Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.

Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.

Controlling Chaos: Periodic Defect Braiding in Active Nematics Confined to a Cardioid.

This work examines self-mixing in active nematics, a class of fluids in which mobile topological defects drive chaotic flows in a system comprised of biological filaments and molecular motors. We present experiments that demonstrate how geometrical confinement can influence the braiding dynamics of the defects. Notably, we show that confinement in cardioid-shaped wells leads to realization of the golden braid, a maximally efficient mixing state of exactly three defects with no defect creation or annihilation. We characterize the golden braid state using different measures of topological entropy and the Lyapunov exponent. In particular, topological entropy measured from the stretching rate of material lines agrees well with an analytical computation from braid theory. Increasing the size of the confining cardioid produces a transition from the golden braid, to the fully chaotic active turbulent state.

Insufficient Evidence for "Autism-Specific" Genes.

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Management of penetrating thoracic wounds from a dog attack in a Nigerian dwarf goat: A case report.

Pet goat ownership has gradually increased in popularity and veterinarians are expected to provide gold-standard treatments for these animals. As in small-animal practice, decision-making regarding thoracic bite injuries is challenging because of the variability in clinical, radiographic, and surgical findings. Mortality rates from dog bite wounds in small animals range between 15.3 and 17.7%, and these cases represent 10% of all traumatic injuries referred to an emergency service; such information is not available regarding pet goats. The aim of this report is to describe a thoracic dog bite wound in a goat. It details the clinical, radiographic, and surgical findings and the repair, and reports the successful outcome, all to provide information to small-ruminant practitioners for treatment or referral. Future retrospective studies will help to determine prognostic factors for outcomes in goats with thoracic dog bite wounds. Key clinical message: Thoracic bite wounds are a challenge to manage, considering the potential severe underlying pathology and the absence of clear external injuries or clinical signs. Referring veterinarians and owners should be advised that goats with the presence of flail chest, pneumothorax, or rib fractures may require a higher level of intervention.

Prise en charge des plaies thoraciques pénétrantes consécutives à une attaque de chien chez une chèvre naine nigériane : rapport de cas. La possession de chèvres de compagnie a progressivement gagné en popularité et les vétérinaires devraient fournir des traitements de référence pour ces animaux. Tout comme dans la pratique des petits animaux, la prise de décision concernant les morsures thoraciques est difficile en raison de la variabilité des résultats cliniques, radiographiques et chirurgicaux. Les taux de mortalité par morsure de chien chez les petits animaux varient entre 15,3 et 17,7 %, et ces cas représentent 10 % de toutes les blessures traumatiques référées à un service d'urgence; ces informations ne sont pas disponibles concernant les chèvres de compagnie. Le but de ce rapport est de décrire une morsure thoracique de chien chez une chèvre. Il détaille les résultats cliniques, radiographiques et chirurgicaux ainsi que la réparation, et rend compte du résultat positif, le tout dans le but de fournir des informations aux praticiens des petits ruminants pour un traitement ou une référence. De futures études rétrospectives aideront à déterminer les facteurs pronostiques des résultats chez les chèvres présentant des morsures thoraciques de chien.Message clinique clé :Les morsures thoraciques sont un défi à gérer, compte tenu de la pathologie sous-jacente potentiellement grave et de l'absence de blessures externes ou de signes cliniques évidents. Les vétérinaires référents et les propriétaires doivent être informés que les chèvres présentant un volet thoracique, un pneumothorax ou des fractures des côtes peuvent nécessiter un niveau d'intervention plus élevé.(Traduit par Dr Serge Messier).

Real-Time Scene Monitoring for Deaf-Blind People.

It is estimated that at least 15 million people worldwide live with severe deaf-blindness, with many more experiencing varying degrees of deaf-blindness. The existing options of assistance are mostly limited to walking canes, guide dogs and human care. We propose a wearable device which harnesses a multi-antenna mmWave radar transceiver and a haptic feedback array for real time detection of a person moving within a scene. We present our findings from a series of workshops with participants classed with multi-sensory impairments (MSI), to demonstrate the relative success of this approach and its potential for integration into existing assistance for the MSI of the future.

Effect of a Biopsychosocial Intervention or Postural Therapy on Disability and Health Care Spending Among Patients With Acute and Subacute Spine Pain: The SPINE CARE Randomized Clinical Trial.

Importance: Low back and neck pain are often self-limited, but health care spending remains high. Objective: To evaluate the effects of 2 interventions that emphasize noninvasive care for spine pain. Design, Setting, and Participants: Pragmatic, cluster, randomized clinical trial conducted at 33 centers in the US that enrolled 2971 participants with neck or back pain of 3 months' duration or less (enrollment, June 2017 to March 2020; final follow-up, March 2021). Interventions: Participants were randomized at the clinic-level to (1) usual care (n = 992); (2) a risk-stratified, multidisciplinary intervention (the identify, coordinate, and enhance [ICE] care model that combines physical therapy, health coach counseling, and consultation from a specialist in pain medicine or rehabilitation) (n = 829); or (3) individualized postural therapy (IPT), a postural therapy approach that combines physical therapy with building self-efficacy and self-management (n = 1150). Main Outcomes and Measures: The primary outcomes were change in Oswestry Disability Index (ODI) score at 3 months (range, 0 [best] to 100 [worst]; minimal clinically important difference, 6) and spine-related health care spending at 1 year. A 2-sided significance threshold of .025 was used to define statistical significance. Results: Among 2971 participants randomized (mean age, 51.7 years; 1792 women [60.3%]), 2733 (92%) finished the trial. Between baseline and 3-month follow-up, mean ODI scores changed from 31.2 to 15.4 for ICE, from 29.3 to 15.4 for IPT, and from 28.9 to 19.5 for usual care. At 3-month follow-up, absolute differences compared with usual care were -5.8 (95% CI, -7.7 to -3.9; P < .001) for ICE and -4.3 (95% CI, -5.9 to -2.6; P < .001) for IPT. Mean 12-month spending was $1448, $2528, and $1587 in the ICE, IPT, and usual care groups, respectively. Differences in spending compared with usual care were -$139 (risk ratio, 0.93 [95% CI, 0.87 to 0.997]; P = .04) for ICE and $941 (risk ratio, 1.40 [95% CI, 1.35 to 1.45]; P < .001) for IPT. Conclusions and Relevance: Among patients with acute or subacute spine pain, a multidisciplinary biopsychosocial intervention or an individualized postural therapy intervention, each compared with usual care, resulted in small but statistically significant reductions in pain-related disability at 3 months. However, compared with usual care, the biopsychosocial intervention resulted in no significant difference in spine-related health care spending and the postural therapy intervention resulted in significantly greater spine-related health care spending at 1 year. Trial Registration: ClinicalTrials.gov Identifier: NCT03083886.

Developmental noise is an overlooked contributor to innate variation in psychological traits.

Stochastic developmental variation is an additional important source of variance - beyond genes and environment - that should be included in considering how our innate psychological predispositions may interact with environment and experience, in a culture-dependent manner, to ultimately shape patterns of human behaviour.

The effect of laparoscopy on intracranial pressure as measured by optic nerve sheath diameter: A review.

Laparoscopic surgery has many benefits over open surgery including lower complication rates, and shorter duration and lower cost of hospitalization. However, recent human literature suggests laparoscopy and carbon dioxide insufflation can result in intracranial hypertension. Invasive monitoring of intracranial pressure is not routinely performed in veterinary medicine, and ultrasonographic evaluation of the optic nerve sheath has been employed as an indirect measure of intracranial pressure in many species. The optic nerve sheath is continuous with the meninges of the brain and becomes distended with intracranial hypertension. Optic nerve sheath diameter is a reliable and consistent measure of intracranial pressure and has been utilized in humans to evaluate patients for intracranial hypertension secondary to laparoscopy and capnoperitoneum. No thorough evaluation of the effects of laparoscopy on intracranial pressure has been performed in dogs. Ultrasonographic evaluation of the optic nerve sheath is a safe, non-invasive, and inexpensive procedure that may allow for the evaluation of intracranial pressure without the need for invasive monitoring systems. As laparoscopic procedures are performed increasingly often, this review aims to inform the reader on the effects of capnoperitoneum and to facilitate appropriate patient selection, anesthetic considerations, and surgical planning.

L'effet de la laparoscopie sur la pression intracrânienne mesurée par le diamètre de la gaine du nerf optique : une revue. La chirurgie laparoscopique présente de nombreux avantages par rapport à la chirurgie ouverte, notamment des taux de complications plus faibles, une durée d'hospitalisation plus courte et un coût moindre. Cependant, la littérature humaine récente suggère que la laparoscopie et l'insufflation de dioxyde de carbone peuvent entraîner une hypertension intracrânienne. La surveillance invasive de la pression intracrânienne n'est pas systématiquement effectuée en médecine vétérinaire, et l'évaluation échographique de la gaine du nerf optique a été utilisée comme mesure indirecte de la pression intracrânienne chez de nombreuses espèces. La gaine du nerf optique est continue avec les méninges du cerveau et se distend avec l'hypertension intracrânienne. Le diamètre de la gaine du nerf optique est une mesure fiable et cohérente de la pression intracrânienne et a été utilisé chez l'homme pour évaluer les patients atteints d'hypertension intracrânienne secondaire à la laparoscopie et au capnopéritoine. Aucune évaluation approfondie des effets de la laparoscopie sur la pression intracrânienne n'a été réalisée chez le chien. L'évaluation échographique de la gaine du nerf optique est une procédure sûre, non invasive et peu coûteuse qui peut permettre l'évaluation de la pression intracrânienne sans avoir besoin de systèmes de surveillance invasifs. Les procédures laparoscopiques étant de plus en plus pratiquées, cette revue vise à informer le lecteur sur les effets du pneumopéritoine et à faciliter la sélection appropriée des patients, les considérations anesthésiques et la planification chirurgicale.(Traduit par Dr Serge Messier).

Naturalising Agent Causation.

The idea of agent causation-that a system such as a living organism can be a cause of things in the world-is often seen as mysterious and deemed to be at odds with the physicalist thesis that is now commonly embraced in science and philosophy. Instead, the causal power of organisms is attributed to mechanistic components within the system or derived from the causal activity at the lowest level of physical description. In either case, the 'agent' itself (i.e., the system as a whole) is left out of the picture entirely, and agent causation is explained away. We argue that this is not the right way to think about causation in biology or in systems more generally. We present a framework of eight criteria that we argue, collectively, describe a system that overcomes the challenges concerning agent causality in an entirely naturalistic and non-mysterious way. They are: (1) thermodynamic autonomy, (2) persistence, (3) endogenous activity, (4) holistic integration, (5) low-level indeterminacy, (6) multiple realisability, (7) historicity, (8) agent-level normativity. Each criterion is taken to be dimensional rather than categorical, and thus we conclude with a short discussion on how researchers working on quantifying agency may use this multidimensional framework to situate and guide their research.

3D Imaging from Multipath Temporal Echoes.

Echo location is a broad approach to imaging and sensing that includes both manmade RADAR, LIDAR, SONAR, and also animal navigation. However, full 3D information based on echo location requires some form of scanning of the scene in order to provide the spatial location of the echo origin-points. Without this spatial information, imaging objects in three-dimensional (3D) is a very challenging task as the inverse retrieval problem is strongly ill-posed. Here, we show that the temporal information encoded in the return echoes that are reflected multiple times within a scene is sufficient to faithfully render an image in 3D. Numerical modeling and an information theoretic perspective prove the concept and provide insight into the role of the multipath information. We experimentally demonstrate the concept by using both radio frequency and acoustic waves for imaging individuals moving in a closed environment.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Fractal generation in a two-dimensional active-nematic fluid.

Active fluids, composed of individual self-propelled agents, can generate complex large-scale coherent flows. A particularly important laboratory realization of such an active fluid is a system composed of microtubules, aligned in a quasi-two-dimensional (2D) nematic phase and driven by adenosine-triphosphate-fueled kinesin motor proteins. This system exhibits robust chaotic advection and gives rise to a pronounced fractal structure in the nematic contours. We characterize such experimentally derived fractals using the power spectrum and discover that the power spectrum decays as k-ß for large wavenumbers k. The parameter ß is measured for several experimental realizations. Though ß is effectively constant in time, it does vary with experimental parameters, indicating differences in the scale-free behavior of the microtubule-based active nematic. Though the fractal patterns generated in this active system are reminiscent of passively advected dye in 2D chaotic flows, the underlying mechanism for fractal generation is more subtle. We provide a simple, physically inspired mathematical model of fractal generation in this system that relies on the material being locally compressible, though the total area of the material is conserved globally. The model also requires that large-scale density variations are injected into the material periodically. The model reproduces the power-spectrum decay k-ß seen in experiments. Linearizing the model of fractal generation about the equilibrium density, we derive an analytic relationship between ß and a single dimensionless quantity r, which characterizes the compressibility.

Trapping of swimmers in a vortex lattice.

We examine the motion of rigid, ellipsoidal swimmers subjected to a steady vortex flow in two dimensions. Numerical simulations of swimmers in a spatially periodic array of vortices reveal a range of possible behaviors, including trapping inside a single vortex and motility-induced diffusion across many vortices. While the trapping probability vanishes at a sufficiently high swimming speed, we find that it exhibits surprisingly large oscillations as this critical swimming speed is approached. Strikingly, at even higher swimming speeds, we find swimmers that swim perpendicular to their elongation direction can again become trapped. To explain this complex behavior, we investigate the underlying swimmer phase-space geometry. We identify the fixed points and periodic orbits of the swimmer equations of motion that regulate swimmer trapping inside a single vortex cell. For low to intermediate swimming speeds, we find that a stable periodic orbit surrounded by invariant tori forms a transport barrier to swimmers and can trap them inside individual vortices. For swimming speeds approaching the maximum fluid speed, we find instead that perpendicular swimmers can be trapped by asymptotically stable fixed points. A bifurcation analysis of the stable periodic orbit and the fixed points explains the complex and non-monotonic breakdown and re-emergence of swimmer trapping as the swimmer speed and shape are varied.

Mushroom body defect is required in parallel to Netrin for midline axon guidance in Drosophila.

The outgrowth of many neurons within the central nervous system is initially directed towards or away from the cells lying at the midline. Recent genetic evidence suggests that a simple model of differential sensitivity to the conserved Netrin attractants and Slit repellents is insufficient to explain the guidance of all axons at the midline. In the Drosophila embryonic ventral nerve cord, many axons still cross the midline in the absence of the Netrin genes (NetA and NetB) or their receptor frazzled. Here we show that mutation of mushroom body defect (mud) dramatically enhances the phenotype of Netrin or frazzled mutants, resulting in many more axons failing to cross the midline, although mutations in mud alone have little effect. This suggests that mud, which encodes a microtubule-binding coiled-coil protein homologous to NuMA and LIN-5, is an essential component of a Netrin-independent pathway that acts in parallel to promote midline crossing. We demonstrate that this novel role of Mud in axon guidance is independent of its previously described role in neural precursor development. These studies identify a parallel pathway controlling midline guidance in Drosophila and highlight a novel role for Mud potentially acting downstream of Frizzled to aid axon guidance.

Antiproliferative Acylated Glycerols from New Zealand Propolis.

Previous work has shown that a number of phenolic components of NZ propolis possess antiproliferative activity against certain human gastrointestinal cancer cell lines. Here we report on a series of acylglycerols isolated from the nonpolar fraction of propolis resin, which represent further bioactive constituents unrelated to the more usual phenolic compounds generally found in propolis. NZ propolis is sourced from poplar trees, and the acylglycerols have been shown to be present in the leaves and buds of some common poplars. The compounds are a series of monoglycerides containing 3,8-dihydroxy fatty acids, many of which are further acylated with acetic acid residues. The dihydroxy fatty acids are C18 to C24, with the most abundant being C20 and C22. These acylglycerols were found to have strong antiproliferative activity against three human gastrointestinal cell lines, particularly gastric cancer cell line NCI-N87, where one example shows an IC50 of less than 50 µM.

Ensemble-based topological entropy calculation (E-tec).

Topological entropy measures the number of distinguishable orbits in a dynamical system, thereby quantifying the complexity of chaotic dynamics. One approach to computing topological entropy in a two-dimensional space is to analyze the collective motion of an ensemble of system trajectories taking into account how trajectories "braid" around one another. In this spirit, we introduce the Ensemble-based Topological Entropy Calculation, or E-tec, a method to derive a lower-bound on topological entropy of two-dimensional systems by considering the evolution of a "rubber band" (piece-wise linear curve) wrapped around the data points and evolving with their trajectories. The topological entropy is bounded below by the exponential growth rate of this band. We use tools from computational geometry to track the evolution of the rubber band as data points strike and deform it. Because we maintain information about the configuration of trajectories with respect to one another, updating the band configuration is performed locally, which allows E-tec to be more computationally efficient than some competing methods. In this work, we validate and illustrate many features of E-tec on a chaotic lid-driven cavity flow. In particular, we demonstrate convergence of E-tec's approximation with respect to both the number of trajectories (ensemble size) and the duration of trajectories in time.

Mode-locking in advection-reaction-diffusion systems: An invariant manifold perspective.

Fronts propagating in two-dimensional advection-reaction-diffusion systems exhibit a rich topological structure. When the underlying fluid flow is periodic in space and time, the reaction front can lock to the driving frequency. We explain this mode-locking phenomenon using the so-called burning invariant manifolds (BIMs). In fact, the mode-locked profile is delineated by a BIM attached to a relative periodic orbit (RPO) of the front element dynamics. Changes in the type (and loss) of mode-locking can be understood in terms of local and global bifurcations of the RPOs and their BIMs. We illustrate these concepts numerically using a chain of alternating vortices in a channel geometry.

Synaesthesia lost and found: two cases of person- and music-colour synaesthesia.

Synaesthesia is a developmental condition involving cross-communication between sensory modalities or substreams whereby an inducer (e.g. a sound) automatically evokes a concurrent percept in another modality (e.g. a colour). Whether this condition arises due to atypical structural connectivity (e.g., between normally unconnected cortical areas) or altered neurochemistry remains a central question. We report the exceptional cases of two synaesthetes - subjects AB and CD - both of whom experience coloured auras around individuals, as well as coloured perceptions in response to music. Both subjects have, in recent years, suffered a complete loss or reduction of their synaesthetic experiences, one (AB) through successive head traumas, including a lightning strike, followed by a number of medications, and the other (CD) while taking anxiolytic medications. Using semi-structured interviews and data from the Synaesthesia Battery and a colourpicker task, we characterize the phenomenological characteristics of their pre-loss synaesthesia, as well as the subsequent restoration of each subject's synaesthetic experiences (in the months post-trauma for AB, and after cessation of medication for CD). Even after years of suppression, the patterns of associations were highly consistent with those experienced pre-injury. The phenomenological experience of synaesthesia can, thus, like most conscious experiences, be modulated by pharmacologically diverse medications or head injury. However, the underlying neural substrates mediating specific synaesthetic pairings appear remarkably 'hard-wired' and can persist over very long periods even under conditions that alter or completely suppress the conscious synaesthetic experience itself.

Polarisation structuring of broadband light.

Spatial structuring of the intensity, phase and polarisation of light is useful in a wide variety of modern applications, from microscopy to optical communications. This shaping is most commonly achieved using liquid crystal spatial light modulators (LC-SLMs). However, the inherent chromatic dispersion of LC-SLMs when used as diffractive elements presents a challenge to the extension of such techniques from monochromatic to broadband light. In this work we demonstrate a method of generating broadband vector beams with dynamically tunable intensity, phase and polarisation over a bandwidth of 100 nm. We use our system to generate radially and azimuthally polarised vector vortex beams carrying orbital angular momentum, and beams whose polarisation states span the majority of the Poincaré sphere. We characterise these broadband vector beams using spatially and spectrally resolved Stokes measurements, and detail the technical and fundamental limitations of our technique, including beam generation fidelity and efficiency. The broadband vector beam shaper that we demonstrate here may find use in applications such as ultrafast beam shaping and white light microscopy.

Comparison of nematic liquid-crystal and DMD based spatial light modulation in complex photonics.

Digital micro-mirror devices (DMDs) have recently emerged as practical spatial light modulators (SLMs) for applications in photonics, primarily due to their modulation rates, which exceed by several orders of magnitude those of the already well-established nematic liquid crystal (LC)-based SLMs. This, however, comes at the expense of limited modulation depth and diffraction efficiency. Here we compare the beam-shaping fidelity of both technologies when applied to light control in complex environments, including an aberrated optical system, a highly scattering layer and a multimode optical fibre. We show that, despite their binary amplitude-only modulation, DMDs are capable of higher beam-shaping fidelity compared to LC-SLMs in all considered regimes.