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We explore formal approximation techniques for Markov chains based on state–space reduction that aim at improving the scalability of the analysis, while providing formal bounds on the approximation error. We first present a comprehensive survey of existing state-reduction techniques based on clustering or truncation. Then, we extend existing frameworks for aggregation-based analysis of Markov chains by allowing them to handle chains with an arbitrary structure of the underlying state space – including continuous-time models – and improve upon existing bounds on the approximation error. Finally, we introduce a new hybrid scheme that utilises both aggregation and truncation of the state space and provides the best available approach for approximating continuous-time models. We conclude with a broad and detailed comparative evaluation of existing and new approximation techniques and investigate how different methods handle various Markov models. The results also show that the introduced hybrid scheme significantly outperforms existing approaches and provides a speedup of the analysis up to a factor of 30 with the corresponding approximation error bounded within 0.1%.

Mice with transgenic expression of human SOD1G93A are a widely used model of ALS, with a caudal–rostral progression of motor impairment. Previous studies have quantified the progression of motoneuron (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93A mice, to investigate whether there is a caudal–rostral progression of MN death. By 3 months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3 months, the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord in SOD1G93A mice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4- months of age. These findings agree with the corticofugal synaptopathy model that α-MNs and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1G93A mice. Hence, there is a spatial and temporal caudal–rostral progression of α-MN and CST degeneration in SOD1G93A mice.

Mice with transgenic expression of human SOD1G93A are a widely used model of ALS, with a caudal–rostral progression of motor impairment. Previous studies have quantified the progression of motoneuron (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93A mice, to investigate whether there is a caudal–rostral progression of MN death. By 3 months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3 months, the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord in SOD1G93A mice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4- months of age. These findings agree with the corticofugal synaptopathy model that α-MNs and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1G93A mice. Hence, there is a spatial and temporal caudal–rostral progression of α-MN and CST degeneration in SOD1G93A mice.

In computational physics it is standard to approximate continuum systems with discretised representations. Here we consider a specific discretisation of the continuum complex Hilbert space of quantum mechanics - a discretisation where squared amplitudes and complex phases are rational numbers. The fineness of this discretisation is determined by a finite (prime-number) parameter $p$. As $p \rightarrow \infty$, unlike standard discretised representations in computational physics, this model does not tend smoothly to the continuum limit. Instead, the state space of quantum mechanics is a singular limit of the discretised model at $p=\infty$. Using number theoretic properties of trigonometric functions, it is shown that for large enough values of $p$, discretised Hilbert space accurately describes ensemble representations of quantum systems within an inherently superdeterministic framework, one where the Statistical Independence assumption in Bell's theorem is formally violated. In this sense, the discretised model can explain the violation of Bell inequalities without appealing to nonlocality or indefinite reality. It is shown that this discretised framework is not fine tuned (and hence not conspiratorial) with respect to its natural state-space $p$-adic metric. As described by Michael Berry, old theories of physics are typically the singular limits of new theories as a parameter of the new theory is set equal to zero or infinity. Using this, we can answer the challenge posed by Scott Aaronson, critic of superderminism: to explain when a great theory in physics (here quantum mechanics) has ever been `grudgingly accommodated' rather than `gloriously explained' by its candidate successor theory (here a superdeterministic theory of quantum physics based on discretised Hilbert space).

Objective\ud \ud To report detailed age-specific outcomes from the first round of an English pilot studying the implementation of high-risk human papillomavirus (HR-HPV) testing in primary cervical screening.\ud \ud \ud \ud Design\ud \ud Observational study with screening in 2013–2016, followed by two early recalls and/or colposcopy until the end of 2019.\ud \ud \ud \ud Setting\ud \ud Six NHS laboratory sites.\ud \ud \ud \ud Population\ud \ud A total of 1 341 584 women undergoing screening with HR-HPV testing or liquid-based cytology (LBC).\ud \ud \ud \ud Methods\ud \ud Early recall tests and colposcopies were recommended, depending on the nature of the screening-detected abnormality.\ud \ud \ud \ud Main outcome measures\ud \ud We reported standard screening process indicators, e.g. proportions with an abnormality, including high-grade cervical intraepithelial neoplasia (CIN2+) or cancer, and the positive predictive value (PPV) of colposcopy for CIN2+, by screening test and age group.\ud \ud \ud \ud Results\ud \ud Among unvaccinated women screened with HR-HPV testing at age 24–29 years, 26.9% had a positive test and 10.4% were directly referred to colposcopy following cytology triage, with a PPV for CIN2+ of 47%. At 50–64 years of age, these proportions were much lower: 5.3%, 1.2% and 27%, respectively. The proportions of women testing positive for HR-HPV without cytological abnormalities, whose early recall HR-HPV tests returned negative results, were similar across the age spans: 54% at 24–29 years and 55% at 50–64 years. Two-thirds of infections at any age were linked to non-16/18 genotypes. Among women with CIN2, CIN3 or cervical cancer, however, the proportion of non-16/18 infections increased with age. As expected, the detection of abnormalities was lower following screening with LBC.\ud \ud \ud \ud Conclusions\ud \ud These data provide a reliable reference for future epidemiological studies, including those concerning the effectiveness of HPV vaccination.

The relationship between 'rough sex' and the criminal law has recently been subject to considerable scrutiny. Much of this debate has focused on male defendants in homicide cases, who have claimed the death of the female victim resulted accidentally from consensual rough sex. As a result, more commonplace occurrences of rough sex that do not result in death have received limited attention. In particular, the role that rough sex plays in abusive relationships, whether and how this is criminalised, has been largely overlooked.\ud \ud This article addresses this gap by illuminating the role that rough sex can play as both an instrument and a manifestation of coercive control. We problematise the 'stories' that are told about rough sex and coercive control in the criminal law. Three constructions of 'rough sex' have historically been applied in the case law: 'violent sexual assault', 'deviant sexuality' and 'accidental injury'. The introduction of a new offence of 'control-ling or coercive behaviour' was an opportunity to uncover a new, more accurate narrative of abusive rough sex. We argue, however, that the courts are still telling the same old stories.

In a recent paper (arXiv:2107.04761), Sen critiques a superdeterministic model of quantum physics, Invariant Set Theory, proposed by one of the authors. He concludes that superdeterminism is `unlikely to solve the puzzle posed by the Bell correlations'. He also claims that the model is neither local nor $\psi$-epistemic. We here detail multiple inaccuracies with Sen's arguments - notably that the hidden-variable model of quantum physics he uses to critique Invariant Set Theory bares no relation to Invariant Set Theory - and use this opportunity to lay out the properties of Invariant Set Theory as clearly as possible., Comment: 6 pages, no figures. Substantial edits to address published version of Sen's paper

Bell's theorem is often said to imply that quantum mechanics violates local causality, and that local causality cannot be restored with a hidden-variables theory. This however is only correct if the hidden-variables theory fulfils an assumption called Statistical Independence. Violations of Statistical Independence are commonly interpreted as correlations between the measurement settings and the hidden variables (which determine the measurement outcomes). Such correlations have been discarded as "finetuning" or a "conspiracy". We here point out that the common interpretation is at best physically ambiguous and at worst incorrect. The problem with the common interpretation is that Statistical Independence might be violated because of a non-trivial measure in state space, a possibility we propose to call "supermeasured". We use Invariant Set Theory as an example of a supermeasured theory that violates the Statistical Independence assumption in Bell's theorem without requiring correlations between hidden variables and measurement settings.

Presentation at Australasian Science Education Research Association (ASERA) Conference 2021 (Conference name: ASERA 52)

Diverse communities of large mammalian herbivores (LMH), once widespread, are now rare. LMH exert strong direct and indirect effects on community structure and ecosystem functions, and measuring these effects is important for testing ecological theory and for understanding past, current, and future environmental change. This in turn requires long-term experimental manipulations, owing to the slow and often nonlinear responses of populations and assemblages to LMH removal. Moreover, the effects of particular species or body-size classes within diverse LMH guilds are difficult to pinpoint, and the magnitude and even direction of these effects often depends on environmental context. Since 2008, we have maintained the Ungulate Herbivory Under Rainfall Uncertainty (UHURU) experiment, a series of size-selective LMH exclosures replicated across a rainfall/productivity gradient in a semi-arid Kenyan savanna. The goals of the UHURU experiment are to measure the effects of removing successively smaller size classes of LMH (mimicking the process of size-biased extirpation) and to establish how these effects are shaped by spatial and temporal variation in rainfall. The UHURU experiment comprises three LMH-exclusion treatments and an unfenced control, applied to 9 randomized blocks of contiguous 1 ha plots (n = 36). The fenced treatments are: “MEGA” (exclusion of megaherbivores, elephant and giraffe); “MESO” (exclusion of herbivores ≥40 kg); and “TOTAL” (exclusion of herbivores ≥5 kg). Each block is replicated three times at three sites across the 20 km rainfall gradient, which has fluctuated over the course of the experiment. The first five years of data were published previously (Ecological Archives E095-064) and have been used in numerous studies. Since publication of this original data paper, we have (a) continued to collect data according to the original protocols, (b) improved the taxonomic resolution and accuracy of plant and small-mammal identifications, and (c) begun collecting several new data sets. Here, we present updated and extended raw data from the first 12 years of the UHURU experiment (2008–2019). Data include daily rainfall data throughout the experiment; annual surveys of understory plant communities; annual censuses of woody-plant communities; annual measurements of individually tagged woody plants; monthly monitoring of flowering and fruiting phenology; every-other-month small-mammal mark-recapture data; and quarterly large-mammal dung surveys.

Data and code that can be used to reproduce the analyses underlying "Experimental evidence that effects of megaherbivores on mesoherbivore space use are influenced by species’ traits" by Wells et al. (2021) https://doi.org/10.1111/1365-2656.13565

1. The extinction of 80% of megaherbivore (>1,000 kg) species towards the end of the Pleistocene altered vegetation structure, fire dynamics, and nutrient cycling worldwide. Ecologists have proposed (re)introducing megaherbivores or their ecological analogues to restore lost ecosystem functions and reinforce extant but declining megaherbivore populations. However, the effects of megaherbivores on smaller herbivores are poorly understood. 2. We used long-term exclusion experiments and multispecies hierarchical models fitted to dung counts to test 1) the effect of megaherbivore (elephant and giraffe) presence-absence on the occurrence (dung presence) and use intensity (dung-pile density) of mesoherbivores (2–1,000 kg), and 2) the extent to which the responses of each mesoherbivore species was predictable based on their traits (diet and shoulder height) and phylogenetic relatedness. 3. Megaherbivores increased the predicted occurrence and use intensity of zebras but reduced the occurrence and use intensity of several other mesoherbivore species. The negative effect of megaherbivores on mesoherbivore occurrence was stronger for shorter species, regardless of diet or relatedness. 4. Megaherbivores substantially reduced the expected total use intensity (i.e., cumulative dung density of all species) of mesoherbivores, but only minimally reduced the expected species richness (i.e., cumulative predicted occurrence probabilities of all species) of mesoherbivores (by

Presentation at Australasian Science Education Research Association (ASERA) Conference 2020: How Students Say They Choose Their Subjects at School and Its Impact on the Choice of Science entitled "How Students Say They Choose Their Subjects at School and Its Impact on the Choice of Science"

New seasonal retrospective forecasts for 1901-2010 show that skill for predicting ENSO, NAO and PNA is reduced during mid-century periods compared to earlier and more recent high-skill decades. Forecasts of seasonal climate anomalies using physically-based global circulation models are routinely made at operational meteorological centers around the world. A crucial component of any seasonal forecast system is the set of retrospective forecasts, or hindcasts, from past years which are used to estimate skill and to calibrate the forecasts. Hindcasts are usually produced over a period of around 20-30 years. However, recent studies have demonstrated that seasonal forecast skill can undergo pronounced multi-decadal variations. These results imply that relatively short hindcasts are not adequate for reliably testing seasonal forecasts and that small hindcast sample sizes can potentially lead to skill estimates that are not robust. Here we present new and unprecedented 110-year-long coupled hindcasts of the next season over the period 1901 to 2010. Their performance for the recent period is in good agreement with those of operational forecast models. While skill for ENSO is very high during recent decades, it is markedly reduced during the 1930s to 1950s. Skill at the beginning of the 20th Century is, however, as high as for recent high-skill periods. Consistent with findings in atmosphere-only hindcasts, a mid-century drop in forecast skill is found for a range of atmospheric fields including large-scale indices such as the NAO and the PNA patterns. As with ENSO, skill scores for these indices recover in the early 20th Century suggesting that the mid-century drop in skill is not due to lack of good observational data. A public dissemination platform for our hindcast data is available and we invite the scientific community to explore them.

Background: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD. Methods and findings: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39–73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10−8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%–93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10−8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation–higher trait; 95% CI: 1.49–1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25–1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56–1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31–2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57–1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02–1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation–higher HDL cholesterol (OR 0.80; 95% CI: 0.75–0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77–0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components. Conclusions: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.

Based on skill estimates from hindcasts made over the last couple of decades, recent studies have suggested that considerable success has been achieved in forecasting winter climate anomalies over the Euro-Atlantic area using current-generation dynamical forecast models. However, previous-generation models had shown that forecasts of winter climate anomalies in the 1960s and 1970s were less successful than forecasts of the 1980s and 1990s. Given that the more recent decades have been dominated by the North Atlantic Oscillation (NAO) in its positive phase, it is important to know whether the performance of current models would be similarly skilful when tested over periods of a predominantly negative NAO. To this end, a new ensemble of atmospheric seasonal hindcasts covering the period 1900-2009 has been created, providing a unique tool to explore many aspects of atmospheric seasonal climate prediction. In this study we focus on two of these: multi-decadal variability in predicting the winter NAO, and the potential value of the long seasonal hindcast datasets for the emerging science of probabilistic event attribution. The existence of relatively low skill levels during the period 1950s-1970s has been confirmed in the new dataset. The skill of the NAO forecasts is larger, however, in earlier and later periods. Whilst these inter-decadal differences in skill are, by themselves, only marginally statistically significant, the variations in skill strongly co-vary with statistics of the general circulation itself suggesting that such differences are indeed physically based. The mid-century period of low forecast skill coincides with a negative NAO phase but the relationship between the NAO phase/amplitude and forecast skill is more complex than linear. Finally, we show how seasonal forecast reliability can be of importance for increasing confidence in statements of causes of extreme weather and climate events, including effects of anthropogenic climate change.

We introduce and study the impact of three stochastic schemes in the EC-Earth climate model: two atmospheric schemes and one stochastic land scheme. These form the basis for a probabilistic Earth system model in atmosphere-only mode. Stochastic parametrization have become standard in several operational weather-forecasting models, in particular due to their beneficial impact on model spread. In recent years, stochastic schemes in the atmospheric component of a model have been shown to improve aspects important for the models long-term climate, such as El Niño–Southern Oscillation (ENSO), North Atlantic weather regimes, and the Indian monsoon. Stochasticity in the land component has been shown to improve the variability of soil processes and improve the representation of heatwaves over Europe. However, the raw impact of such schemes on the model mean is less well studied. It is shown that the inclusion of all three schemes notably changes the model mean state. While many of the impacts are beneficial, some are too large in amplitude, leading to significant changes in the model's energy budget and atmospheric circulation. This implies that in order to maintain the benefits of stochastic physics without shifting the mean state too far from observations, a full re-tuning of the model will typically be required.

Although the partial differential equations that describe the physical climate system are deterministic, there is an important reason why the computational representations of these equations should be stochastic: such representations better respect the scaling symmetries of these underlying differential equations, as described in this Perspective. This Perspective also surveys the ways in which introducing stochasticity into the parameterized representations of subgrid processes in comprehensive weather and climate models has improved the skill of forecasts and has reduced systematic model error, notably in simulating persistent flow anomalies. The pertinence of stochasticity is also discussed in the context of the question of how many bits of useful information are contained in the numerical representations of variables, a question that is critical for the design of next-generation climate models. The accuracy of fluid simulation may be further increased if future-generation supercomputer hardware becomes partially stochastic. Although the differential equations that describe the physical climate system are deterministic, there are reasons, both theoretical and practical, why computational representations of these equations should be stochastic. This Perspective surveys the benefits of stochastic modelling of weather and climate.

This report presents findings from the External Independent Evaluation and Research for Primary Connections Stage 6 (2014–2018) conducted by a research team from the University of Technology Sydney (UTS).

Stochastic schemes, designed to represent unresolved sub-grid scale variability, are frequently used in short and medium-range weather forecasts, where they are found to improve several aspects of the model. In recent years, the impact of stochastic physics has also been found to be beneficial for the model's long term climate. In this paper, we demonstrate for the first time that the inclusion of a stochastic physics scheme can notably affect a model's projection of global warming, as well as its historical climatological global temperature. Specifically, we find that when including the 'stochastically perturbed parametrisation tendencies' scheme (SPPT) in the fully coupled climate model EC-Earth v3.1, the predicted level of global warming between 1850 and 2100 is reduced by 10% under an RCP8.5 forcing scenario. We link this reduction in climate sensitivity to a change in the cloud feedbacks with SPPT. In particular, the scheme appears to reduce the positive low cloud cover feedback, and increase the negative cloud optical feedback. A key role is played by a robust, rapid increase in cloud liquid water with SPPT, which we speculate is due to the scheme's non-linear interaction with condensation., Comment: Under review in Journal of Geophysical Research: Atmospheres

Bell's Theorem requires any theory which obeys the technical definitions of Free Choice and Local Causality to satisfy the Bell inequality. Invariant set theory is a finite theory of quantum physics which violates the Bell inequality exactly as does quantum theory: in it neither Free Choice nor Local Causality hold, consistent with Bell's Theorem. However, within the proposed theory, the mathematical expressions of both Free Choice and Local Causality involve states which, for number-theoretic reasons, cannot be ontic (cannot lie on the theory's fractal-like invariant set $I_U$ in state space). Weaker versions of Free Choice and Local Causality are proposed involving only the theory's ontic states. Conventional hidden-variable theories satisfying only these weaker definitions still obey the Bell inequality. However, invariant set theory, which violates the Bell inequality, satisfies these weaker definitions. It is argued that the weaker definitions are consistent with the physical meaning behind free choice and local causality as defined in space-time, and hence that Free Choice and Local Causality are physically too strong. It is concluded that the experimental violation of the Bell inequality may have less to do with free choice or local causality \emph{per se}, and more to do with the presence of a holistic but causal state-space geometry onto which quantum ontic states are constrained.

The use of reduced numerical precision within an atmospheric data assimilation system is investigated. An atmospheric model with a spectral dynamical core is used to generate synthetic observations, which are then assimilated back into the same model using an ensemble Kalman filter. The effect on the analysis error of reducing precision from 64 bits to only 22 bits is measured and found to depend strongly on the degree of model uncertainty within the system. When the model used to generate the observations is identical to the model used to assimilate observations, the reduced‐precision results suffer substantially. However, when model error is introduced by changing the diffusion scheme in the assimilation model or by using a higher‐resolution model to generate observations, the difference in analysis quality between the two levels of precision is almost eliminated. Lower‐precision arithmetic has a lower computational cost, so lowering precision could free up computational resources in operational data assimilation and allow an increase in ensemble size or grid resolution.

An arbitrarily dense discretisation of the Bloch sphere of complex Hilbert states is constructed, where points correspond to bit strings of fixed finite length. Number-theoretic properties of trigonometric functions (not part of the quantum-theoretic canon) are used to show that this constructive discretised representation incorporates many of the defining characteristics of quantum systems: completementarity, uncertainty relationships and (with a simple Cartesian product of discretised spheres) entanglement. Unlike Meyer's earlier discretisation of the Bloch Sphere, there are no orthonormal triples, hence the Kocken-Specker theorem is not nullified. A physical interpretation of points on the discretised Bloch sphere is given in terms of ensembles of trajectories on a dynamically invariant fractal set in state space, where states of physical reality correspond to points on the invariant set. This deterministic construction provides a new way to understand the violation of the Bell inequality without violating statistical independence or factorisation, where these conditions are defined solely from states on the invariant set. In this finite representation there is an upper limit to the number of qubits that can be entangled, a property with potential experimental consequences., Proceedings of the Royal Society A. To appear

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.Molecular Psychiatry advance online publication, 21 March 2017; doi:10.1038/mp.2017.15. © 2017 The Author(s) Cited By :1; Export Date: 17 July 2017; Article in Press

It has recently been argued that single-model seasonal forecast ensembles are overdispersive, implying that the real world is more predictable than indicated by estimates of so-called perfect model predictability, particularly over the North Atlantic. However, such estimates are based on relatively short forecast data sets comprising just 20 years of seasonal predictions. Here we study longer 40 year seasonal forecast data sets from multimodel seasonal forecast ensemble projects and show that sampling uncertainty due to the length of the hindcast periods is large. The skill of forecasting the North Atlantic Oscillation during winter varies within the 40 year data sets with high levels of skill found for some subperiods. It is demonstrated that while 20 year estimates of seasonal reliability can show evidence of overdispersive behavior, the 40 year estimates are more stable and show no evidence of overdispersion. Instead, the predominant feature on these longer time scales is underdispersion, particularly in the tropics. Key Points Predictions can appear overdispersive due to hindcast length sampling error Longer hindcasts are more robust and underdispersive, especially in the tropics Twenty hindcasts are an inadequate sample size to assess seasonal forecast skill

Background: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. Methods: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. Results: The new method showed the strongest agreement with the expert. At 20x resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10x resolution, it was more accurate than and twice as fast as all other methods at 20x resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. Conclusions: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers. Funding Agencies|Fraunhofer Society, Munich, Germany; Swedish Research Council of Medicine and Health; Swedish Research Council of Science and Engineering; Vinnova

The synthesis of quantum and gravitational physics is sought through a finite, realistic, locally causal theory where gravity plays a vital role not only during decoherent measurement but also during non-decoherent unitary evolution. Invariant set theory is built on geometric properties of a compact fractal-like subset $I_U$ of cosmological state space on which the universe is assumed to evolve and from which the laws of physics are assumed to derive. Consistent with the primacy of $I_U$, a non-Euclidean (and hence non-classical) state-space metric $g_p$ is defined, related to the $p$-adic metric of number theory where $p$ is a large but finite Pythagorean prime. Uncertain states on $I_U$ are described using complex Hilbert states, but only if their squared amplitudes are rational and corresponding complex phase angles are rational multiples of $2 \pi$. Such Hilbert states are necessarily $g_p$-distant from states with either irrational squared amplitudes or irrational phase angles. The gappy fractal nature of $I_U$ accounts for quantum complementarity and is characterised numerically by a generic number-theoretic incommensurateness between rational angles and rational cosines of angles. The Bell inequality, whose violation would be inconsistent with local realism, is shown to be $g_p$-distant from all forms of the inequality that are violated in any finite-precision experiment. The delayed-choice paradox is resolved through the computational irreducibility of $I_U$. The Schr\"odinger and Dirac equations describe evolution on $I_U$ in the singular limit at $p=\infty$. By contrast, an extension of the Einstein field equations on $I_U$ is proposed which reduces smoothly to general relativity as $p \rightarrow \infty$. Novel proposals for the dark universe and the elimination of classical space-time singularities are given and experimental implications outlined.

Science study at school has been linked to the provision of a scientifically capable workforce and a scientifically literate society. Concern has been expressed by educators, academics and policymakers that too few students are choosing post-compulsory science at school. Gender-based preferences for some science subjects has been cited as an important factor affecting choice of science at school. A Best-Worst Scaling survey was used to measure the relative importance of 21 factors that male and female students consider when choosing and rejecting subjects. Results from 333 Year 10 (age 14–17) students suggest that male and female students choose and reject subjects in a similar manner but there are differences in the degree of importance students place on some factors. Girls considered their interest, enjoyment, past ability and type of classwork as being relatively more important than boys did when choosing subjects. Girls considered their past ability and difficulty of a subject as more important than boys did when rejecting subjects. This research indicates that overall girls and boys rank the factors for choosing and rejecting subjects in a similar manner but there are differences in the importance they place on individual factors.

Objective: To measure patterns of clinical activity at colposcopy before and after vaccinated women entered the Scottish Cervical Screening Programme (SCSP). Design: Population-based observational study using nationally collected data. Setting: Scottish colposcopy clinics. Sample: All women with a date of birth on or after 1 January 1985 who attended colposcopy in Scotland between 2008-2014. Methods: Routinely collected data from the Scottish National Colposcopy Clinical Information Audit System (NCCIAS) was extracted, including: referral criteria, referral cervical cytology, colposcopic findings, clinical procedures and histology results. Analysis was restricted to those referred to colposcopy at age 20 or 21 years. Main outcome measures: Referral criteria, positive predictive value of colposcopy, default rates and rates of cervical biopsies and treatments. Results: 7372 women referred for colposcopy at age 20/ 21 years were identified. There was a downward trend in the proportion of those referred with abnormal cytology (2008/9: 91.0%, 2013/14: 90.3%, linear trend p value = 0.03). Women were less likely to have diagnostic or therapeutic interventions. The proportion with no biopsy (2008/9: 19.5%, 2013/14: 26.9%, linear trend p value < 0.0001) and no treatment (2008/9: 74.9%, 2013/14: 91.8%, linear trend p value < 0.0001) increased over the period of observation. Conclusions: A reduction in clinical activity related to abnormal screening referrals is likely to be associated with the HPV catch-up immunisation programme. Referral criteria and service provision of colposcopy needs to be planned carefully taking account of the increasing number of HPV- immunised women that will be entering cervical screening programmes worldwide.

Seasonal hindcast experiments, using prescribed SSTs, are analysed for Northern Hemisphere winters from 1900-2010. Ensemble mean Pacific/North American index (PNA) skill varies dramatically, dropping towards zero during the mid-twentieth century, with similar variability in North Atlantic Oscillation (NAO) hindcast skill. The PNA skill closely follows the correlation between the observed PNA index and tropical Pacific SST anomalies. During the mid-century period the PNA and NAO hindcast errors are closely related. The drop in PNA predictability is due to mid-century negative PNA events, which were not forced in a predictable manner by tropical Pacific SST anomalies. Overall, negative PNA events are less predictable and seem likely to arise more from internal atmospheric variability than positive PNA events. Our results suggest that seasonal forecasting systems assessed over the recent 30-year period may be less skillful in periods, such as the mid-twentieth century, with relatively weak forcing from tropical Pacific SST anomalies.

Increasing the resolution of numerical models has played a large part in improving the accuracy of weather and climate forecasts in recent years. Until now, this has required the use of ever more powerful computers, the energy costs of which are becoming increasingly problematic. It has therefore been proposed that forecasters switch to using more efficient ‘reduced precision’ hardware capable of sacrificing unnecessary numerical precision to save costs. Here, an extended form of the Lorenz ‘96 idealized model atmosphere is used to test whether more accurate forecasts could be produced by lowering numerical precision more at smaller spatial scales in order to increase the model resolution. Both a scale-dependent mixture of single- and half-precision – where numbers are represented with fewer bits of information on smaller spatial scales – and ‘stochastic processors’ – where random ‘bit-flips’ are allowed for small-scale variables – are emulated on conventional hardware. It is found that high-resolution parametrized models with scale-selective reduced precision yield better short-term and climatological forecasts than lower resolution parametrized models with conventional precision for a relatively small increase in computational cost. This suggests that a similar approach in real-world models could lead to more accurate and efficient weather and climate forecasts.

Background In previous systematic reviews, predominantly of randomised controlled trials, pulmonary rehabilitation (PR) has been shown to reduce hospital admissions for acute exacerbations of COPD (AECOPD). However, findings have been less consistent for cohort studies. We aimed to compare rates of hospitalized and general practice (GP) treated AECOPD before and after PR. Methods Using anonymised data from the Clinical Practice Research Datalink and Hospital Episode Statistics, hospital admissions and GP visits for AECOPD were compared one year before and after PR in patients referred for PR. Exacerbation rates were also compared between individuals eligible and referred for PR with those eligible and not referred. Results 69,089 (64%) of the COPD patients in the cohort were eligible for PR. Of these, only 6,436 (9.3%) were recorded as having been referred for rehabilitation. 62, 019 (89.8%) were not referred and 634 (0.98%) declined referral. When combining GP and hospital exacerbations, people who were eligible and were referred for PR had a slightly higher but not statistically significant exacerbation rate (2.83 exacerbations/patient-year 95% CI: 2.66, 3.00) than those who were eligible but not referred (2.17 exacerbations/patient-year 95% CI: 2.11, 2.24). Conclusions This study found that less than 10% of patients who were eligible for PR were actually referred. Patients who were eligible and referred for (but not necessarily completed) PR did not have fewer GP visits and hospitalizations for AECOPD in the year after PR compared to those not referred or compared to the year before PR.

Stochastic schemes to represent model uncertainty in the European Centre for Medium-Range Weather Forecasts (ECMWF) ensemble prediction system has helped improve its probabilistic forecast skill over the past decade by both improving its reliability and reducing the ensemble mean error. The largest uncertainties in the model arise from the model physics parameterizations. In the tropics, the parameterization of moist convection presents a major challenge for the accurate prediction of weather and climate. Superparameterization is a promising alternative strategy for including the effects of moist convection through explicit turbulent fluxes calculated from a cloud-resolving model (CRM) embedded within a global climate model (GCM). In this paper, we compare the impact of initial random perturbations in embedded CRMs, within the ECMWF ensemble prediction system, with stochastically perturbed physical tendency (SPPT) scheme as a way to represent model uncertainty in medium-range tropical weather forecasts. We especially focus on forecasts of tropical convection and dynamics during MJO events in October–November 2011. These are well-studied events for MJO dynamics as they were also heavily observed during the DYNAMO field campaign. We show that a multiscale ensemble modeling approach helps improve forecasts of certain aspects of tropical convection during the MJO events, while it also tends to deteriorate certain large-scale dynamic fields with respect to stochastically perturbed physical tendencies approach that is used operationally at ECMWF.

Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease. Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding. Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors. Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin. Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education. Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D). Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile. Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker., What's New? Circulating insulin‐like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. To address this question, the authors used Mendelian randomization, a method that uses genetic variants as proxies for measured exposures. Their results implicate the IGF pathway in general in prostate cancer development but specific biomarkers remain to be determined.

Background: Acute exacerbations of COPD are a major cause of morbidity and mortality and have a heavy burden on healthcare resources. Pulmonary rehabilitation (PR) has been shown to reduce hospital admissions and improve quality of life, but few studies have investigated the effect of PR on exacerbation rate using routinely collected health records. Methods: Primary care data from the Clinical Practice Research Datalink and Hospital Episode Statistics (HES) on acute exacerbations were combined to determine the effects of PR on acute exacerbations of COPD one year before and after PR in patients who received PR compared to patients who did not. Findings: 108,042 patients were included in the analysis between 1 st January 2004 and 31st March 2014. Of those, 38,952 (36%) were not eligible for PR. Of the 69,090 eligible; 6,436 (9.3%) were recorded a having received PR, 62,019 (89.8%) were not referred and 634 (0.9%) were referred but declined. When combining primary care events with HES events, people who received PR had a higher incidence rate (IR) of acute exacerbations (IR = 3.18 95% CI: 3.02, 3.35) compared to people who did not receive PR (IR = 3.04 95% CI: 2.88, 3.20). Conclusions: This study highlights that a high proportion of COPD patients eligible for PR in the UK are not being referred. In addition, poorer outcomes (defined as acute exacerbations) following PR suggest that either higher risk patients are being referred for PR, or PR as currently delivered is ineffective. Higher quality, standardised PR programmes should be encouraged to ensure outcomes from randomised controlled trials can be replicated in real life.

We present several atmospheric general circulation experiments which model the atmospheric response to SST anomalies in the tropical East and West Pacific. We have found that the extratropical response to a relatively small West Pacific anomaly can be stronger than, and qualitatively different from the response to a much larger East Pacific anomaly. These experiments suggest a possible explanation for the difference in mid-latitude response during the 1976-77 El Nino winter and the El Nino winters of 1972-73 and 1982-83.-from Authors

A basic objective is to study the influence of model climatology on the response to a tropical s.s.t. anomaly. This was done both by comparing our results with those from a lower resolution GCM (the NCAR Community Climate Model) with an identical s.s.t. anomaly, and by performing control and anomaly integrations with both mean and envelope orography. The specification of orography strongly influences the strength of the mean zonal flow, and stationary and transient wave activity in our model. Overall, we conclude that a GCM's response is strongly sensitive to the basic model climatology. In trying to understand dynamically the GCM response it was concluded that the PNA pattern may not simply be the result of Rossby wave dispersion from a tropical source. The PNA pattern may also be associated with a combination of two separate influences, the interaction with the anomalous mean flow of enhanced storm track activity over the Pacific, and with orography on the North American continent. -from Authors

The relative merits of three forecast systems addressing the impact of model uncertainty on seasonal/annual forecasts are described. One system consists of a multi-model, whereas two other systems sample uncertainties by perturbing the parametrization of reference models through perturbed parameter and stochastic physics techniques. Ensemble reforecasts over 1991 to 2001 were performed with coupled climate models started from realistic initial conditions. Forecast quality varies due to the different strategies for sampling uncertainties, but also to differences in initialisation methods and in the reference forecast system. Both the stochastic-physics and perturbed-parameter ensembles improve the reliability with respect to their reference forecast systems, but not the discrimination ability. Although the multi-model experiment has an ensemble size larger than the other two experiments, most of the assessment was done using equally-sized ensembles. The three ensembles show similar levels of skill: significant differences in performance typically range between 5 and 20%. However, a nine-member multi-model shows better results for seasonal predictions with lead times shorter than five months, followed by the stochastic-physics and perturbed-parameter ensembles. Conversely, for seasonal predictions with lead times longer than four months, the perturbed-parameter ensemble gives more often better results. All systems suggest that spread cannot be considered a useful predictor of skill. Annual-mean predictions showed lower forecast quality than seasonal predictions. Only small differences between the systems were found. The full multi-model ensemble has improved quality with respect to all other systems, mainly from the larger ensemble size for lead times longer than four months and annual predictions. © 2009 Royal Meteorological Society and Crown Copyright.

Results from 4 pairs of 50-day wintertime integrations of the Meteorological Office's 5-level general circulation model, with warm and cold sea surface temperature (s.s.t.) anomalies of about 3K in the NW Atlantic, are described. Difference fields between the warm and cold integrations are statistically significant at the 1% level with positive geopotential height over the central N Atlantic, and weaker negative height over Europe. The storm track over the Atlantic is displaced from its normal position. Results from 4 further pairs of integrations with halved s.s.t. anomalies are also described. The response is approximately linear, with systematic differences in 500mb geopotential height over the Atlantic, parts of which are just significant at the 10% level with half the full s.s.t. anomaly. Overall, however, the model's response is weaker than could be obtained with tropical s.s.t. anomalies of the same magnitude. Results from the model integrations are compared with results from an observational study of the relationship between wintertime s.s.t. in the NW Atlantic, and mean sea level pressure and 500mb height. Two independent 30yr periods were chosen for study, thus minimizing the influence of long-term trends in s.s.t. Over the Atlantic and Europe the model results compared well with the observations. With s.s.t. data lagging the atmosphere by one month, the observational study appears to show that the s.s.t. anomalies are initially forced by perturbations in the atmospheric circulation. -from Authors

The probabilistic skill of ensemble forecasts for the first month and the first season of the forecasts is assessed, where model uncertainty is represented by the a) multi-model, b) perturbed parameters, and c) stochastic parameterisation ensembles. The main foci of the assessment are the Brier Skill Score for near-surface temperature and precipitation over land areas and the spread-skill relationship of sea surface temperature in the tropical equatorial Pacific. On the monthly timescale, the ensemble forecast system with stochastic parameterisation provides overall the most skilful probabilistic forecasts. On the seasonal timescale the results depend on the variable under study: for near surface temperature the multi-model ensemble is most skilful for most land regions and for global land areas. For precipitation, the ensemble with stochastic parameterisation most often produces the highest scores on global and regional scales. Our results indicate that stochastic parameterisations should now be developed for multi-decadal climate predictions using earth-system models. Copyright 2011 by the American Geophysical Union.

The twin arginine protein transport (Tat) system transports folded proteins across the cytoplasmic membranes of prokaryotes and the thylakoid membranes of plant chloroplasts. In Escherichia coli, the TatB and TatC components form a multivalent receptor complex that binds Tat substrates. Here, we have used a genetic fusion approach to construct covalent TatC oligomers in order to probe the organisation of TatC. A fused dimer of TatC supported Tat transport activity and was fully stable in vivo. Inactivating point mutations in one or other of the TatC units in the fused TatC dimer did not inactivate TatC function, indicating that only one TatC protomer in the TatC fused dimer needs to be active. Larger covalent fusions of TatC also supported Tat transport activity but were degraded in vivo to release smaller TatC forms. Taken together, these results strongly suggest that TatC forms a functional dimer, and support the idea that there is an even number of TatC protomers in the TatBC complex.

The influence of mid-latitude oceanic variability on the atmospheric general circulation is not well understood. Nevertheless, some modelling and observational evidence is presented to suggest that, in winter-time, persistent sea surface temperature anomalies near Newfoundland could influence climate downstream over Europe. The discussion is summary of a more extensive paper which recently appeared in the Quarterly Journal of the Royal Meteorological Society.-Author