Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies

Evidence for a spin-aligned neutron-proton paired phase from the level structure of 92^{92}Pd

The general phenomenon of shell structure in atomic nuclei has been understood since the pioneering work of Goeppert-Mayer, Haxel, Jensen and Suess.They realized that the experimental evidence for nuclear magic numbers could be explained by introducing a strong spin-orbit interaction in the nuclear shell model potential. However, our detailed knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers ($N = Z$), the unique nature of the atomic nucleus as an object composed of two distinct types of fermions can be expressed as enhanced correlations arising between neutrons and protons occupying orbitals with the same quantum numbers. Such correlations have been predicted to favor a new type of nuclear superfluidity; isoscalar neutron-proton pairing, in addition to normal isovector pairing (see Fig. 1). Despite many experimental efforts these predictions have not been confirmed. Here, we report on the first observation of excited states in $N = Z = 46$ nucleus $^{92}$Pd. Gamma rays emitted following the $^{58}$Ni($^{36}$Ar,2$n$)$^{92}$Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution {\gamma}-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. The strong isoscalar neutron- proton correlations in these $N = Z$ nuclei are predicted to have a considerable impact on their level structures, and to influence the dynamics of the stellar rapid proton capture nucleosynthesis process.Comment: 13 pages, 3 figure

M1 and E2 transition rates from core-excited states in semi-magic 94Ru

Lifetimes of high-spin states have been measured in the semi-magic (N= 50) nucleus 94Ru. Excited states in 94Ru were populated in the 58Ni(40Ca, 4p)94Ru* fusion-evaporation reaction at the Grand Accélérateur National d’Ions Lourds (GANIL) accelerator complex. DSAM lifetime analysis was performed on the Doppler broadened line shapes in energy spectra obtained from γ-rays emitted while the residual nuclei were slowing down in a thick 6mg/cm^2 metallic 58Ni target. In total eight excited-state lifetimes in the angular momentum range I= (13 - 20) ℏ have been measured, five of which were determined for the first time. The corresponding B(M1) and B(E2) reduced transition strengths are discussed within the framework of large-scale shell model calculations to study the contribution of different particle-hole configurations, in particular for analyzing contributions from core-excited configurations

Evidence for spherical-oblate shape coexistence in Tc 87

Excited states in the neutron-deficient nucleus Tc87 have been studied via the fusion-evaporation reaction Fe54(Ar36,2n1p)Tc87 at 115 MeV beam energy. The AGATA γ-ray spectrometer coupled to the DIAMANT, NEDA, and Neutron Wall detector arrays for light-particle detection was used to measure the prompt coincidence of γ rays and light particles. Six transitions from the deexcitation of excited states belonging to a new band in Tc87 were identified by comparing γ-ray intensities in the spectra gated under different reaction channel selection conditions. The constructed level structure was compared with the shell model and total Routhian surface calculations. The results indicate that the new band structure in Tc87 is built on a spherical configuration, which is different from that assigned to the previously identified oblate yrast rotational band

Measuring the Effects of Tourists\u27 Relative Willingness to Spend and Third-degree Price Discrimination on Inbound Tourism Expenditure Differentials

Tourism expenditures are determined by a set of antecedents that reflect tourists\u27 willingness and ability to spend, and de facto incremental monetary outlays at which willingness and ability is transformed into total expenditures. Based on the neoclassical theoretical argument of utility-constrained expenditure minimization, we extend the current literature by applying a sustainability-based segmentation criterion, namely, the Legatum Prosperity IndexTM to the decomposition of a total expenditure differential into tourists\u27 relative willingness to spend and an upper bound of third-degree price discrimination, using mean-level and conditional quantile estimates. Our results indicate that understanding the price–quantity composition of international inbound tourism expenditure differentials assists agents in the tourism industry in their quest for profit maximization

Erratum: Cognitive Profiles in Patients with Multi-Infarct Dementia: An Omani Study

<b><i>Background:</i></b> Studies on neurocognitive impairment among patients presenting with multi-infarct dementia (MID) have received little attention from non-Western societies, and the Arab world is no exception. To our knowledge, this is the first study to characterize neurocognitive, affective and vegetative functioning in patients with MID in Oman. <b><i>Methods:</i></b> In this study, we recruited 20 Omani patients presenting with MID and age- and gender-matched controls at the outpatient clinic of the Department of Behavioral Medicine, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman. In addition to the collection of clinical and demographic information, various cognitive batteries were administered to the consenting participants, including those indexing nonverbal reasoning abilities, working memory (attention, concentration and recall) and executive functioning. Questionnaires that elicit the affective range and the quality of sleep were also administered. <b><i>Results:</i></b> Compared with the matched healthy subjects, the patients diagnosed with MID significantly differed in the presently operationalized indices of visuospatial function, semantic memory and affective and vegetative functioning. In contrast, episodic memory and some attentional capacities were not significantly different compared with the control subjects. <b><i>Conclusions:</i></b> The present study was explorative and clinically designed to describe neurocognitive functioning in patients with MID seeking consultation at a tertiary care center in Oman. Our data are necessary for planning and setting up community services and health care programs for demented patients in a society where dementia is a growing silent epidemic. © 2014 S. Karger AG, Base