Differential cross section and recoil polarization measurements for the gamma p to K+ Lambda reaction using CLAS at Jefferson Lab

We present measurements of the differential cross section and Lambda recoil polarization for the gamma p to K+ Lambda reaction made using the CLAS detector at Jefferson Lab. These measurements cover the center-of-mass energy range from 1.62 to 2.84 GeV and a wide range of center-of-mass K+ production angles. Independent analyses were performed using the K+ p pi- and K+ p (missing pi -) final-state topologies; results from these analyses were found to exhibit good agreement. These differential cross section measurements show excellent agreement with previous CLAS and LEPS results and offer increased precision and a 300 MeV increase in energy coverage. The recoil polarization data agree well with previous results and offer a large increase in precision and a 500 MeV extension in energy range. The increased center-of-mass energy range that these data represent will allow for independent study of non-resonant K+ Lambda photoproduction mechanisms at all production angles.Comment: 22 pages, 16 figure

First measurement of direct f0(980)f_0(980) photoproduction on the proton

We report on the results of the first measurement of exclusive $f_0(980)$ meson photoproduction on protons for $E_\gamma=3.0 - 3.8$ GeV and $-t = 0.4-1.0$ GeV$^2$. Data were collected with the CLAS detector at the Thomas Jefferson National Accelerator Facility. The resonance was detected via its decay in the $\pi^+ \pi^-$ channel by performing a partial wave analysis of the reaction $\gamma p \to p \pi^+ \pi^-$. Clear evidence of the $f_0(980)$ meson was found in the interference between $P$ and $S$ waves at $M_{\pi^+ \pi^-}\sim 1$ GeV. The $S$-wave differential cross section integrated in the mass range of the $f_0(980)$ was found to be a factor of 50 smaller than the cross section for the $\rho$ meson. This is the first time the $f_0(980)$ meson has been measured in a photoproduction experiment

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant)

Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor β signaling

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. Methods: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Results: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Conclusions: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.Genetics of disease, diagnosis and treatmen

Differential cross section of γn→K+Σ− on bound neutrons with incident photons from 1.1 to 3.6 GeV

Differential cross sections of the reaction γd→K+Σ−(p) have been measured with the CLAS detector at Jefferson Lab using incident photons with energies between 1.1 and 3.6 GeV. This is the first complete set of strangeness photoproduction data on the neutron covering a broad angular range. At energies close to threshold and up to Eγ∼1.8 GeV, the shape of the angular distribution is suggestive of the presence of s -channel production mechanisms. For Eγ>1.8 GeV, a clear forward peak appears and becomes more prominent as the photon energy increases, suggesting contributions from t-channel production mechanisms. These data can be used to constrain future analysis of this reaction

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited

Electroexcitation of nucleon resonances from CLAS data on single pion electroproduction

We present results on the electroexcitation of the low mass resonances Δ(1232)P<sub>33</sub>, N(1440)P<sub>11</sub>, N(1520)D<sub>13</sub>, and N(1535)S<sub>11</sub> in a wide range of Q<sup>2</sup>. The results were obtained in the comprehensive analysis of data from the Continuous Electron Beam Accelerator Facility (CEBAF) large acceptance spectrometer (CLAS) detector at the Thomas Jefferson National Accelerator Facility (JLab) on differential cross sections, longitudinally polarized beam asymmetries, and longitudinal target and beam-target asymmetries for π electroproduction off the proton. The data were analyzed using two conceptually different approaches—fixed-t dispersion relations and a unitary isobar model—allowing us to draw conclusions on the model sensitivity of the obtained electrocoupling amplitudes. The amplitudes for the Δ(1232)P<sub>33</sub> show the importance of a meson-cloud contribution to quantitatively explain the magnetic dipole strength, as well as the electric and scalar quadrupole transitions. They do not show any tendency of approaching the pQCD regime for Q<sup>2</sup>⩽6 GeV<sup>2</sup>. For the Roper resonance, N(1440)P<sub>11</sub>, the data provide strong evidence that this state is a predominantly radial excitation of a three-quark (3q) ground state. Measured in pion electroproduction, the transverse helicity amplitude for the N(1535)S<sub>11</sub> allowed us to obtain the branching ratios of this state to the πN and ηN channels via comparison with the results extracted from η electroproduction. The extensive CLAS data also enabled the extraction of the γ*p→N(1520)D<sub>13</sub> and N(1535)S<sub>11</sub> longitudinal helicity amplitudes with good precision. For the N(1535)S<sub>11</sub>, these results became a challenge for quark models and may be indicative of large meson-cloud contributions or of representations of this state that differ from a 3q excitation. The transverse amplitudes for the N(1520)D<sub>13</sub> clearly show the rapid changeover from helicity-3/2 dominance at the real photon point to helicity-1/2 dominance at Q<sup>2</sup>>1 GeV<sup>2</sup>, confirming a long-standing prediction of the constituent quark model

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.Genetics of disease, diagnosis and treatmen