 2018

In the context of a rising populism and the othering of migrating minorities this article proposes that a reconstruction of the public identity of a minority Church (The United Methodist Church) provides an important disruptive element directed toward a more just and inclusive democracy. The article draws on biblical and traditional resources, particularly those from within the Methodism to develop an alternative vision of the church. These resources are then brought into dialogue with the Swiss concept of an Eidegenossenschaft in order to propose an image of the church as God’s Eidgenossenschaft as contextually relevant and potentially fruitful way of imagining the church.
Experiments in (Radical) Public Theology: In Conversation with Critchley and Caputo
Authors: Ullrich Calvin Dieter
Published: May 2018

This article seeks to offer insights into what is called a radical public theology. Such a theology views contemporary religious uncertainty as an opportunity rather than as a site for apologetic resistance. The article sketches the linguistic-hermeneutic turn, before reflecting on an example of a new proposal of faith from the philosopher Simon Critchley. In conversation with the prominent radical theologian, John D. Caputo, the article argues that Critchley’s (ir)religious faith can be read idiomatically as a radical theology. This reading carves a space for a public theological reflection, which is ‘public’ because it engages and is responsive to the call of ‘the least of these’ in society. Finally, it is argued that a radical public theology offers resources toward the notion of ‘meontological communities,’ functioning to deepen theological reflection on the public nature of faith and life of the church.
Calotropis procera, Apple of Sodom
Authors: Yaniv Zohara , Koltai Hinanit
Published: May 2018

The desert plant, Calortopis procera, known also as the apple of Sodom, is an important but less known medicinal plant. This plant has many ethnic medicinal uses especially for skin-related symptoms in the countries of its origin: India, Africa, Saudi, Yemen, Lebanon, Israel, Jordan, Sudan, Iran, and Afghanistan. The plant is also known and used in traditional medicine in South and tropical America, due to its introduction and cultivation in that part of the world. Skin problems treated by the plant include: wounds, scabies, sores, external infections, swellings, rheumatic pains, leprosy, toothaches, eczema and even the treatment of paralyzed limbs. Other traditional uses include: asthma, cough, diarrhea, malaria, cancer, dysentery jaundice and many more. An insight into the scientific activity of C. procera derived extracts and compounds suggest that these extracts have antidiabetic, anticancer, anti-inflammatory and antibacterial activities. Moreover, a compound with high activity against cancer cell was developed from cardenolides present in C. procera root bark, presenting a significant prospect in the use of this plant for modern medicine. The purpose of this communication is to review the full extent of the ethnobotanical uses of the apple of Sodom, and to shed a light on this high-potential lesser-known desert medicinal plant.
Two new species of Pisolithus (Sclerodermataceae) from Australasia, and an assessment of the confused nomenclature of P. tinctorius
Authors: LEBEL TERESA , PENNYCOOK SHAUN , BARRETT MATTHEW
Published: May 2018

Based on morphological data and ITS nrDNA sequence analyses, we formally describe two species from the phylogenetic grouping ‘Martin sp. 10’ as Pisolithus thermaeus sp. nov., endemic to New Zealand, and P. tympanobaculus sp. nov. from Australia. All Pisolithus species in New Zealand are restricted in distribution to geothermally active areas, in ectomycorrhizal association with Kunzea tenuicaulis. In Australia species occur in a broad range of habitats in association with Eucalyptus or Acacia species; and in New Caledonia species form associations with various Myrtaceae or an Acacia species. The distribution ranges of Pisolithus albus, P. marmoratus and P. croceorrhizus are extended to include the Kimberley and Top End regions of northern Australia. We also confirm that neither P. arenarius, nor P. tinctorius sensu stricto, nor P. arhizus are currently known to occur in Australia or New Zealand. The long-used but never formalized combination Pisolithus albus (Cooke & Massee) Priest is validated here and nomenclatural knots relating to three different usages of the name Pisolithus tinctorius are unraveled and suggestions made for their resolution.
Simple Estimates of Polar Amplification in Moist Diffusive Energy Balance Models
Authors: Merlis Timothy M. , Henry Matthew
Published: May 2018

Diffusive energy balance models (EBMs) that use moist static energy, rather than temperature, as the thermodynamic variable to determine the energy transport provide an idealized framework to understand the pattern of radiatively forced surface warming. These models have a polar amplified warming pattern that is quantitatively similar to general circulation model simulations. Even without surface albedo changes or other spatially varying feedbacks, they simulate polar amplification that results from increased poleward energy transport with warming. Here, two estimates for polar amplification are presented that do not require numerical solution of the EBM governing equation. They are evaluated relative to the results of numerical moist EBM solutions. One estimate considers only changes in a moist thermodynamic quantity (assuming that the increase in energy transport results in a spatially uniform change in moist static energy in the warmed climate) and has more polar amplification than the EBM solution. The other estimate uses a new solution of a truncated form of the moist EBM equation, which allows for a temperature change that is consistent with both the dry and latent energy transport changes, as well as radiative changes. The truncated EBM solution provides an estimate for polar amplification that is nearly identical to that of the numerical EBM solution and only depends on the EBM parameters and climatology of temperature. This solution sheds light on the dependence of polar amplification on the climatological temperature distribution and offers an estimate of the residual polar warming in solar radiation management geoengineered climates.
Track and Circulation Analysis of Tropical and Extratropical Cyclones that Cause Strong Precipitation and Streamflow Events in the New York City Watershed
Authors: Towey Katherine L. , Booth James F. , Frei Allan , Sinclair Mark R.
Published: May 2018

The top 100 basin-scale 1-day precipitation, multiday precipitation, and 1-day streamflow events from 1950 to 2012 are examined for the Ashokan reservoir, a key water source for New York City. Through a cyclone association algorithm, extratropical cyclones (ETCs) are found to be associated with the majority of the top 100 precipitation and streamflow events. Tropical cyclones (TCs) generate the second-most top 100 one-day and multiday precipitation events, with more than two-thirds of these TCs having undergone extratropical transition. Furthermore, TCs that pass over the region are approximately 7 and 4 times more likely to generate a top 100 one-day precipitation and one-day streamflow event, respectively, than ETCs. Lagrangian cyclone track analysis shows cool season ETCs take a more meridional path compared to warm season ETCs. A composite analysis shows that for the top 100 one-day precipitation events, ETCs have relatively less moisture but stronger upper-level support than TCs. Due in part to TCs, heavy precipitation events occur more often in the warm season, whereas high streamflow events occur mainly in the cool season. Despite this difference, approximately 43% of the top 100 events, which represent many of the very strongest events, overlap for all three metrics. While high temperature and specific humidity anomalies accompany all top 100 events, the magnitude of the anomalies is greatest for isolated streamflow events. This analysis provides a reference to forecasters and water managers regarding the relative and synoptic-scale behavior of different storm types for isolated and concurrent precipitation and streamflow events.