Development of models for predicting Torsade de Pointes cardiac arrhythmias using perceptron neural networks

Blockage of some ion channels and in particular, the hERG cardiac potassium channel delays cardiac repolarization and can induce arrhythmia. In some cases it leads to a potentially life-threatening arrhythmia known as Torsade de Pointes (TdP). Therefore recognizing drugs with TdP risk is essential. Candidate drugs that are determined not to cause cardiac ion channel blockage are more likely to pass successfully through clinical phases II and III trials (and preclinical work) and not be withdrawn even later from the marketplace due to cardiotoxic effects. The objective of the present study is to develop an SAR model that can be used as an early screen for torsadogenic (causing TdP arrhythmias) potential in drug candidates. The method is performed using descriptors comprised of atomic NMR chemical shifts and corresponding interatomic distances which are combined into a 3D abstract space matrix. The method is called 3D-SDAR (3 dimensional spectral data-activity relationship) and can be interrogated to identify molecular features responsible for the activity, which can in turn yield simplified hERG toxicophores. A dataset of 55 hERG potassium channel inhibitors collected from Kramer et al. consisting of 32 drugs with TdP risk and 23 with no TdP risk was used for training the 3D-SDAR model.An ANN model with multilayer perceptron was used to define collinearities among the independent 3D-SDAR features. A composite model from 200 random iterations with 25% of the molecules in each case yielded the following figures of merit: training, 99.2 %; internal test sets, 66.7%; external (blind validation) test set, 68.4%. In the external test set, 70.3% of positive TdP drugs were correctly predicted. Moreover, toxicophores were generated from TdP drugs. A 3D-SDAR was successfully used to build a predictive model for drug-induced torsadogenic and non-torsadogenic drugs.Comment: Accepted for publication in BMC Bioinformatics (Springer) July 201

The 'Good' Teacher? Constructing Teacher Identities for Lifelong Learning

The symposium will focus on trans-national constructions of the 'good' teacher through popular culture, through professional development orthodoxies and through professional practices such as professional growth plans, inspection and teacher regulation

On the generalized Ramanujan and Arthur conjectures over function fields

Let $G$ be a simple group over a global function field $K$, and let $\pi$ be a cuspidal automorphic representation of $G$. Suppose $K$ has two places $u$ and $v$ (satisfying a mild restriction on the residue field cardinality), at which the group $G$ is quasi-split, such that $\pi_u$ is tempered and $\pi_v$ is unramified and generic. We prove that $\pi_w$ is tempered at all unramified places $K_w$ at which $G$ is unramified quasi-split. More generally, the set of unitary spherical representations is partitioned according to nilpotent conjugacy classes in the Lie algebra of $G$. We show that if $\pi_v$ is in the set corresponding to the nilpotent class $N$, and if $\pi_u$ satisfies an analogous hypothesis, then $\pi_w$ belongs to the same class $N$, where $w$ is as above. These results are consistent with conjectures of Shahidi and Arthur. The proofs use the Galois parametrization of cuspidal representations due to V. Lafforgue to relate the local Satake parameters of $\pi$ to Deligne's theory of Frobenius weights. The main observation is that, in view of the classification of unitary spherical representations, due to Barbasch and the first-named author, the theory of weights excludes almost all complementary series as possible local components of $\pi$. This in turn determines the local Frobenius weights at all unramified places. In order to apply this observation in practice we need a result of the second-named author with Gan and Sawin on the weights of discrete series representations.Comment: Expands and replaces "On the generalized Ramanujan conjecture over function fields," arXiv:2204.0605

Internet-of-Things Devices, Intellectual Property, Venture Capital, China Manufacturing, and the Art of a Clean Deal: Who Owns What?

Internet-of-Things Devices, Intellectual Property, Venture Capital, China Manufacturing, and the Art of a Clean Deal: Who Owns What

A national facilitation project to improve primary palliative care : impact of the Gold Standards Framework on process and self-ratings of quality

Background: Improving quality of end-of-life care is a key driver of UK policy. The Gold Standards Framework (GSF) for Palliative Care aims to strengthen primary palliative care through facilitating implementation of systematic clinical and organisational processes. Objectives: To describe the general practices that participated in the GSF programme in 2003–5 and the changes in process and perception of quality that occurred in the year following entry into the programme, and to identify factors associated with the extent of change. Methods: Participating practices completed a questionnaire at baseline and another approximately 12 months later. Data were derived from categorical questions about the implementation of 35 organisational and clinical processes, and self-rated assessments of quality, associated with palliative care provision. Participants: 1305 practices (total registered population almost 10 million). Follow-up questionnaire completed by 955 (73.2%) practices (after mean (SD) 12.8 (2.8) months; median 13 months). Findings: Mean increase in total number of processes implemented (maximum = 35) was 9.6 (95% CI 9.0 to 10.2; p<0.001; baseline: 15.7 (SD 6.4), follow-up: 25.2 (SD 5.2)). Extent of change was largest for practices with low baseline scores. Aspects of process related to coordination and communication showed the greatest change. All dimensions of quality improved following GSF implementation; change was highest for the "quality of palliative care for cancer patients" and "confidence in assessing, recording and addressing the physical and psychosocial areas of patient care". Conclusion: Implementation of the GSF seems to have resulted in substantial improvements in process and quality of palliative care. Further research is required of the extent to which this has enhanced care (physical, practical and psychological outcomes) for patients and carers

Country classifications for a changing world

"The distinction between developing and developed countries has long been central to development studies and to debates on development policy. In earlier decades, it was in many respects accurate, and was for many purposes useful. Although the world is still very much divided between rich and poor countries, relationships among countries have changed so much that the developing-developed country distinction has become an obstacle to understanding current problems and opportunities and, even more, to thinking productively about the future. It is time to stop using it. Many alternative ways of categorising countries have been suggested. In recent years in particular, large numbers of organisations have begun annually to rank countries according to a wide variety of criteria: from economic vulnerability, bribe payers, competitiveness, digital access, ease of doing business, food insecurity, governance, and happiness to water poverty and welfare. These do not adequately capture the structural and relational changes that have occurred in our multi-polar world with substantially altered flows of ideas, resources and influence. Focusing on the needs of European policymakers, this paper suggests two axes for classifying countries. The first is the external capacity of states to influence and work with other states. This is captured in the (measureable) concept of 'anchor countries' developed by the German Development Institute and beginning to be put into practice in the enlargement from the G8 to the G20. The second is internal state capacity, as shaped by the sources of government income, in particular contrasting tax, aid, and oil. Using sources of public revenue as a way of classifying countries requires more work but would help to steer the development debate toward the key issue of improving the quality of governance and thus strengthening the capacity of poor countries to help themselves." (author's abstract

Incentives Toward Conservation of Argaii Ovis Ammon: A Case Study of Trophy Hunting in Western China

We investigated management of wildlife, habitat and the hunting programme in Aksai County, Gansu Province, People\u27s Republic of China, during 1997-2000. Argali Ovis amnion is the focal species both for conservation and hunting. The hunting programme is intended to produce incentives to conserve wildlife and habitat. Poaching, a serious concern throughout western China, has been reduced in recent years in Aksai. Wildlife population trends are unknown because standardized surveys were begun only in 2000. Threats to argali in Aksai include livestock grazing, placer gold mining, and development of a dam, reservoir and aqueduct. The number of hunters participating in the programme (c. 3 per year) could provide considerable funding (c. $60,000 per year), but the allocation of these funds within China has provided too little for conservation at the local level, thus undermining the intended incentive system. Because local wildlife protection officials have been denied both funding and authority to deal with threats to the wildlife, the programme\u27s contribution to conservation has been minor. We recommend that hunters pay fees directly to county-level staff, thus increasing the proportion of funds retained at county-level, and that this added income is used to obtain wildlife grazing rights on important seasonal habitats for argali. These changes would promote local wildlife conservation without the need for additional external funding

Parental Co‐Construction of 5‐ to 13‐Year‐Olds\u27 Global Self‐Esteem Through Reminiscing About Past Events

The current study explored parental processes associated with children\u27s global self‐esteem development. Eighty 5‐ to 13‐year‐olds and one of their parents provided qualitative and quantitative data through questionnaires, open‐ended questions, and a laboratory‐based reminiscing task. Parents who included more explanations of emotions when writing about the lowest points in their lives were more likely to discuss explanations of emotions experienced in negative past events with their child, which was associated with child attachment security. Attachment was associated with concurrent self‐esteem, which predicted relative increases in self‐esteem 16 months later, on average. Finally, parent support also predicted residual increases in self‐esteem. Findings extend prior research by including younger ages and uncovering a process by which two theoretically relevant parenting behaviors impact self‐esteem development

An Analysis of Environmental, Social, and Corporate Governance (ESG) Ratings of Lean Versus Non-Lean Companies

Lean manufacturing is a business philosophy concerned with continually eliminating waste from business processes while producing quality products with greater efficiency. In addition to profits, organizations worldwide are beginning to focus on environmental, social, and corporate-governance (ESG) factors because of the changing global environment. The Environmental Protection Agency has specifically stated that many organizations have found that implementing lean manufacturing concepts and tools results in improvements in environmental performance. This study uses a matched-pairs design, matching lean companies with non-lean companies, and assesses whether lean companies experienced better Sustainalytics ESG risk ratings than non-lean companies. Results show that lean companies achieved more favorable ratings in environmental, social, and corporate-governance factors than did non-lean companies