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Social motivation is critical to the development of typical social functioning. The root of the social challenges characteristic of autism is hypothesized to be a deficit in social motivation, specifically in one or more subcomponents (e.g. social reward seeking or social orienting). We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits. This repository includes the detailed protocols for assembly and operation of equipment, parts lists, and annotated scripts for data processing and analysis.

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into the role of Mecp2 in functional circuit development. Thus, we applied widefield optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex both at postnatal day (P)35 in development and during the disease-related decline. We found that FC between numerous cortical regions was disrupted in Mecp2 mutant males both in juvenile development and early adulthood. Female Mecp2 mice displayed an increase in homotopic contralateral FC in the motor cortex at P35 but not in adulthood, where instead more posterior parietal regions were implicated. An increase in the amplitude of connection strength, both with more positive correlations and more negative anticorrelations, was observed across the male cortex in numerous functional regions. Widespread rescue of MeCP2 protein in GABAergic neurons rescued none of these functional deficits, nor, surprisingly, the expected male lifespan. Altogether, the female results identify early signs of disease progression, while the results in males indicate MeCP2 protein is required for typical FC in the brain.

Williams Syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams Syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, includingGTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams Syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias, and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A ‘Complete Deletion’ mouse, heterozygously eliminating the syntenic Williams Syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role ofGtf2ird1in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressingGtf2ird1, which can be used both to model duplication of this gene alone and to rescueGtf2ird1expression in the Complete Deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams Syndrome Critical Region regulates social motivation along with motor and anxiety phenotypes, but thatGtf2ird1complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However,Gtf2ird1complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

Acipenseriformes (sturgeons and paddlefishes) are of substantial conservation concern, and development of genomic resources for these species is difficult due to past whole genome duplication. Development of disomic markers for polyploid organisms can be challenging due to difficulty in resolving alleles at a single locus from those among duplicated loci. In this study, we detail the development of disomic markers for the endangered pallid sturgeon (Scaphirhynchus albus) found in North America. One of the strategies for pallid sturgeon conservation is to stock U.S. rivers with offspring of pure pallid sturgeon, but introgression with the sympatric shovelnose sturgeon (S. platorynchus) threatens pallid sturgeon genetic integrity. Currently, 19 microsatellite loci are used to differentiate between both species and their hybrids, but the markers are insufficient to robustly identify backcrosses. We performed double digest restriction site-associated DNA sequencing (ddRADseq) on shovelnose sturgeon haploid gynogens to produce a reduced-representation genomic reference. Contiguous sequences that were heterozygous within a haploid individual were flagged as potentially encompassing multiple loci. Approximately 60 individuals of each species from two management units were sequenced, and reads were mapped to the haploid reference to identify single nucleotide polymorphisms (SNPs) at individual loci. The final data set contained 11,082 microhaplotyped loci which offer at least an order of magnitude greater resolution for species discrimination than the current panel of 19 microsatellites. These markers will be used to examine a larger sample of Scaphirhynchus individuals throughout their ranges to determine the extent and trajectory of hybridization.

Essential habitat is required for a given species to complete its lifecycle and includes habitat for breeding, feeding, and growth. Estuaries provide essential habitat for many fishes, including elasmobranchs, particularly as nurseries. Shore-based, gillnet surveys have documented ten elasmobranch species (sharks and batoids) inhabiting Texas estuaries; however, limitations in the methodology, spatial, and temporal scope employed mean the role of these estuaries as elasmobranch nurseries remains uncertain. Therefore, an alternative sampling technique was implemented to survey open water locations in two Texas estuaries during the peak time of putative elasmobranch nursery usage (May to October). Ten species of elasmobranch were observed, including a shark, Carcharhinus porosus, and batoid species, Hypanus americanus, that were not documented in previous surveys. The most commonly encountered species, Carcharhinus brevipinna, comprised 45% of individuals caught, in contrast to previous surveys of these estuaries, in which the species was less than 1% of the total elasmobranch catch. The results revealed a distinction between sharks and batoids in terms of the life history stages present, as well as the depths and distances from the tidal inlet of areas in which they were encountered. Young-of-the-year and small juvenile Carcharhinus brevipinna and Sphyrna lewini were observed across multiple years and in multiple months within years at one site, suggesting that one of the sampled estuaries functions as a nursery. Although putative nurseries for these species have been identified elsewhere in the world, estuaries serving as nursery grounds in the western Gulf of Mexico are not well described.

Social motivation is critical to the development of healthy social functioning. Autism spectrum condition (ASC) is characterized in part by challenges with social communication and social interaction. The root of these challenges is hypothesized to be a deficit in social motivation, specifically in one or more subcomponents (e.g. social reward reward seeking or social orienting). Current social behavior assays lack the ability to quantitatively measure both social reward seeking and social orienting simultaneously. We have developed an automated socially-rewarded operant conditioning task coupled with video tracking, to quantify effort to achieve access to a social partner and concurrent social orienting behavior in mice. We established that adult wildtype mice will work for access to a social partner, that male mice exhibit greater social motivation compared to females, and there is high test-retest reliability in the task across multiple days. We then benchmarked the method with two test-case manipulations. We first tested a mouse model of Phelan-McDermid syndrome, a neurodevelopmental disorder associated with ASC. These Shank3B mutants failed to show social reward seeking and exhibited reduced social orienting. Next, we demonstrated that oxytocin receptor antagonism decreased social motivation in wildtype mice, consistent with its role in social reward circuitry. Intriguingly, only male mice were vulnerable to Shank3B mutation, while females were more vulnerable to oxytocin blockade, a double dissociation suggesting separate circuits for social motivation in male and female brain. Overall, we believe this method provides a valuable addition to the assessment of social phenotypes in rodent models of ASC and the mapping of potentially sex-specific social motivation circuits in the brain.

In utero opioid exposure is associated with lower weight and a Neonatal Opioid Withdrawal Syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Therefore, we implemented a rodent perinatal opioid exposure model of Oxycodone (Oxy) exposure for comparison of long-term consequences of Oxy exposure until birth (Short Oxy) to the impact of continued postnatal opioid exposure (Long Oxy) spanning gestation through birth and lactation. Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males, sex-dependent changes in morphine conditioned place preference, and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following Short or Long Oxy exposure. Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett Syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into Mecp2’s role in functional circuit development. Thus, we applied optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex prior to symptom onset as well as during decline. We found that FC was profoundly disrupted in Mecp2 males both in juvenile development and early adulthood. Female Mecp2 mice displayed a subtle homotopic contralateral increase in motor cortex as juveniles but not in adulthood, where instead parietal regions were implicated. Additionally, conditional rescue studies indicated FC phenotypes are driven by excitatory neurons. Altogether, the female results identify subtle candidate translatable biomarkers of disease progression, while the male results indicate MeCP2 protein is needed in a circuit-specific manner for FC.

Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues1-4. H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca2+ increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.

Differential cross sections for Compton scattering from the proton have been measured at scattering angles of $55^\circ$, $90^\circ$, and $125^\circ$ in the laboratory frame using quasimonoenergetic linearly (circularly) polarized photon beams with a weighted mean energy value of 83.4\,MeV (81.3\,MeV). These measurements were performed at the High Intensity Gamma-Ray Source facility at the Triangle Universities Nuclear Laboratory. The results are compared to previous measurements and are interpreted in the chiral effective field theory framework to extract the electromagnetic dipole polarizabilities of the proton, which gives $\alpha_{E1}^p = 13.8\pm1.2_{\rm stat}\pm0.1_{\rm BSR}\pm0.3_{\rm theo}, \beta_{M1}^p = 0.2\mp1.2_{\rm stat}\pm0.1_{\rm BSR}\mp0.3_{\rm theo}$ in units of 10$^{-4}$\, fm$^3$., Comment: 6 pages, 4 figures. Version identical to the published letter

Polarized photon beams provide a unique experimental tool for the study of various polarization-dependent physical processes. Here, we report the experimental demonstration of full polarization control of an oscillator free-electron laser (FEL) using helical undulators of opposite helicities. Using two helical undulator magnets of opposite helicities and a buncher magnet in between, we have generated a linearly polarized FEL beam with any desirable polarization direction. With the development of a high-precision FEL polarimeter, we are able to optimize the highly polarized FEL beams in visible wavelengths and measure the polarization with high accuracy, demonstrating linear polarization ${P}_{\mathrm{lin}}g0.99$ on the routine basis and with the maximum polarization reaching ${P}_{\mathrm{lin}}=0.998$. In this paper, we describe the FEL configuration, experimental setup, and related beam diagnostics, including the newly developed high-precision FEL polarimeter. We report our experimental approaches to generate, tune up, and characterize the polarization controllable FEL beams and share a new insight into how high-degree polarization is realized based upon our investigation of the temporal structure of the FEL beam. This FEL polarization control technique has been used successfully to generate a polarization controllable Compton $\ensuremath{\gamma}$-ray beam for nuclear physics experiments.

Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral anomalies including hyperactivity, muscle weakness and fatigue, and social alterations with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

The short wavelength operation of free-electron laser (FEL) oscillators is limited by the availability of high-reflectivity, thermally stable, and radiation-resistant FEL mirrors in the vacuum UV (VUV) wavelength. We report our recent work to extend the shortest lasing wavelength of the oscillator FEL to 168.6 nm using a storage ring FEL. This progress has been made possible by developing a new FEL configuration with substantially reduced undulator harmonic radiation on the FEL mirror, a thermally stable FEL optical cavity, and a new type of high-reflectivity fluoride-based multilayer coating with a protective capping layer. Using these fluoride-based mirrors, we have demonstrated storage ring FEL lasing from 168.6 to 179.7 nm with excellent beam stability. Employing this VUV FEL in Compton scattering, we have produced the first 120 MeV gamma rays at the High Intensity Gamma-ray Source (HIGS). Operating the HIGS in this new high-energy region will create many new opportunities for photonuclear physics research, in particular, the low-energy quantum chromodynamics research.

Differential cross sections for elastic Compton scattering from $^4$He have been measured with high statistical precision at the High Intensity $\gamma$-ray Source at laboratory scattering angles of $55^\circ$, $90^\circ$, and $125^\circ$ using a quasi-monoenergetic photon beam with a weighted mean energy value of $81.3$ MeV. The results are compared to previous measurements and similar fore-aft asymmetry in the angular distribution of the differential cross sections is observed. This experimental work is expected to strongly motivate the development of effective-field-theory calculations of Compton scattering from $^4$He to fully interpret the data.

EPJ Web of Conferences, 219, ISSN:2100-014X, ISSN:2101-6275, International Workshop on Particle Physics at Neutron Sources (PPNS 2018), Grenoble, France, May 24–26, 2018, ISBN:978-2-7598-9082-8

It has been proposed recently that a previously unobserved neutron decay branch to a dark matter particle (χ) could account for the discrepancy in the neutron lifetime observed in experiments that use two different measurement techniques. One of the possible final states discussed includes a single χ along with an e^+e^− pair. We use data from the UCNA (Ultracold Neutron Asymmetry) experiment to set limits on this decay channel. Coincident electron-like events are detected with ∼4π acceptance using a pair of detectors that observe a volume of stored Ultracold Neutrons (UCNs). The summed kinetic energy (E_(e^+e^−)) from such events is used to set limits, as a function of the χ mass, on the branching fraction for this decay channel. For χ masses consistent with resolving the neutron lifetime discrepancy, we exclude this as the dominant dark matter decay channel at ≫ 5σlevel for 100 keV < E_(e^+e^−) < 644 keV. If the χ + e^+e^− final state is not the only one, we set limits on its branching fraction of 90% confidence level.

Hearing the boss utter the phrase “We are engaging consultants” has made many a pharmacy enterprise leader shudder. They reflexively tremble because productivity consultants have historically been engaged by personnel at the executive level. This was evidenced by data from a 2012 survey of

Background: The neutron β-decay asymmetry parameter A_0 defines the angular correlation between the spin of the neutron and the momentum of the emitted electron. Values for A_0 permit an extraction of the ratio of the weak axial-vector to vector coupling constants, λ≡gA/gV, which under assumption of the conserved vector current hypothesis (gV=1) determines gA. Precise values for gA are important as a benchmark for lattice QCD calculations and as a test of the standard model. Purpose: The UCNA experiment, carried out at the Ultracold Neutron (UCN) source at the Los Alamos Neutron Science Center, was the first measurement of any neutron β-decay angular correlation performed with UCN. This article reports the most precise result for A_0 obtained to date from the UCNA experiment, as a result of higher statistics and reduced key systematic uncertainties, including from the neutron polarization and the characterization of the electron detector response. Methods: UCN produced via the downscattering of moderated spallation neutrons in a solid deuterium crystal were polarized via transport through a 7 T polarizing magnet and a spin flipper, which permitted selection of either spin state. The UCN were then contained within a 3-m long cylindrical decay volume, situated along the central axis of a superconducting 1 T solenoidal spectrometer. With the neutron spins then oriented parallel or anti-parallel to the solenoidal field, an asymmetry in the numbers of emitted decay electrons detected in two electron detector packages located on both ends of the spectrometer permitted an extraction of A_0. Results: The UCNA experiment reports a new 0.67% precision result for A_0 of A_0=−0.12054(44)_(stat)(68)_(syst), which yields λ=gA/gV=−1.2783(22). Combination with the previous UCNA result and accounting for correlated systematic uncertainties produces A0=−0.12015(34)stat(63)syst and λ=gA/gV=−1.2772(20). Conclusions: This new result for A0 and gA/gV from the UCNA experiment has provided confirmation of the shift in values for gA/gV that has emerged in the published results from more recent experiments, which are in striking disagreement with the results from older experiments. Individual systematic corrections to the asymmetries in older experiments (published prior to 2002) were >10%, whereas those in the more recent ones (published after 2002) have been of the scale of

Phylogenetic relationships among members of the New World searobin genera Bellator and Prionotus (Family Triglidae, Subfamily Prionotinae) and among other searobins in the families Triglidae and Peristediidae were investigated using both mitochondrial and nuclear DNA sequences. Phylogenetic hypotheses derived from maximum likelihood and Bayesian methodologies supported a monophyletic Prionotinae that included four well resolved clades of uncertain relationship; three contained species in the genus Prionotus and one contained species in the genus Bellator. Bellator was always recovered within the genus Prionotus, a result supported by post hoc model testing. Two nominal species of Prionotus (P. alatus and P. paralatus) were not recovered as exclusive lineages, suggesting the two may comprise a single species. Phylogenetic hypotheses also supported a monophyletic Triglidae but only if armored searobins (Family Peristediidae) were included. A robust morphological assessment is needed to further characterize relationships and suggest classification of clades within Prionotinae; for the time being we recommend that Bellator be considered a synonym of Prionotus. Relationships between armored searobins (Family Peristediidae) and searobins (Family Triglidae) and relationships within Triglidae also warrant further study.

In January, 2018, Fornal and Grinstein proposed that a previously unobserved neutron decay branch to a dark matter particle (χ) could account for the discrepancy in the neutron lifetime observed in two different types of experiments. One of the possible final states discussed includes a single χ along with an e+e− pair. We use data from the UCNA (Ultracold Neutron Asymmetry) experiment to set limits on this decay channel. Coincident electron-like events are detected with ∼ 4π acceptance using a pair of detectors that observe a volume of stored Ultracold Neutrons (UCNs). We use the timing information of coincidence events to select candidate dark sector particle decays by applying a timing calibration and selecting events within a physically-forbidden timing region for conventional n → p + e- + ν̅e decays. The summed kinetic energy (Ee+e−) from such events is reconstructed and used to set limits, as a function of the χ mass, on the branching fraction for this decay channel.

Objectives Niemann Pick type C (NP-C) disease is a clinically heterogeneous disorder with variable onset and rate of progression of neurological deterioration. There is a lack of validated objective assessments to monitor disease progress and response to treatments. We explored the utility of the data routinely collected in outpatient clinics for NP-C monitoring. Methods A retrospective longitudinal study identified clinical data from NP-C patients attending a large UK centre from 2008–2015. Physiotherapy assessments (Gaitrite analysis of gait and Movement ABC-2 tool assessment of fine motor skills) and Speech and Language data (utilising the Functional Oral Intake Scale, FOIS) were collected and analysed. Results 9 patients were identified in whom regular clinic follow-up assessments were available for retrospective analysis. 6/9 patients were treated with zavesca. Follow up duration ranged from 12 to 67 months. Gaitrite data was available in 6/9 patients. Bead threading and coin posting data were available in 6/9 and 7/9 patients, respectively. FOIS data were available in all patients. Intra- and inter-patient variability was high in most assessments and many parameters had a tendency to improve with age, which often contradicted function loss reported by the parents and clinicians. After the initial presentation of neurological symptoms FOIS demonstrated a consistent tendency for deterioration in most patients. Conclusions The lack of objective tools to monitor disease progression impairs the clinician's ability to give accurate prognosis to the families and complicates the assessment of the effect of novel therapies. Current quantitative tools do not accurately depict disease severity and rely heavily on patient cooperation (not always granted in paediatric populations). The FOIS is promising but further validation in a larger cohort is needed. The utility of affordable technological advances such as wearable technology that may provide objective functional measures needs to be urgently assessed in NP-C patients.