Enforcing Intellectual Property Rights: A Methodology for Understanding the Enforcement Problem in China

[Excerpt] “Intellectual property rights are neither protected nor enforced in strict uniformity throughout the world. However, it can be said that in most developed countries, intellectual property is preciously guarded, as evidenced by a plethora of intellectual property statutes, penalties for infringement, and consistent attempts to convince less developed nations to adopt strong—or stronger—intellectual property protections. Despite continued vigilance by developed countries in bringing about increased international harmony among intellectual property regimes, some developing countries sustain questionable enforcement policies. What the driving force is behind intellectual property enforcement policies—or more appropriately, the lack thereof—is a matter of disagreement. In order to predict whether or not a country that is currently not enforcing its laws will enforce them in the future, it is undoubtedly necessary to understand the factors driving a country’s current enforcement policy. For instance, cultural, economic, or political factors, or a combination thereof, may result in stricter enforcement practices, while others may discourage or delay them.

A Combined Limit on the Neutrino Mass from Neutrinoless Double-Beta Decay and Constraints on Sterile Majorana Neutrinos

We present a framework to combine data from the latest neutrinoless double-beta decay experiments for multiple isotopes and derive a limit on the effective neutrino mass using the experimental energy distributions. The combined limits on the effective mass range between 130-310 meV, where the spread is due to different model calculations of nuclear matrix elements (NMEs). The statistical consistency (p values) between this result and the signal observation claimed by the Heidelberg-Moscow experiment is derived. The limits on the effective mass are also evaluated in a (3+1) sterile neutrino model, assuming all neutrinos are Majorana particles.Comment: 8 pages, 8 figures. Version accepted by Phys Rev D, including latest CUORE-0 result

Transesophageal Echocardiographically-Confirmed Pulmonary Vein Thrombosis in Association with Posterior Circulation Infarction

Pulmonary venous thromboembolism has only been identified as a cause of stroke with pulmonary arteriovenous malformations/fistulae, pulmonary neoplasia, transplantation or lobectomy, and following percutaneous radiofrequency ablation of pulmonary vein ostia in patients with atrial fibrillation. A 59-year-old man presented with a posterior circulation ischemic stroke. ‘Unheralded’ pulmonary vein thrombosis was identified on transesophageal echocardiography as the likely etiology. He had no further cerebrovascular events after intensifying antithrombotic therapy. Twenty-eight months after initial presentation, he was diagnosed with metastatic pancreatic adenocarcinoma and died 3 months later. This report illustrates the importance of doing transesophageal echocardiography in presumed ‘cardioembolic’ stroke, and that potential ‘pulmonary venous thromboembolic’ stroke may occur in patients without traditional risk factors for venous thromboembolism. Consideration should be given to screening such patients for occult malignancy

Formalizing Atom-typing and the Dissemination of Force Fields with Foyer

A key component to enhancing reproducibility in the molecular simulation community is reducing ambiguity in the parameterization of molecular models. Ambiguity in molecular models often stems from the dissemination of molecular force fields in a format that is not directly usable or is ambiguously documented via a non-machine readable mechanism. Specifically, the lack of a general tool for performing automated atom-typing under the rules of a particular force field facilitates errors in model parameterization that may go unnoticed if other researchers are unable reproduce this process. Here, we present Foyer, a Python tool that enables users to define force field atom-typing rules in a format that is both machine- and human-readable thus eliminating ambiguity in atom-typing and additionally providing a framework for force field dissemination. Foyer defines force fields in an XML format, where SMARTS strings are used to define the chemical context of a particular atom type. Herein we describe the underlying methodology of the Foyer package, highlighting its advantages over typical atom-typing approaches and demonstrate is application in several use-cases.Comment: 39 Page, 4 Figures, 8 Listing

Towards Molecular Simulations that are Transparent, Reproducible, Usable By Others, and Extensible (TRUE)

Systems composed of soft matter (e.g., liquids, polymers, foams, gels, colloids, and most biological materials) are ubiquitous in science and engineering, but molecular simulations of such systems pose particular computational challenges, requiring time and/or ensemble-averaged data to be collected over long simulation trajectories for property evaluation. Performing a molecular simulation of a soft matter system involves multiple steps, which have traditionally been performed by researchers in a "bespoke" fashion, resulting in many published soft matter simulations not being reproducible based on the information provided in the publications. To address the issue of reproducibility and to provide tools for computational screening, we have been developing the open-source Molecular Simulation and Design Framework (MoSDeF) software suite. In this paper, we propose a set of principles to create Transparent, Reproducible, Usable by others, and Extensible (TRUE) molecular simulations. MoSDeF facilitates the publication and dissemination of TRUE simulations by automating many of the critical steps in molecular simulation, thus enhancing their reproducibility. We provide several examples of TRUE molecular simulations: All of the steps involved in creating, running and extracting properties from the simulations are distributed on open-source platforms (within MoSDeF and on GitHub), thus meeting the definition of TRUE simulations

Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principles governing heritability remain unclear. We take a quantitative computational modeling approach to describe propagation of histone H3K27 and H3K36 methylation states. We measure combinatorial H3K27 and H3K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that H3K27me3 on pre-existing histones stimulates the rate of de novo H3K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed quantitative picture of the mutual antagonism between H3K27 and H3K36 methylation and propose that it stabilizes epigenetic states across cell division

The role of topography, soil, and remotely sensed vegetation condition towards predicting crop yield

Foreknowledge of the spatiotemporal drivers of crop yield would provide a valuable source of information to optimize on-farm inputs and maximize profitability. In recent years, an abundance of spatial data providing information on soils, topography, and vegetation condition have become available from both proximal and remote sensing platforms. Given the wide range of data costs (between USD $0−50/ha), it is important to understand where often limited financial resources should be directed to optimize field production. Two key questions arise. First, will these data actually aid in better fine-resolution yield prediction to help optimize crop management and farm economics? Second, what level of priority should stakeholders commit to in order to obtain these data? Before fully addressing these questions a remaining challenge is the complex nature of spatiotemporal yield variation. Here, a methodological framework is presented to separate the spatial and temporal components of crop yield variation at the subfield level. The framework can also be used to quantify the benefits of different data types on the predicted crop yield as well to better understand the connection of that data to underlying mechanisms controlling yield. Here, fine-resolution (10 m) datasets were assembled for eight 64 ha field sites, spanning a range of climatic, topographic, and soil conditions across Nebraska. Using Empirical Orthogonal Function (EOF) analysis, we found the first axis of variation contained 60–85 % of the explained variance from any particular field, thus greatly reducing the dimensionality of the problem. Using Multiple Linear Regression (MLR) and Random Forest (RF) approaches, we quantified that location within the field had the largest relative importance for modeling crop yield patterns. Secondary factors included a combination of vegetation condition, soil water content, and topography. With respect to predicting spatiotemporal crop yield patterns, we found the RF approach (prediction RMSE of 0.2−0.4 Mg/ha for maize) was superior to MLR (0.3−0.8 Mg/ha). While not directly comparable to MLR and RF the EOF approach had relatively low error (0.5–1.7 Mg/ha) and is intriguing as it requires few calibration parameters (2–6 used here) and utilizes the climate-based aridity index, allowing for pragmatic long-term predictions of subfield crop yield

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471

Exploring Mechanisms of Action: Using a Testing Typology to Understand Intervention Performance in an HIV Self-Testing RCT in England and Wales.

SELPHI involves two interventions: (A) It provides one HIV self-testing (HIVST) kit; (B) It offers 3-monthly repeat HIVST kits if participants report ongoing risk. A logic model underpinned by the Behaviour Change Wheel informed the design of the intervention. SELPHI recruited 10,135 cis-men and trans people in England and Wales, all reporting anal sex with a man. This paper explores how the interventions were experienced and the pathways to impact for different groups of trial participants. In-depth interviews with 37 cis-men who have sex with men (MSM) were used to inductively categorise participants based on sexual and HIV testing histories. Themes relating to intervention experiences and impacts were mapped onto SELPHI-hypothesised intermediate outcomes to consider intervention impacts. Three groups were identified: 'Inexperienced testers' engaged with SELPHI to overcome motivational and social and physical opportunity testing barriers. For 'pro self-testers', testing frequency was constrained by psychological and social barriers and lack of opportunity. 'Opportunistic adopters' engaged in HIVST for novelty and convenience. Perceived impacts for inexperienced testers were most closely aligned with the logic model, but for opportunistic adopters there was little evidence of impact. Distinctive groups were discernible with divergent intervention experiences. Using COM-B as a model for understanding behaviour change in relation to HIVST, our results indicate how HIVST interventions could be adapted to respond to different needs based on the target population's demographic and behavioural features