Variation in Expression of the HECT E3 Ligase UPL3 Modulates LEC2 Levels, Seed Size, and Crop Yields in Brassica napus.

Identifying genetic variation that increases crop yields is a primary objective in plant breeding. We used association analyses of oilseed rape/canola (Brassica napus) accessions to identify genetic variation that influences seed size, lipid content, and final crop yield. Variation in the promoter region of the HECT E3 ligase gene BnaUPL3 C03 made a major contribution to variation in seed weight per pod, with accessions exhibiting high seed weight per pod having lower levels of BnaUPL3 C03 expression. We defined a mechanism in which UPL3 mediated the proteasomal degradation of LEC2, a master transcriptional regulator of seed maturation. Accessions with reduced UPL3 expression had increased LEC2 protein levels, larger seeds, and prolonged expression of lipid biosynthetic genes during seed maturation. Natural variation in BnaUPL3 C03 expression appears not to have been exploited in current B napus breeding lines and could therefore be used as a new approach to maximize future yields in this important oil crop.

Using natural variation to understand plant responses to iron availability.

Iron bioavailability varies dramatically between soil types across the globe. This has given rise to high levels of natural variation in plant iron responses, allowing members of even a single species to thrive across a wide range of soil types. In recent years we have seen the use of genome-wide association analysis to identify natural variants underlying plant responses to changes in iron availability in both Arabidopsis and important crop species. These studies have provided insights into which genes have been important in shaping local adaptation to iron availability in different plant species and have allowed the discovery of novel regulators and mechanisms, not previously identified using mutagenesis approaches. Furthermore, these studies have allowed the identification of markers that can be used to accelerate breeding of future elite varieties with increased resilience to iron stress and improved nutritional quality. The studies highlighted here show that, in addition to studying plant responses to iron alone, it is important to consider these responses within the context of plant nutrition more broadly and to also consider iron regulation in relation to additional traits of agronomic importance such as yield and disease resistance.

Variation in the expression of a transmembrane protein influences cell growth in Arabidopsis thaliana petals by altering auxin responses.

BACKGROUND: The same species of plant can exhibit very diverse sizes and shapes of organs that are genetically determined. Characterising genetic variation underlying this morphological diversity is an important objective in evolutionary studies and it also helps identify the functions of genes influencing plant growth and development. Extensive screens of mutagenised Arabidopsis populations have identified multiple genes and mechanisms affecting organ size and shape, but relatively few studies have exploited the rich diversity of natural populations to identify genes involved in growth control. RESULTS: We screened a relatively well characterised collection of Arabidopsis thaliana accessions for variation in petal size. Association analyses identified sequence and gene expression variation on chromosome 4 that made a substantial contribution to differences in petal area. Variation in the expression of a previously uncharacterised gene At4g16850 (named as KSK) had a substantial role on variation in organ size by influencing cell size. Over-expression of KSK led to larger petals with larger cells and promoted the formation of stamenoid features. The expression of auxin-responsive genes known to limit cell growth was reduced in response to KSK over-expression. ANT expression was also reduced in KSK over-expression lines, consistent with altered floral identities. Auxin responses were reduced in KSK over-expressing cells, consistent with changes in auxin-responsive gene expression. KSK may therefore influence auxin responses during petal development. CONCLUSIONS: Understanding how genetic variation influences plant growth is important for both evolutionary and mechanistic studies. We used natural populations of Arabidopsis thaliana to identify sequence variation in a promoter region of Arabidopsis accessions that mediated differences in the expression of a previously uncharacterised membrane protein. This variation contributed to altered auxin responses and cell size during petal growth.

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

BACKGROUND AND OBJECTIVES: Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. METHODS: We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. RESULTS: We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). CONCLUSIONS: Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Limb phase flexibility in walking: a test case in the squirrel monkey (Saimiri sciureus).

BACKGROUND: Previous analyses of factors influencing footfall timings and gait selection in quadrupeds have focused on the implications for energetic cost or gait mechanics separately. Here we present a model for symmetrical walking gaits in quadrupedal mammals that combines both factors, and aims to predict the substrate contexts in which animals will select certain ranges of footfall timings that (1) minimize energetic cost, (2) minimize rolling and pitching moments, or (3) balance the two. We hypothesize that energy recovery will be a priority on all surfaces, and will be the dominant factor determining footfall timings on flat, ground-like surfaces. The ability to resist pitch and roll, however, will play a larger role in determining footfall choice on narrower and more complex branch-like substrates. As a preliminary test of the expectations of the model, we collected sample data on footfall timings in a primate with relatively high flexibility in footfall timings - the squirrel monkey (Saimiri sciureus) - walking on a flat surface, straight pole, and a pole with laterally-projecting branches to simulate simplified ground and branch substrates. We compare limb phase values on these supports to the expectations of the model. RESULTS: As predicted, walking steps on the flat surface tended towards limb phase values that promote energy exchange. Both pole substrates induced limb phase values predicted to favor reduced pitching and rolling moments. CONCLUSIONS: These data provide novel insight into the ways in which animals may choose to adjust their behavior in response to movement on flat versus complex substrates and the competing selective factors that influence footfall timing in mammals. These data further suggest a pathway for future investigations using this perspective.

Resistance and tolerance: The role of nutrients on pathogen dynamics and infection outcomes in an insect host.

Tolerance and resistance are the two ways in which hosts can lessen the effects of infection. Tolerance aims to minimize the fitness effects resulting from incumbent pathogen populations, whereas resistance aims to reduce the pathogen population size within the host. While environmental impacts on resistance have been extensively, recorded their impacts on variation in tolerance are virtually unexplored. Here, we ask how the environment, namely the host diet, influences the capacity of an organism to tolerate and resist infection, using a model host-parasite system, the burying beetle, Nicrophorus vespilloides and the entomopathogenic bacteria, Photorhabdus luminescens. We first considered dose-responses and pathogen dynamics within the host, and compared our findings to responses known from other host species. We then investigated how investment in tolerance and resistance changed under different nutritional regimes. Beetles were maintained on one of five diets that varied in their ratio of protein to fat for 48 hr and then injected with P. luminescens. Survival was monitored and the phenoloxidase (PO) response and bacterial load at 24-hr postinfection were ascertained. The dose required to kill 50% of individuals in this species was several magnitudes higher than in other species and the bacteria were shown to display massive decreases in population size, in contrast to patterns of proliferation found in other host species. Diet strongly modified host survival after infection, with those on the high fat/low protein diet showing 30% survival at 8 days, vs. almost 0% survival on the low-fat/high-protein diet. However, this was independent of bacterial load or variation in PO, providing evidence for diet-mediated tolerance mechanisms rather than immune-driven resistance. Evolutionary ecology has long focussed on immune resistance when investigating how organisms avoid succumbing to infection. Tolerance of infection has recently become a much more prominent concept and is suggested to be influential in disease dynamics. This is one of the first studies to find diet-mediated tolerance.

Elucidation of the genetic basis of variation for stem strength characteristics in bread wheat by Associative Transcriptomics.

BACKGROUND: The current approach to reducing the tendency for wheat grown under high fertilizer conditions to collapse (lodge) under the weight of its grain is based on reducing stem height via the introduction of Rht genes. However, these reduce the yield of straw (itself an important commodity) and introduce other undesirable characteristics. Identification of alternative height-control loci is therefore of key interest. In addition, the improvement of stem mechanical strength provides a further way through which lodging can be reduced. RESULTS: To investigate the prospects for genetic alternatives to Rht, we assessed variation for plant height and stem strength properties in a training genetic diversity panel of 100 wheat accessions fixed for Rht. Using mRNAseq data derived from RNA purified from leaves, functional genotypes were developed for the panel comprising 42,066 Single Nucleotide Polymorphism (SNP) markers and 94,060 Gene Expression Markers (GEMs). In the first application in wheat of the recently-developed method of Associative Transcriptomics, we identified associations between trait variation and both SNPs and GEMs. Analysis of marker-trait associations revealed candidates for the causative genes underlying the trait variation, implicating xylan acetylation and the COP9 signalosome as contributing to stem strength and auxin in the control of the observed variation for plant height. Predictive capabilities of key markers for stem strength were validated using a test genetic diversity panel of 30 further wheat accessions. CONCLUSIONS: This work illustrates the power of Associative Transcriptomics for the exploration of complex traits of high agronomic importance in wheat. The careful selection of genotypes included in the analysis, allowed for high resolution mapping of novel trait-controlling loci in this staple crop. The use of Gene Expression markers coupled with the more traditional sequence-based markers, provides the power required to understand the biological context of the marker-trait associations observed. This not only adds to the wealth of knowledge that we strive to accumulate regarding gene function and plant adaptation, but also provides breeders with the information required to make more informed decisions regarding the potential consequences of incorporating the use of particular markers into future breeding programmes.

First total synthesis of the marine natural products clavulolactones II and III.

The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the ß-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine steps, in overall yields of 21 and 7% respectively.

Understanding the evolution of the windlass mechanism of the human foot from comparative anatomy: Insights, obstacles, and future directions.

Humans stand alone from other primates in that we propel our bodies forward on a relatively stiff and arched foot and do so by employing an anatomical arrangement of bones and ligaments in the foot that can operate like a "windlass." This is a significant evolutionary innovation, but it is currently unknown when during hominin evolution this mechanism developed and within what genera or species it originated. The presence of recently discovered fossils along with novel research in the past two decades have improved our understanding of foot mechanics in humans and other apes, making it possible to consider this question more fully. Here we review the main elements thought to be involved in the production of an effective, modern human-like windlass mechanism. These elements are the triceps surae, plantar aponeurosis, medial longitudinal arch, and metatarsophalangeal joints. We discuss what is presently known about the evolution of these features and the challenges associated with identifying each of these specific components and/or their function in living and extinct primates for the purpose of predicting the presence of the windlass mechanism in our ancestors. In some cases we recommend alternative pathways for inferring foot mechanics and for testing the hypothesis that the windlass mechanism evolved to increase the speed and energetic efficiency of bipedal gait in hominins.

Lumbar vertebral morphology of flying, gliding, and suspensory mammals: implications for the locomotor behavior of the subfossil lemurs Palaeopropithecus and Babakotia.

Lumbar vertebral morphology has been used as an indicator of locomotor behavior in living and fossil mammals. Rigidity within the lumbar region is thought to be important for increasing overall axial rigidity during various forms of locomotion, including bridging between supports, inverted quadrupedalism, gliding, and flying. However, distinguishing between those behaviors using bony features has been challenging. This study used osteological characters of the lumbar vertebrae to attempt to develop fine-grade functional distinctions among different mammalian species in order to make more complete inferences about how the axial skeleton affects locomotor behavior in extant mammals. These same lumbar characters were measured in two extinct species for which locomotor behaviors are well known, the sloth lemurs (Palaeopropithecus and Babakotia radofilai), in order to further evaluate their locomotor behaviors. Results from a principal components analysis of seven measurements, determined to be functionally significant from previous studies, demonstrate that inverted quadrupeds in the sample are characterized by dorsoventrally short and cranio-caudally expanded spinous processes, dorsally oriented transverse processes, and mediolaterally short and dorsoventrally high vertebral bodies compared with mammals that are relatively pronograde, vertical clingers, or gliders. Antipronograde mammals, dermopterans, and chiropterans also exhibit these traits, but not to the same extent as the inverted quadrupeds. In accordance with previous studies, our data show that the sloth lemur B. radofilai groups closely with antipronograde mammals like lorises, while Palaeopropithecus groups with extant sloths. These findings suggest that Palaeopropithecus was engaged in inverted quadrupedalism at a high frequency, while B. radofilai may have engaged in a more diverse array of locomotor and positional behaviors. The osteological features used here reflect differences in lumbar mobility and suggest that axial rigidity is advantageous for suspensory locomotion and possibly flight in bats.

Arabidopsis transcriptome responses to low water potential using high-throughput plate assays.

Soil-free assays that induce water stress are routinely used to investigate drought responses in the plant Arabidopsis thaliana. Due to their ease of use, the research community often relies on polyethylene glycol (PEG), mannitol, and salt (NaCl) treatments to reduce the water potential of agar media, and thus induce drought conditions in the laboratory. However, while these types of stress can create phenotypes that resemble those of water deficit experienced by soil-grown plants, it remains unclear how these treatments compare at the transcriptional level. Here, we demonstrate that these different methods of lowering water potential elicit both shared and distinct transcriptional responses in Arabidopsis shoot and root tissue. When we compared these transcriptional responses to those found in Arabidopsis roots subject to vermiculite drying, we discovered many genes induced by vermiculite drying were repressed by low water potential treatments on agar plates (and vice versa). Additionally, we also tested another method for lowering water potential of agar media. By increasing the nutrient content and tensile strength of agar, we show the 'hard agar' (HA) treatment can be leveraged as a high-throughput assay to investigate natural variation in Arabidopsis growth responses to low water potential.

An investigation of the dynamic relationship between navicular drop and first metatarsophalangeal joint dorsal excursion.

The modern human foot is a complex biomechanical structure that must act both as a shock absorber and as a propulsive strut during the stance phase of gait. Understanding the ways in which foot segments interact can illuminate the mechanics of foot function in healthy and pathological humans. It has been proposed that increased values of medial longitudinal arch deformation can limit metatarsophalangeal joint excursion via tension in the plantar aponeurosis. However, this model has not been tested directly in a dynamic setting. In this study, we tested the hypothesis that during the stance phase, subtalar pronation (stretching of the plantar aponeurosis and subsequent lowering of the medial longitudinal arch) will negatively affect the amount of first metatarsophalangeal joint excursion occurring at push-off. Vertical descent of the navicular (a proxy for subtalar pronation) and first metatarsophalangeal joint dorsal excursion were measured during steady locomotion over a flat substrate on a novel sample consisting of asymptomatic adult males and females, many of whom are habitually unshod. Least-squares regression analyses indicated that, contrary to the hypothesis, navicular drop did not explain a significant amount of variation in first metatarsophalangeal joint dorsal excursion. These results suggest that, in an asymptomatic subject, the plantar aponeurosis and the associated foot bones can function effectively within the normal range of subtalar pronation that takes place during walking gait. From a clinical standpoint, this study highlights the need for investigating the in vivo kinematic relationship between subtalar pronation and metatarsophalangeal joint dorsiflexion in symptomatic populations, and also the need to explore other factors that may affect the kinematics of asymptomatic feet.

Integration of biomechanical compliance, leverage, and power in elephant limbs.

The structure and motion of elephant limbs are unusual compared with those of other animals. Elephants stand and move with straighter limbs (at least when walking), and have limited speed and gait. We devised novel experiments to examine how the limbs of elephants support and propel their mass and to explore the factors that may constrain locomotor performance in these largest of living land animals. We demonstrate that elephant limbs are remarkably compliant even in walking, which maintains low peak forces. Dogma defines elephant limbs as extremely "columnar" for effective weight support, but we demonstrate that limb effective mechanical advantage (EMA) is roughly one-third of that predicted for their size. EMA in elephants is actually smaller than that in horses, which are only one-tenth their mass; it is comparable to human limb values. EMA drops sharply with speed in elephants, as it does in humans. Muscle forces therefore must increase as the limbs become more flexed, and we show how this flexion translates to greater volumes of muscle recruited for locomotion and hence metabolic cost. Surprisingly, elephants use their forelimbs and hindlimbs in similar braking and propulsive roles, not dividing these functions among limbs as was previously assumed or as in other quadrupeds. Thus, their limb function is analogous to four-wheel-drive vehicles. To achieve the observed limb compliance and low peak forces, elephants synchronize their limb dynamics in the vertical direction, but incur considerable mechanical costs from limbs working against each other horizontally.

Synthesis and biological evaluation of novel isoellipticine derivatives and salts.

Synthesis of novel 7-substituted isoellipticines and isoellipticinium salts is described, with optimisation of routes, representing a new class of anti-cancer agent. Initial assessment of biological activity using a topoisomerase II decatenation assay and NCI screening highlighted strong anti-cancer activity, further developed in a panel of isoellipticinium salts. Interestingly, low correlation between results of the topoisomerase II decatenation assay and NCI screen throughout the panel suggest that topo II is not the most important biological target with respect to anti-cancer activity in this new class of compounds. Results also suggest that solubility is not the limiting factor in activity of the isoellipticinium salts. Overall, 20 novel ellipticine analogues were prepared and full anti-cancer profiling was completed for 13 isoellipticine derivatives and salts. Two compounds display significant specificity towards CNS cancer cell lines and are lead compounds for future development.

A stronger role for long-term moisture change than for CO2 in determining tropical woody vegetation change.

Anthropogenically elevated CO2 (eCO2) concentrations have been suggested to increase woody cover within tropical ecosystems through fertilization. The effect of eCO2 is built into Earth system models, although testing the relationship over long periods remains challenging. Here, we explore the relative importance of six drivers of vegetation change in western Africa over the past ~500,000 years (moisture availability, fire activity, mammalian herbivore density, temperature, temperature seasonality, CO2) by coupling past environmental change data from Lake Bosumtwi (Ghana) with global data. We found that moisture availability and fire activity were the most important factors in determining woody cover, whereas the effect of CO2 was small. Our findings suggest that the role of eCO2 effects on tropical vegetation in predictive models must be reconsidered.

The southern rural health and mortality penalty: A review of regional health inequities in the United States.

Rural-urban differences in morbidity and mortality across the United States have been well documented and termed the "rural mortality penalty". However, research studies frequently treat rural areas as homogeneous and often do not account for geospatial variability in rural health risks by both county, state, region, race, and sex within the United States. Additionally, people living in the rural South of the US have higher rates of morbidity and mortality compared to both their urban counterparts and other rural areas. Of those living in southern rural communities, people of color experience higher rates of death and disease compared to white populations. Although there is a wealth of research that uses individual-level behaviors to explain rural-urban health disparities, there is less focus on how community and structural factors influence these differences. This review focuses on the "southern rural health penalty", a term coined by the authors, which refers to the high rate of mortality and morbidity in southern rural areas in the USA compared to both urban areas and non-southern rural places. We use macrosocial determinants of health to explain possible reasons for the "southern rural health penalty". This review can guide future research on rural health between southern and non-southern populations in the US and examine if macrosocial determinants of health can explain health disparities within southern rural populations.

Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness.

The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.

A Serum Proteomic Signature Predicting Survival in Patients with Glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most common form of brain tumor and has a uniformly poor prognosis. Development of prognostic biomarkers in easily accessible serum samples have the potential to improve the outcomes of patients with GBM through personalized therapy planning. MATERIAL/METHODS: In this study pre-treatment serum samples from 30 patients newly diagnosed with GBM were evaluated using a 40-protein multiplex ELISA platform. Analysis of potentially relevant gene targets using The Cancer Genome Atlas database was done using the Glioblastoma Bio Discovery Portal (GBM-BioDP). A ten-biomarker subgroup of clinically relevant molecules was selected using a functional grouping analysis of the 40 plex genes with two genes selected from each group on the basis of degree of variance, lack of co-linearity with other biomarkers and clinical interest. A Multivariate Cox proportional hazard approach was used to analyze the relationship between overall survival (OS), gene expression, and resection status as covariates. RESULTS: Thirty of 40 of the MSD molecules mapped to known genes within TCGA and separated the patient cohort into two main clusters centered predominantly around a grouping of classical and proneural versus the mesenchymal subtype as classified by Verhaak. Using the values for the 30 proteins in a prognostic index (PI) demonstrated that patients in the entire cohort with a PI below the median lived longer than those patients with a PI above the median (HR 1.8, p=0.001) even when stratified by both age and MGMT status. This finding was also consistent within each Verhaak subclass and highly significant (range p=0.0001-0.011). Additionally, a subset of ten proteins including, CRP, SAA, VCAM1, VEGF, MDC, TNFA, IL7, IL8, IL10, IL16 were found to have prognostic value within the TCGA database and a positive correlation with overall survival in GBM patients who had received gross tumor resection followed by conventional radiation therapy and temozolomide treatment concurrent with the addition of valproic acid. CONCLUSION: These findings demonstrate that proteomic approaches to the development of prognostic assays for treatment of GBM may hold potential clinical value.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Pitch control and speed limitation during overground deceleration in lemurid primates.

An animal's fitness is influenced by the ability to move safely through its environment. Recent models have shown that aspects of body geometry, for example, limb length and center of mass (COM) position, appear to set limits for pitch control in cursorial quadrupeds. Models of pitch control predict that the body shape of these and certain other primates, with short forelimbs and posteriorly positioned COM, should allow them to decelerate rapidly while minimizing the risk of pitching forward. We chose to test these models in two non-cursorial lemurs: Lemur catta, the highly terrestrial ring-tailed lemur, and Eulemur fulvus, the highly arboreal brown lemur. We modeled the effects of changes in limb length and COM position on maximum decelerative potential for both species, as well as collecting data on maximal decelerations across whole strides. In both species, maximum measured decelerations fell below the range of pitch-limited deceleration values predicted by the geometric model, with the ring-tailed lemur approaching its pitch limit more closely. Both lemurs showed decelerative potential equivalent to or higher than horses, the only comparative model currently available. These data reinforce the hypothesis that a relatively simple model of body geometry can predict aspects of maximum performance in animals. In this case, it appears that the body geometry of primates is skewed toward avoiding forward pitch in maximal decelerations.