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Representation learning and \emph{de novo} generation of proteins are pivotal computational biology tasks. Whilst natural language processing (NLP) techniques have proven highly effective for protein sequence modelling, structure modelling presents a complex challenge, primarily due to its continuous and three-dimensional nature. Motivated by this discrepancy, we introduce an approach using a vector-quantized autoencoder that effectively tokenizes protein structures into discrete representations. This method transforms the continuous, complex space of protein structures into a manageable, discrete format with a codebook ranging from 4096 to 64000 tokens, achieving high-fidelity reconstructions with backbone root mean square deviations (RMSD) of approximately 1-5 \AA. To demonstrate the efficacy of our learned representations, we show that a simple GPT model trained on our codebooks can generate novel, diverse, and designable protein structures. Our approach not only provides representations of protein structure, but also mitigates the challenges of disparate modal representations and sets a foundation for seamless, multi-modal integration, enhancing the capabilities of computational methods in protein design.

Wilhelm (Forthcom Synth 199:6357–6369, 2021) has recently defended a criterion for comparing structure of mathematical objects, which he calls Subgroup. He argues that Subgroup is better than SYM ∗ , another widely adopted criterion. We argue that this is mistaken; Subgroup is strictly worse than SYM ∗ . We then formulate a new criterion that improves on both SYM ∗ and Subgroup, answering Wilhelm’s criticisms of SYM ∗ along the way. We conclude by arguing that no criterion that looks only to the automorphisms of mathematical objects to compare their structure can be fully satisfactory.

This is an essay review of Jill North’s book Physics, Structure, and Reality. It focuses on two of the main topics of the book. The first is North’s idea that we can use coordinates as a window into the structure that a theory posits; the second is North’s argument for the inequivalence of Lagrangian and Newtonian mechanics.

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

A central concern of metaphysicians of science is uncovering the metaphysical content of our best scientific theories. One method for uncovering this content is with the use of indispensability arguments. These arguments infer the existence of some entity or structure on the basis of its presence in the formulation of some theory. While promised as a general argumentative strategy, the literature on indispensability arguments is generally concerned with the question of whether numbers are indispensable to our best scientific theories. In this dissertation, I cash in on the promise that indispensability arguments are generalizable by examining whether composite objects are indispensable to our best scientific theories. The first half of the dissertation (Chapters 2, 3, and 4) examines this question head on. I argue that the extant arguments for the indispensability of composite objects are not convincing, but once we sharpen our definition of indispensability, we see that there are good reasons to think that composites are, indeed, indispensable to our best scientific theories. In the second half, I examine the idea that indispensability is a guide to ontology from the perspective of philosophy of language. In Chapter 5, I present a novel interpretation of Putnam's original indispensability argument, where I argue that he is using the logic of linguistic presupposition. In Chapter 6, I try to show that sometimes it is permissible to linguistically subtract one's ontological commitment to some indispensable entity.

We present a hierarchy of symmetry conditions within the context of general relativity. The weakest condition captures a sense in which spacetime is free of symmetry "holes" of a certain type. All standard models of general relativity satisfy the condition but we show that violations can occur if the Hausdorff assumption is dropped. On the other extreme, the strongest condition of the hierarchy is satisfied whenever a model is completely devoid of symmetries. In these "Heraclitus" spacetimes, no pair of distinct points can be mapped (even locally) into one another. We prove that such spacetimes exist. We also show a sense in which Heraclitus spacetimes are completely determined by their local properties. We close with a brief comment on the prospect of using the symmetries of a spacetime as a guide to how much "structure" it possesses.

Recent advancements in large language models (LLMs) underscore their potential for responding to inquiries in various domains. However, ensuring that generative agents provide accurate and reliable answers remains an ongoing challenge. In this context, multi-agent debate (MAD) has emerged as a promising strategy for enhancing the truthfulness of LLMs. We benchmark a range of debating and prompting strategies to explore the trade-offs between cost, time, and accuracy. Importantly, we find that multi-agent debating systems, in their current form, do not reliably outperform other proposed prompting strategies, such as self-consistency and ensembling using multiple reasoning paths. However, when performing hyperparameter tuning, several MAD systems, such as Multi-Persona, perform better. This suggests that MAD protocols might not be inherently worse than other approaches, but that they are more sensitive to different hyperparameter settings and difficult to optimize. We build on these results to offer insights into improving debating strategies, such as adjusting agent agreement levels, which can significantly enhance performance and even surpass all other non-debate protocols we evaluated. We provide an open-source repository to the community with several state-of-the-art protocols together with evaluation scripts to benchmark across popular research datasets., Comment: 2 pages, 13 figures

Combinatorial Optimization underpins many real-world applications and yet, designing performant algorithms to solve these complex, typically NP-hard, problems remains a significant research challenge. Reinforcement Learning (RL) provides a versatile framework for designing heuristics across a broad spectrum of problem domains. However, despite notable progress, RL has not yet supplanted industrial solvers as the go-to solution. Current approaches emphasize pre-training heuristics that construct solutions but often rely on search procedures with limited variance, such as stochastically sampling numerous solutions from a single policy or employing computationally expensive fine-tuning of the policy on individual problem instances. Building on the intuition that performant search at inference time should be anticipated during pre-training, we propose COMPASS, a novel RL approach that parameterizes a distribution of diverse and specialized policies conditioned on a continuous latent space. We evaluate COMPASS across three canonical problems - Travelling Salesman, Capacitated Vehicle Routing, and Job-Shop Scheduling - and demonstrate that our search strategy (i) outperforms state-of-the-art approaches on 11 standard benchmarking tasks and (ii) generalizes better, surpassing all other approaches on a set of 18 procedurally transformed instance distributions., Comment: Fix typo in formula and add a reference

It has been suggested that we can tell whether two theories are equivalent by comparing the structure that they ascribe to the world. If two theories posit different structures, then they must be inequivalent. The aim of this article is to evaluate the extent to which this desideratum holds for the different standards of equivalence that are currently on the table.

Applying reinforcement learning (RL) to combinatorial optimization problems is attractive as it removes the need for expert knowledge or pre-solved instances. However, it is unrealistic to expect an agent to solve these (often NP-)hard problems in a single shot at inference due to their inherent complexity. Thus, leading approaches often implement additional search strategies, from stochastic sampling and beam search to explicit fine-tuning. In this paper, we argue for the benefits of learning a population of complementary policies, which can be simultaneously rolled out at inference. To this end, we introduce Poppy, a simple training procedure for populations. Instead of relying on a predefined or hand-crafted notion of diversity, Poppy induces an unsupervised specialization targeted solely at maximizing the performance of the population. We show that Poppy produces a set of complementary policies, and obtains state-of-the-art RL results on four popular NP-hard problems: traveling salesman, capacitated vehicle routing, 0-1 knapsack, and job-shop scheduling.

We present a hierarchy of symmetry conditions within the context of general relativity. The weakest condition captures a sense in which spacetime is free of symmetry "holes" of a certain type. All standard models of general relativity satisfy the condition but we show that violations can occur if the Hausdorff assumption is dropped. On the other extreme, the strongest condition of the hierarchy is satisfied whenever a model is completely devoid of symmetries. In these "Heraclitus spacetimes," no pair of distinct points can be mapped (even locally) into one another. We prove that such spacetimes exist. We also show a sense in which Heraclitus spacetimes are completely determined by their local properties. We close with a brief comment on the prospect of using the symmetries of a spacetime as a guide to how much "structure" it possesses.

Wilhelm (2021) has recently defended a criterion for comparing structure of mathematical objects, which he calls Subgroup. He argues that Subgroup is better than SYM * , another widely adopted criterion. We argue that this is mistaken; Subgroup is strictly worse than SYM *. We then formulate a new criterion that improves on both SYM * and Subgroup, answering Wilhelm's criticisms of SYM * along the way. We conclude by arguing that no criterion that looks only to the automorphisms of mathematical objects to compare their structure can be fully satisfactory.

Allowing agents to share information through communication is crucial for solving complex tasks in multi-agent reinforcement learning. In this work, we consider the question of whether a given communication protocol can express an arbitrary policy. By observing that many existing protocols can be viewed as instances of graph neural networks (GNNs), we demonstrate the equivalence of joint action selection to node labelling. With standard GNN approaches provably limited in their expressive capacity, we draw from existing GNN literature and consider augmenting agent observations with: (1) unique agent IDs and (2) random noise. We provide a theoretical analysis as to how these approaches yield universally expressive communication, and also prove them capable of targeting arbitrary sets of actions for identical agents. Empirically, these augmentations are found to improve performance on tasks where expressive communication is required, whilst, in general, the optimal communication protocol is found to be task-dependent., Comment: Published in NeurIPS 2022

From logistics to the natural sciences, combinatorial optimisation on graphs underpins numerous real-world applications. Reinforcement learning (RL) has shown particular promise in this setting as it can adapt to specific problem structures and does not require pre-solved instances for these, often NP-hard, problems. However, state-of-the-art (SOTA) approaches typically suffer from severe scalability issues, primarily due to their reliance on expensive graph neural networks (GNNs) at each decision step. We introduce ECORD; a novel RL algorithm that alleviates this expense by restricting the GNN to a single pre-processing step, before entering a fast-acting exploratory phase directed by a recurrent unit. Experimentally, ECORD achieves a new SOTA for RL algorithms on the Maximum Cut problem, whilst also providing orders of magnitude improvement in speed and scalability. Compared to the nearest competitor, ECORD reduces the optimality gap by up to 73% on 500 vertex graphs with a decreased wall-clock time. Moreover, ECORD retains strong performance when generalising to larger graphs with up to 10000 vertices.

Combinatorial optimisation problems framed as mixed integer linear programmes (MILPs) are ubiquitous across a range of real-world applications. The canonical branch-and-bound algorithm seeks to exactly solve MILPs by constructing a search tree of increasingly constrained sub-problems. In practice, its solving time performance is dependent on heuristics, such as the choice of the next variable to constrain ('branching'). Recently, machine learning (ML) has emerged as a promising paradigm for branching. However, prior works have struggled to apply reinforcement learning (RL), citing sparse rewards, difficult exploration, and partial observability as significant challenges. Instead, leading ML methodologies resort to approximating high quality handcrafted heuristics with imitation learning (IL), which precludes the discovery of novel policies and requires expensive data labelling. In this work, we propose retro branching; a simple yet effective approach to RL for branching. By retrospectively deconstructing the search tree into multiple paths each contained within a sub-tree, we enable the agent to learn from shorter trajectories with more predictable next states. In experiments on four combinatorial tasks, our approach enables learning-to-branch without any expert guidance or pre-training. We outperform the current state-of-the-art RL branching algorithm by 3-5x and come within 20% of the best IL method's performance on MILPs with 500 constraints and 1000 variables, with ablations verifying that our retrospectively constructed trajectories are essential to achieving these results., Comment: Accepted to AAAI'23: Proceedings of the Thirty-Seventh AAAI Conference on Artificial Intelligence

This paper presents a simple pair of first-order theories that are not definitionally (nor Morita) equivalent, yet are mutually conservatively translatable and mutually ‘surjectively’ translatable. We use these re- sults to clarify the overall geography of standards of equivalence and to show that the structural commitments that theories make behave in a more subtle manner than has been recognized.

This is an essay review of Jill North's book Physics, Structure, and Reality. I focus on just two of the main topics of the book. The first is North's idea that we can use coordinates as a window into the structure that a theory posits. The second is North's argument for the inequivalence of Lagrangian and Newtonian mechanics.

Self-tuning algorithms that adapt the learning process online encourage more effective and robust learning. Among all the methods available, meta-gradients have emerged as a promising approach. They leverage the differentiability of the learning rule with respect to some hyper-parameters to adapt them in an online fashion. Although meta-gradients can be accumulated over multiple learning steps to avoid myopic updates, this is rarely used in practice. In this work, we demonstrate that whilst multi-step meta-gradients do provide a better learning signal in expectation, this comes at the cost of a significant increase in variance, hindering performance. In the light of this analysis, we introduce a novel method mixing multiple inner steps that enjoys a more accurate and robust meta-gradient signal, essentially trading off bias and variance in meta-gradient estimation. When applied to the Snake game, the mixing meta-gradient algorithm can cut the variance by a factor of 3 while achieving similar or higher performance., Comment: 14 pages, 6 figures, 2 tables

In recent years, neural network quantum states (NNQS) have emerged as powerful tools for the study of quantum many-body systems. Electronic structure calculations are one such canonical many-body problem that have attracted significant research efforts spanning multiple decades, whilst only recently being attempted with NNQS. However, the complex non-local interactions and high sample complexity are significant challenges that call for bespoke solutions. Here, we parameterise the electronic wavefunction with a novel autoregressive neural network (ARN) that permits highly efficient and scalable sampling, whilst also embedding physical priors reflecting the structure of molecular systems without sacrificing expressibility. This allows us to perform electronic structure calculations on molecules with up to 30 spin-orbitals -- at least an order of magnitude more Slater determinants than previous applications of conventional NNQS -- and we find that our ansatz can outperform the de-facto gold-standard coupled cluster methods even in the presence of strong quantum correlations. With a highly expressive neural network for which sampling is no longer a computational bottleneck, we conclude that the barriers to further scaling are not associated with the wavefunction ansatz itself, but rather are inherent to any variational Monte Carlo approach., Comment: 8 pages, plus Methods and Supplementary Information

Understanding the origin and evolution of the lunar volatile system is not only compelling lunar science, but also fundamental Solar System science. This white paper (submitted to the US National Academies' Decadal Survey in Planetary Science and Astrobiology 2023-2032) summarizes recent advances in our understanding of lunar volatiles, identifies outstanding questions for the next decade, and discusses key steps required to address these questions.

Learning disentangled representations is a key step towards effectively discovering and modelling the underlying structure of environments. In the natural sciences, physics has found great success by describing the universe in terms of symmetry preserving transformations. Inspired by this formalism, we propose a framework, built upon the theory of group representation, for learning representations of a dynamical environment structured around the transformations that generate its evolution. Experimentally, we learn the structure of explicitly symmetric environments without supervision from observational data generated by sequential interactions. We further introduce an intuitive disentanglement regularisation to ensure the interpretability of the learnt representations. We show that our method enables accurate long-horizon predictions, and demonstrate a correlation between the quality of predictions and disentanglement in the latent space., Comment: Accepted to NeurIPS 2020

Backpropagation through nonlinear neurons is an outstanding challenge to the field of optical neural networks and the major conceptual barrier to all-optical training schemes. Each neuron is required to exhibit a directionally dependent response to propagating optical signals, with the backwards response conditioned on the forward signal, which is highly non-trivial to implement optically. We propose a practical and surprisingly simple solution that uses saturable absorption to provide the network nonlinearity. We find that the backward propagating gradients required to train the network can be approximated in a pump-probe scheme that requires only passive optical elements. Simulations show that, with readily obtainable optical depths, our approach can achieve equivalent performance to state-of-the-art computational networks on image classification benchmarks, even in deep networks with multiple sequential gradient approximations. This scheme is compatible with leading optical neural network proposals and therefore provides a feasible path towards end-to-end optical training., Comment: Error fixed in Fig.1

Many real-world problems can be reduced to combinatorial optimization on a graph, where the subset or ordering of vertices that maximize some objective function must be found. With such tasks often NP-hard and analytically intractable, reinforcement learning (RL) has shown promise as a framework with which efficient heuristic methods to tackle these problems can be learned. Previous works construct the solution subset incrementally, adding one element at a time, however, the irreversible nature of this approach prevents the agent from revising its earlier decisions, which may be necessary given the complexity of the optimization task. We instead propose that the agent should seek to continuously improve the solution by learning to explore at test time. Our approach of exploratory combinatorial optimization (ECO-DQN) is, in principle, applicable to any combinatorial problem that can be defined on a graph. Experimentally, we show our method to produce state-of-the-art RL performance on the Maximum Cut problem. Moreover, because ECO-DQN can start from any arbitrary configuration, it can be combined with other search methods to further improve performance, which we demonstrate using a simple random search., Comment: In Proceedings of the 34th National Conference on Artificial Intelligence, AAAI 2020

INTRODUCTION: Tympanostomy tube insertion is very frequent in Denmark. Using electronic patient-reported outcome (ePRO) data, we investigated Danish ear, nose og throat (ENT) specialists' adherence to the 2015 national clinical guideline (NCG) on first-time tympanostomy tube (TT) insertion in children aged 0-5 years with otitis media (OM).METHODS: Data on children aged 0-5 years with OM undergoing first-time TT insertion were extracted from the Danish ENT Specialists Organisation (DØNHO) database. Pre-operative questionnaires were used to obtain information on symptom duration, and the number of acute OM (AOM) episodes was analysed. The following criteria were established to define NCG adherence: 1) A symptom duration of three months or longer, 2) three or more AOM episodes within six months and 3) four or more AOM episodes within 12 months. These criteria are in accordance with the NCG definition of chronic OM with effusion (COME) and recurrent AOM (RAOM).RESULTS: A total of 1,495 children were included in the study. In total, 91.0% of the parents reported a symptom duration of three months or more and/or RAOM within 6-12 months prior to TT insertion in accordance with the adherence criteria; 4.6% reported a symptom duration of less than three months with few or no episodes of AOM and did not meet the recommended TT insertion criteria. Finally, 4.4% of the parents were undecided with respect to symptom duration, number of AOM episodes or both at 6-12 months prior to TT insertion.CONCLUSIONS: Using solely ePRO data, we found that Danish practicing ENT specialists adhere to the 2015 NCG in regard to OM symptom duration and RAOM.FUNDING: none.TRIAL REGISTRATION: not relevant.

INTRODUCTION: The objective of this study was to investigate parent satisfaction and symptom relief in children younger than 12 years undergoing tympanostomy tube (TT) insertion for otitis media (OM) using electronic patient-reported outcome (ePRO) data in private ear, nose and throat (ENT) practice settings.METHODS: A total of 3,553 children aged 0-11 years and registered in the Danish ENT Specialists Organisation (DØNHO) database were included. Following parental consent to participate, we e-mailed a pre-surgical questionnaire two days prior to surgery. Follow-up questionnaires were sent one, three, six, nine and 12 months after surgery. The pre-operative questionnaire collected information on symptom duration, number of acute OM (AOM) episodes within one year before TT insertion and ear-related symptoms. The post-operative questionnaires collected information on symptom relief, number of AOM episodes and parental satisfaction.RESULTS: Pre- and post-operative questionnaires from 2,462 children were eligible for complete analysis. Before surgery, 89.8% of parents reported a symptom duration of three months or longer and/or recurrent AOM (RAOM). Complete symptom regression was reported in more than half of the children post-operatively. For the rest, significant symptom relief was reported 1-12 months following TT insertion. Parent satisfaction rose from 94.8% to 97.2% in the course of the observation period.CONCLUSIONS: We report a consistent, high rate of symptom relief 1-12 months following TT insertion in children < 12 years of age. Furthermore, parental satisfaction throughout the 12-month observation period was compelling.FUNDING: none.TRIAL REGISTRATION: The database was approved by the Danish Data Protection Agency as a private, clinical database (no. 2016-42-3152). According to Danish law, approval by the Danish Research Ethics Committee system was not necessary.

INTRODUCTION: The objective of this study was to investigate parent satisfaction and symptom relief in children younger than 12 years undergoing tympanostomy tube (TT) insertion for otitis media (OM) using electronic patient-reported outcome (ePRO) data in private ear, nose and throat (ENT) practice settings.METHODS: A total of 3,553 children aged 0-11 years and registered in the Danish ENT Specialists Organisation (DØNHO) database were included. Following parental consent to participate, we e-mailed a pre-surgical questionnaire two days prior to surgery. Follow-up questionnaires were sent one, three, six, nine and 12 months after surgery. The pre-operative questionnaire collected information on symptom duration, number of acute OM (AOM) episodes within one year before TT insertion and ear-related symptoms. The post-operative questionnaires collected information on symptom relief, number of AOM episodes and parental satisfaction.RESULTS: Pre- and post-operative questionnaires from 2,462 children were eligible for complete analysis. Before surgery, 89.8% of parents reported a symptom duration of three months or longer and/or recurrent AOM (RAOM). Complete symptom regression was reported in more than half of the children post-operatively. For the rest, significant symptom relief was reported 1-12 months following TT insertion. Parent satisfaction rose from 94.8% to 97.2% in the course of the observation period.CONCLUSIONS: We report a consistent, high rate of symptom relief 1-12 months following TT insertion in children < 12 years of age. Furthermore, parental satisfaction throughout the 12-month observation period was compelling.FUNDING: none.TRIAL REGISTRATION: The database was approved by the Danish Data Protection Agency as a private, clinical database (no. 2016-42-3152). According to Danish law, approval by the Danish Research Ethics Committee system was not necessary.

INTRODUCTION: Tympanostomy tube insertion is very frequent in Denmark. Using electronic patient-reported outcome (ePRO) data, we investigated Danish ear, nose og throat (ENT) specialists' adherence to the 2015 national clinical guideline (NCG) on first-time tympanostomy tube (TT) insertion in children aged 0-5 years with otitis media (OM).METHODS: Data on children aged 0-5 years with OM undergoing first-time TT insertion were extracted from the Danish ENT Specialists Organisation (DØNHO) database. Pre-operative questionnaires were used to obtain information on symptom duration, and the number of acute OM (AOM) episodes was analysed. The following criteria were established to define NCG adherence: 1) A symptom duration of three months or longer, 2) three or more AOM episodes within six months and 3) four or more AOM episodes within 12 months. These criteria are in accordance with the NCG definition of chronic OM with effusion (COME) and recurrent AOM (RAOM).RESULTS: A total of 1,495 children were included in the study. In total, 91.0% of the parents reported a symptom duration of three months or more and/or RAOM within 6-12 months prior to TT insertion in accordance with the adherence criteria; 4.6% reported a symptom duration of less than three months with few or no episodes of AOM and did not meet the recommended TT insertion criteria. Finally, 4.4% of the parents were undecided with respect to symptom duration, number of AOM episodes or both at 6-12 months prior to TT insertion.CONCLUSIONS: Using solely ePRO data, we found that Danish practicing ENT specialists adhere to the 2015 NCG in regard to OM symptom duration and RAOM.FUNDING: none.TRIAL REGISTRATION: not relevant.

It has been suggested that we can tell whether two theories are equivalent by comparing the structure that they ascribe to the world. If two theories posit different structures, then they must be inequivalent. The aim of this paper is to evaluate the extent to which this desideratum holds of the different standards of equivalence that are currently on the table.

Most conservation research aims to inform management of environmental challenges, but scientific evidence is used inconsistently in environmental programmes and practice. We used semi-structured retrospective interviews to ask 12 environmental scientists and 14 practitioners (land managers, park rangers, project managers and planners from natural resource management agencies) about factors that facilitated and hindered the use of scientific input during 15 environmental projects. We used the common factors from interviews to develop a process model describing how scientific input informs programmes and practice. The model emphasised the social dimensions of environmental projects which are often overlooked when these projects are planned, managed and evaluated. It highlighted the pivotal role of relationships in achieving outcomes which include creating practical, useful products and tools, and robust, credible and trusted evidence. By clarifying the process of how scientific knowledge informs environmental programmes and practice, the model enabled us to provide guidance about how to undertake transdisciplinary work and suggest indicators to track progress. Although derived from environmental projects, the guidance is likely to apply to other fields, particularly where different disciplines work together.

In this paper, I examine whether or not the Hamiltonian and Lagrangian formulations of classical mechanics are equivalent theories. I do so by applying a standard for equivalence that was recently introduced into philosophy of science by Halvorson and Weatherall. This case study yields three general philosophical payoffs. The first is a specific plea for clarity in our discussions of equivalence, while the second and third concern how we should interpret what our physical theories say about the world.

Mathematicians, physicists, and philosophers of physics often look to the symmetries of an object for insight into the structure or constitution of the object. My aim in this paper is to explain why this practice is successful. In order to do so, I prove two theorems that are closely related to (and in a sense, generalizations of) Beth's and Svenonius' theorems.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

The purported fact that geometric theories formulated in terms of points and geometric theories formulated in terms of lines are "equally correct" is often invoked in arguments for conceptual relativity, in particular by Putnam and Goodman. We discuss a few notions of equivalence between first-order theories, and we then demonstrate a precise sense in which this purported fact is true. We argue, however, that this fact does not undermine metaphysical realism.

Mulkey, Inc. is participating in a stream restoration study with the Ecosystem Enhancement Program in Yadkin County, North Carolina. The purpose of this study is to restore approximately 4,300 linear feet of Rocky Branch, a second order stream locatedin the western Piedmont of North Carolina. Stream restoration in North Carolina is generally conducted to provide compensatory mitigation for stream impacts from both highway construction and private development. Since the late 1990s, North Carolina has served at the forefront for stream restoration activities due to the state’s tremendous population growth and stringent water quality standards. In an effort to provide mitigation for the state’s needs in an efficient manner, the Ecosystem Enhancement Program was created in 2003 under an agreement with the North Carolina Department of Environment and Natural Resources, the North Carolina Department of Transportation, and the U.S. Army Corps of Engineers. There are approximately 400 streams and wetland restoration projects that are currently under development across 54 watersheds in North Carolina. Those resources having the greatest repair needs are prioritized and the Ecosystem Enhancement Program works with public and private organizations in an effort to restore, to enhance and to preserve wetlands, streams, and buffers, statewide. The Ecosystem Enhancement Program serves as the nucleus for consolidating and streamlining mitigation activities within the state. The project presented here is one of the many projects this program administers in an effort to meet the ever growing mitigation needs in the state.The Rocky Branch site comprises approximately 24 acres of pasture and woodlands immediately adjacent to the Interstate 77 corridor in Yadkin County, North Carolina. The project site has a drainage area of approximately 3.1 square miles and is part of the South Yadkin River Watershed. The site was once heavily forested, but over the last 100 years has been cleared pri

Mulkey, Inc. is participating in a stream restoration study with the Ecosystem Enhancement Program in Yadkin County, North Carolina. The purpose of this study is to restore approximately 4,300 linear feet of Rocky Branch, a second order stream locatedin the western Piedmont of North Carolina. Stream restoration in North Carolina is generally conducted to provide compensatory mitigation for stream impacts from both highway construction and private development. Since the late 1990s, North Carolina has served at the forefront for stream restoration activities due to the state’s tremendous population growth and stringent water quality standards. In an effort to provide mitigation for the state’s needs in an efficient manner, the Ecosystem Enhancement Program was created in 2003 under an agreement with the North Carolina Department of Environment and Natural Resources, the North Carolina Department of Transportation, and the U.S. Army Corps of Engineers. There are approximately 400 streams and wetland restoration projects that are currently under development across 54 watersheds in North Carolina. Those resources having the greatest repair needs are prioritized and the Ecosystem Enhancement Program works with public and private organizations in an effort to restore, to enhance and to preserve wetlands, streams, and buffers, statewide. The Ecosystem Enhancement Program serves as the nucleus for consolidating and streamlining mitigation activities within the state. The project presented here is one of the many projects this program administers in an effort to meet the ever growing mitigation needs in the state.The Rocky Branch site comprises approximately 24 acres of pasture and woodlands immediately adjacent to the Interstate 77 corridor in Yadkin County, North Carolina. The project site has a drainage area of approximately 3.1 square miles and is part of the South Yadkin River Watershed. The site was once heavily forested, but over the last 100 years has been cleared pri

In this paper, we examine the relationship between general relativity and the theory of Einstein algebras. We show that according to a formal criterion for theoretical equivalence recently proposed by Halvorson (2012, 2015) and Weatherall (2015), the two are equivalent theories.

In this paper, we examine the relationship between general relativity and the theory of Einstein algebras. We show that according to a formal criterion for theoretical equivalence recently proposed by Halvorson (2012, 2015) and Weatherall (2015), the two are equivalent theories.

Glymour (1970, 1977, 1980) and Quine (1975) propose two different formal criteria for theoretical equivalence. In this paper we examine the relationships between these criteria.

In this paper we settle a conjecture suggested by Quine (1937, 1938, 1951, 1956, 1960, 1963). Our theorem makes precise the relationship between many-sorted logic and single-sorted logic and yields a remark about a criterion for theoretical equivalence proposed by Glymour (1970, 1977, 1980).

Quine often argued for a simple, untyped system of logic rather than the typed systems that were championed by Russell and Carnap, among others. He claimed that nothing important would be lost by eliminating sorts, and the result would be additional simplicity and elegance. In support of this claim, Quine conjectured that every many-sorted theory is equivalent to a single-sorted theory. We make this conjecture precise, and prove that it's true, at least according to one reasonable notion of theoretical equivalence. Our clarification of Quine's conjecture, however, exposes the shortcomings of his argument against many-sorted logic.

Logicians and philosophers of science have proposed various formal criteria for theoretical equivalence. In this paper, we examine two such proposals: definitional equivalence and categorical equivalence. In order to show precisely how these two well-known criteria are related to one another, we investigate an intermediate criterion called Morita equivalence.

This paper makes an observation about the ``amount of structure'' that different classical and relativistic spacetimes posit. The observation substantiates a suggestion made by Earman (1989) and yields a cautionary remark concerning the scope and applicability of structural parsimony principles.

Krishna Devarakonda,1 Terri Morton,1 Rachel Margulis,2 Michael Giuliani,3 Thomas Barrett4 1Clinical Pharmacology and Pharmacokinetics, 2Clinical Operations, 3Research and Development, 4Clinical Affairs, Mallinckrodt Inc., Hazelwood, MO, USA Background: XARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed. Methods: This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP. Results: Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food. Conclusion: The findings from this study suggest that ER OC/APAP

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.