Head-on and co-directional RNA polymerase collisions orchestrate bidirectional transcription termination.

Genomic DNA is a crowded track where motor proteins frequently collide. It remains underexplored whether these collisions carry physiological function. In this work, we develop a single-molecule assay to visualize the trafficking of individual E. coli RNA polymerases (RNAPs) on DNA. Based on transcriptomic data, we hypothesize that RNAP collisions drive bidirectional transcription termination of convergent gene pairs. Single-molecule results show that the head-on collision between two converging RNAPs is necessary to prevent transcriptional readthrough but insufficient to release the RNAPs from the DNA. Remarkably, co-directional collision of a trailing RNAP into the head-on collided complex dramatically increases the termination efficiency. Furthermore, stem-loop structures formed in the nascent RNA are required for collisions to occur at well-defined positions between convergent genes. These findings suggest that physical collisions between RNAPs furnish a mechanism for transcription termination and that programmed genomic conflicts can be exploited to co-regulate the expression of multiple genes.

Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies.

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.

Automated Crystal Orientation Mapping in py4DSTEM using Sparse Correlation Matching.

Crystalline materials used in technological applications are often complex assemblies composed of multiple phases and differently oriented grains. Robust identification of the phases and orientation relationships from these samples is crucial, but the information extracted from the diffraction condition probed by an electron beam is often incomplete. We have developed an automated crystal orientation mapping (ACOM) procedure which uses a converged electron probe to collect diffraction patterns from multiple locations across a complex sample. We provide an algorithm to determine the orientation of each diffraction pattern based on a fast sparse correlation method. We demonstrate the speed and accuracy of our method by indexing diffraction patterns generated using both kinematical and dynamical simulations. We have also measured orientation maps from an experimental dataset consisting of a complex polycrystalline twisted helical AuAgPd nanowire. From these maps we identify twin planes between adjacent grains, which may be responsible for the twisted helical structure. All of our methods are made freely available as open source code, including tutorials which can be easily adapted to perform ACOM measurements on diffraction pattern datasets.

Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.

SEND harmonization & cross-study analysis: A proposal to better harvest the value from SEND data.

The Standard for Exchange of Nonclinical Data (SEND) identifies an approach for representing nonclinical data in a structured format which has been widely adopted by the pharmaceutical industry as it is required for data submission to the United States Food & Drug Administration (US FDA). The SEND Implementation Guide (SENDIG) allows for considerable flexibility in how data is represented; interpretation of these guidelines has led to significant variability in the approach to SEND dataset creation. The purposes of this manuscript are to identify common variability in certain SEND domains and to describe how variability can be managed to enable valuable cross-study analysis use cases. The example of extracting a commonly used data point, animal age, is used to illustrate the complexity and variability of SEND datasets. Developing a solution framework to the variability problem that includes all stakeholders involved in the creation and use of SEND datasets may enable future, routine analysis of warehoused SEND data. Harmonizing the implementation and use of SEND is expected to benefit all involved stakeholders and to ultimately contribute to the goal of increased productivity in nonclinical research.

Design and Realization of an Efficient Large-Area Event-Driven E-Skin.

The sense of touch enables us to safely interact and control our contacts with our surroundings. Many technical systems and applications could profit from a similar type of sense. Yet, despite the emergence of e-skin systems covering more extensive areas, large-area realizations of e-skin effectively boosting applications are still rare. Recent advancements have improved the deployability and robustness of e-skin systems laying the basis for their scalability. However, the upscaling of e-skin systems introduces yet another challenge-the challenge of handling a large amount of heterogeneous tactile information with complex spatial relations between sensing points. We targeted this challenge and proposed an event-driven approach for large-area skin systems. While our previous works focused on the implementation and the experimental validation of the approach, this work now provides the consolidated foundations for realizing, designing, and understanding large-area event-driven e-skin systems for effective applications. This work homogenizes the different perspectives on event-driven systems and assesses the applicability of existing event-driven implementations in large-area skin systems. Additionally, we provide novel guidelines for tuning the novelty-threshold of event generators. Overall, this work develops a systematic approach towards realizing a flexible event-driven information handling system on standard computer systems for large-scale e-skin with detailed descriptions on the effective design of event generators and decoders. All designs and guidelines are validated by outlining their impacts on our implementations, and by consolidating various experimental results. The resulting system design for e-skin systems is scalable, efficient, flexible, and capable of handling large amounts of information without customized hardware. The system provides the feasibility of complex large-area tactile applications, for instance in robotics.

Four-Dimensional Scanning Transmission Electron Microscopy (4D-STEM): From Scanning Nanodiffraction to Ptychography and Beyond.

Scanning transmission electron microscopy (STEM) is widely used for imaging, diffraction, and spectroscopy of materials down to atomic resolution. Recent advances in detector technology and computational methods have enabled many experiments that record a full image of the STEM probe for many probe positions, either in diffraction space or real space. In this paper, we review the use of these four-dimensional STEM experiments for virtual diffraction imaging, phase, orientation and strain mapping, measurements of medium-range order, thickness and tilt of samples, and phase contrast imaging methods, including differential phase contrast, ptychography, and others.

State-of-the-Art and Practical Guide to Ultrasonic Transducers for Harsh Environments Including Temperatures above 2120 °F (1000 °C) and Neutron Flux above 1013 n/cm2.

In field applications currently used for health monitoring and nondestructive testing, ultrasonic transducers primarily employ PZT5-H as the piezoelectric element for ultrasound transmission and detection. This material has a Curie-Weiss temperature that limits its use to about 210 °C. Some industrial applications require much higher temperatures, i.e., 1000-1200 °C and possible nuclear radiation up to 1020 n/cm2 when performance is required in a reactor environment. The goal of this paper is the survey and review of piezoelectric elements for use in harsh environments for the ultimate purpose for structural health monitoring (SHM), non-destructive evaluation (NDE) and material characterization (NDMC). The survey comprises the following categories: 1. High-temperature applications with single crystals, thick-film ceramics, and composite ceramics, 2. Radiation-tolerant materials, and 3. Spray-on transducers for harsh-environment applications. In each category the known characteristics are listed, and examples are given of performance in harsh environments. Highlighting some examples, the performance of single-crystal lithium niobate wafers is demonstrated up to 1100 °C. The wafers with the C-direction normal to the wafer plane were mounted on steel cylinders with high-temperature Sauereisen and silver paste wire mountings and tested in air. In another example, the practical use in harsh radiation environments aluminum nitride (AlN) was found to be a good candidate operating well in two different nuclear reactors. The radiation hardness of AlN was evident from the unaltered piezoelectric coefficient after a fast and thermal neutron exposure in a nuclear reactor core (thermal flux = 2.12 × 1013 ncm-2; fast flux 2 (>1.0 MeV) = 4.05 × 1013 ncm-2; gamma dose rate: 1 × 109 r/h; temperature: 400-500 °C). Additionally, some of the high-temperature transducers are shown to be capable of mounting without requiring coupling material. Pulse-echo signal amplitudes (peak-to-peak) for the first two reflections as a function of the temperature for lithium niobate thick-film, spray-on transducers were observed to temperatures of about 900 °C. Guided-wave send-and-receive operation in the 2-4 MHz range was demonstrated on 2-3 mm thick Aluminum (6061) structures for possible field deployable applications where standard ultrasonic coupling media do not survive because of the harsh environment. This approach would benefit steam generators and steam pipes where temperatures are above 210 °C. In summary, there are several promising approaches to ultrasonic transducers for harsh environments and this paper presents a survey based on literature searches and in-house laboratory observations.

Establishment of the Global SEND Alliance (G-SEND) in Japan and efficient creation of electronic SEND datasets between CROs.

The Standard for Exchange of Nonclinical Data (SEND), adopted by the US Food and Drug Administration (FDA), is a set of regulations for digitalization and standardization of nonclinical study data; thus, related organizations have begun implementing processes in support of SEND. The Global Editorial and Steering Committee (GESC), which provides oversight of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND), has prepared the SEND Controlled Terminology (CT) for toxicologic pathology. SEND provides electronic data standards created by the Clinical Data Interchange Standards Consortium (CDISC), and CDISC also collaborates in the implementation of SEND. Furthermore, the Pharmaceutical Users Software Exchange (PhUSE), which includes members of the US FDA, has conducted various activities to promote realistic and effective methods to implement SEND. As we reported in 2015, there is a significant variation in the efficiency and quality of SEND data implementation across pharmaceutical companies and contractors (CROs) globally. To address this problem, the Global SEND Alliance (G-SEND) was established in August 2018 to facilitate the coordination and standardization of SEND datasets across CROs in Asia. This paper reports the first method for organizationally and jointly creating consistent SEND datasets between CROs using G-SEND.

The Standard for the Exchange of Nonclinical Data (SEND): Challenges and Promises.

The Standard for the Exchange of Nonclinical Data (SEND) is an implementation of the Study Data Tabulation Model for nonclinical studies that enables the U.S. Food and Drug Administration (FDA) to modernize and streamline the review process. As a result, patients may benefit from speedier approval of new drugs. However, SEND implementation and compliance can be challenging and require effective cooperation between pharmaceutical companies and contract research organizations. In order to improve Society of Toxicologic Pathology (STP) members' awareness about SEND, including the steps, obstacles, and mistakes to avoid in its implementation while applying for FDA approval, the Career Development and Outreach Committee of the STP sponsored a career development lunchtime series panel discussion entitled "The Standard for the Exchange of Nonclinical Data (SEND): Challenges and Promise" in conjunction with the STP 37th Annual Symposium. The presentations and discussion at this workshop provided perspectives of experts including pathologists and information technology professionals familiar with the SEND submission process and FDA reviewers. This article is designed to provide brief summaries of their talks as well as the questions asked during this well-received panel discussion.

Brief Synopsis: Review of Renal Tubule and Interstitial Anatomy and Physiology and Renal INHAND, SEND, and DIKI Nomenclature.

This article provides a synopsis of the first two presentations from the second scientific session of the 37th Annual Symposium of the Society of Toxicologic Pathology in Indianapolis, Indiana, on June 18, 2018; the session focused on acute kidney injury. The first presentation, given by Dr. Kevin McDorman, focused on "Fundamentals of Renal Tubule and Interstitial Anatomy and Physiology." Several common background findings from toxicity studies were additionally discussed. Lastly, factors that impact the relevance and usefulness of historical control data, such as quality and consistency of histopathology, were discussed. The second presentation, given by Dr. Torrie Crabbs, provided a review of International Harmonization of Nomenclature and Diagnostic Criteria (INHAND), Standard for Exchange of Nonclinical Data (SEND), and drug-induced kidney injury (DIKI) nomenclature. INHAND is a global collaborative project that provides internationally accepted standardized nomenclature and diagnostic criteria for proliferative and nonproliferative changes in laboratory animals in toxicity and carcinogenicity studies. SEND is currently a required standard for data submission to the Food and Drug Administration (FDA). Since the FDA has indicated its preference for INHAND nomenclature, SEND will predominately use INHAND terminology; thus, familiarity with INHAND terminology is critical for toxicologic pathologists. The diagnostic features of three common DIKI findings, in addition to several complicated INHAND terminologies, were reviewed.

Making sense of SEND; the Standard for Exchange of Nonclinical Data.

The Standard for Exchange of Nonclinical Data (SEND) is currently the preferred submission format for nonclinical animal data by the US FDA and became a requirement on the 18th December 2016. Application of these data standards is the first step to being able to perform cross-study querying and is expected to open up opportunities for data mining and meta-analysis by the pharmaceutical industry. This paper reports on our experiences in developing a tool to allow recent SEND formatted studies to be explored alongside historical nonclinical data already gathered as part of the eTOX project. Combining SEND data with historical data will positively impact the power of any analysis performed and increase the likelihood of being able to detect rare effects. It describes the use of KNIME in generating dose group averages and incidences from individual animal level data captured in SEND. There are a number of options for opening and reading SEND files but the benefits of using KNIME are that it is a free, open source data mining framework which allows the data to be viewed in a holistic manner rather than one domain at a time. Additionally it incorporates several nodes useful for aggregating and visualising the data to more easily identify patterns and trends.

Basic Send-on-Delta Sampling for Signal Tracking-Error Reduction.

This paper investigates the dynamic selection of an appropriate threshold for basic Send-on-Delta (SoD) sampling strategies, given an available transmission rate to reduce the signal tracking-error. The paper formulates the error-reduction principle and proposes an algorithm that calculates, in real time, the amplitude threshold value (also called delta value) for a desired mean transmission rate. The algorithm is implemented to be computed in a Send-on-Delta driver and is tested with three signals that match the step response of a second order control system. Comparison results with a conformant periodic transmission strategy reveals that it improves deeply the tracking-error while maintaining the desired average throughput.

[Complications arising out of insufficient reporting of clinical data to the pathologist investigating placentas]. / Komplikace vyplývající z neposkytnutí relevantních klinických údaju patologovi vysetrujícímu placenty.

OBJECTIVE: To inform gynecologists-obstetricians about the problems associated with pathological examination of placentas, with special regard to the possibility of crucial role of complete and relevant clinical data in establishing the correct pathological diagnosis. DESIGN: Case report and overview of the problems associated with examination of placentas by pathologist. SETTING: Sikl´s Institute of Pathology, Faculty Hospital and Medical Faculty Pilzen of the Charles University in Prague; Biopticka laborator, s.r.o., Pilzen. METHODS: Own observation in the setting of routine pathological examination. RESULTS: Case report representing a typical complication resulting from insufficient interdisciplinary communication describes a case of unsatisfactory result of pathological investigation of placenta due to the missing clinical information about complications of the late phase of pregnancy which eventually led to intrauterine death of the fetus. Due to the absence of the clinical information of paramount importance, the initial investigation of placenta was untargeted and thus imperfect. Therefore, the primary investigation of the placenta did not reveal pathological changes responsible for the complications of pregnancy. It was only the revision of material necessitated by the information additionally conveyed by gynecologist-obstetrician leading to the final correct pathological diagnosis, which even averted the possibility of serious forensic consequences. CONCLUSION: The basic prerequisite for proper pathological examination of placenta is sharing the available clinical data with the pathologist performing the morphological investigation, mainly focusing on complications of pregnancy. Lack of such information causes examination of placenta more difficult and sometimes even unable to interpret, as the interpretation of morphological changes of placenta have to interpreted in the context of clinical data on the course of pregnancy. Regarding the extreme emotional and possibly even legal consequences of lethal complications of pregnancy or delivery, the correct pathological diagnosis may be of crucial importance.

Specific pathologist responses for Standard for Exchange of Nonclinical Data (SEND).

The Standard for Exchange of Nonclinical Data (SEND), introduced by the US Food and Drug Administration (FDA), is a scheme for the computerization, electronic application, and screening of preclinical data. Since its establishment, related organizations have been working together to implement SEND. However, it is difficult for individual pharmaceutical companies that often outsource to achieve complete compliance with SEND; hence, the cooperation of contract research organizations (CROs) and SEND Registered Solution Providers (RSPs) is indispensable. In SEND, most data, including those on pathology findings, are converted into controlled terminology (CT), but it is not a simple process to convert findings or levels of severity in the field of pathology, which is a descriptive science. The authors have successfully completed an FDA trial submission for a toxicology test conducted at a CRO and in doing so acquired important knowledge. This article presents a clear picture of such important knowledge from a pathologist's viewpoint.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) for Lesions in the Minipig.

The International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) is a global project establishing diagnostic criteria and nomenclature for both proliferative and nonproliferative changes in laboratory animals. Nonrodent working groups (NRWGs) have been established for the dog, nonhuman primate, minipig, and the rabbit. The Global Editorial and Steering Committee (GESC) oversees the activities of the INHAND projects and is composed of toxicologic pathologists from all of the participating societies. In 2012, INHAND GESC began a collaboration with the U.S. Food and Drug Administration (USFDA) in adapting INHAND terminology for standardized nonclinical data submission to the FDA. The Standard for Exchange of Nonclinical Data is an implementation of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model for nonclinical studies. The NRWG for the minipig consists of toxicologic and diagnostic pathologists from Japan, North America, and Europe, and the group has 15 members including a GESC representative. The NRWGs are reviewing the applicability of the rodent nomenclature for the species and providing terminology unique for the species as well as determining rodent terminology not appropriate for the species. This information will be published with representative illustrations and references.

Graphical display of histopathology data from toxicology studies for drug discovery and development: An industry perspective.

Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, and tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses. A subgroup of the FDA-PhUSE Nonclinical Working Group conducted intra-industry surveys regarding the use of graphical displays of histopathology data. Visual cues, use-cases, the value of cross-domain and cross-study visualizations, and limitations were topics for discussion in the context of the surveys. The subgroup came to the following conclusions. Graphical displays appear advantageous as a communication tool to both pathologists and non-pathologists, and provide an efficient means for communicating pathology findings to project teams. Graphics can support hypothesis-generation which could include cross-domain interactive visualizations and/-or aggregating large datasets from multiple studies to observe and/or display patterns and trends. Incorporation of the SEND standard will provide a platform by which visualization tools will be able to aggregate, select and display information from complex and disparate datasets.

Responses to the Standard for Exchange of Nonclinical Data (SEND) in non-US countries.

The Standard for the Exchange of Nonclinical Data (SEND), adopted by the US FDA, is part of a set of regulations and guidances requiring the submission of standardized electronic study data for nonclinical and clinical data submissions. SEND is the nonclinical implementation of SDTM (Study Data Tabulation Model), the standard electronic format for clinical regulatory submissions to FDA. SEND, SDTM, and the associated Controlled Terminology have been developed by CDISC (Clinical Data Interchange Standards Consortium). In order to successfully implement SEND, interdisciplinary contributions between sponsors and CROs, need a model for task allocation. This is being undertaken by the Pharmaceutical Users Software Exchange (PhUSE). Because SEND is currently the preferred submission format of the US FDA only and will become required by it starting in December 2016, only American academic societies and companies are actively involved. An exception to this is the INHAND initiative, which leads the way in standardizing terminology for toxicological pathology. On the other hand, international globalization of other clinical and nonclinical practices is not feasible because there are substantial differences between the US and non-US countries in CRO involvement in drug development. Thus, non-US countries must consider and develop approaches to SEND that meet their needs. This paper summarizes the activities of the major organizations involved in SEND development and implementation, discusses the effective use of SEND, and details a compliance scheme (research material of the Showa University School of Medicine) illustrating how pharmaceutical companies can complete a large amount of work up to an FDA application with the effective utilization of CROs and solution providers.

Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.