Why Do African Elephants (Loxodonta africana) Simulate Oestrus? An Analysis of Longitudinal Data

Female African elephants signal oestrus via chemicals in their urine, but they also exhibit characteristic changes to their posture, gait and behaviour when sexually receptive. Free-ranging females visually signal receptivity by holding their heads and tails high, walking with an exaggerated gait, and displaying increased tactile behaviour towards males. Parous females occasionally exhibit these visual signals at times when they are thought not to be cycling and without attracting interest from musth males. Using demographic and behavioural records spanning a continuous 28-year period, we investigated the occurrence of this “simulated” oestrus behaviour. We show that parous females in the Amboseli elephant population do simulate receptive oestrus behaviours, and this false oestrus occurs disproportionately in the presence of naïve female kin who are observed coming into oestrus for the first time. We compare several alternative hypotheses for the occurrence of this simulation: 1) false oestrus has no functional purpose (e.g., it merely results from abnormal hormonal changes); 2) false oestrus increases the reproductive success of the simulating female, by inducing sexual receptivity; and 3) false oestrus increases the inclusive fitness of the simulating female, either by increasing the access of related females to suitable males, or by encouraging appropriate oestrus behaviours from female relatives who are not responding correctly to males. Although the observed data do not fully conform to the predictions of any of these hypotheses, we rule out the first two, and tentatively suggest that parous females most likely exhibit false oestrus behaviours in order to demonstrate to naïve relatives at whom to direct their behaviour

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach

The ELBA Force Field for Coarse-Grain Modeling of Lipid Membranes

A new coarse-grain model for molecular dynamics simulation of lipid membranes is presented. Following a simple and conventional approach, lipid molecules are modeled by spherical sites, each representing a group of several atoms. In contrast to common coarse-grain methods, two original (interdependent) features are here adopted. First, the main electrostatics are modeled explicitly by charges and dipoles, which interact realistically through a relative dielectric constant of unity (). Second, water molecules are represented individually through a new parametrization of the simple Stockmayer potential for polar fluids; each water molecule is therefore described by a single spherical site embedded with a point dipole. The force field is shown to accurately reproduce the main physical properties of single-species phospholipid bilayers comprising dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) in the liquid crystal phase, as well as distearoylphosphatidylcholine (DSPC) in the liquid crystal and gel phases. Insights are presented into fundamental properties and phenomena that can be difficult or impossible to study with alternative computational or experimental methods. For example, we investigate the internal pressure distribution, dipole potential, lipid diffusion, and spontaneous self-assembly. Simulations lasting up to 1.5 microseconds were conducted for systems of different sizes (128, 512 and 1058 lipids); this also allowed us to identify size-dependent artifacts that are expected to affect membrane simulations in general. Future extensions and applications are discussed, particularly in relation to the methodology's inherent multiscale capabilities

Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Negative Regulation of Endogenous Stem Cells in Sensory Neuroepithelia: Implications for Neurotherapeutics

Stem cell therapies to treat central nervous system (CNS) injuries and diseases face many obstacles, one of which is the fact that the adult CNS often presents an environment hostile to the development and differentiation of neural stem and progenitor cells. Close examination of two regions of the nervous system – the olfactory epithelium (OE), which regenerates, and the neural retina, which does not – have helped identify endogenous signals, made by differentiated neurons, which act to inhibit neurogenesis by stem/progenitor cells within these tissues. In this chapter, we provide background information on these systems and their neurogenic signaling systems, with the goal of providing insight into how manipulation of endogenous signaling molecules may enhance the efficacy of stem cell neurotherapeutics