Comments on QED with background electric fields

It is well known that there is a total cancellation of the \emph{factorizable} IR divergences in unitary interacting field theories, such as QED and quantum gravity. In this note we show that such a cancellation does not happen in QED with background electric fields which can produce pairs. There is no factorization of the IR divergences.Comment: 14 pages, 1 figur

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans

Abundance analysis of two late A-type stars HD 32115 and HD 37594

We have performed abundance analysis of two slowly rotating, late A-type stars, HD 32115 (HR 1613) and HD 37594 (HR 1940), based on obtained echelle spectra covering the spectral range 4000-9850 AAngstrom. These spectra allowed us to identify an extensive line list for 31 chemical elements, the most complete to date for A-type stars. Two approaches to abundance analysis were used, namely a ``manual'' (interactive) and a semi-automatic procedure for comparison of synthetic and observed spectra and equivalent widths. For some elements non-LTE (NLTE) calculations were carried out and the corresponding corrections have been applied. The abundance pattern of HD 32115 was found to be very close to the solar abundance pattern, and thus may be used as an abundance standard for chemical composition studies in middle and late A stars. Further, its H-alpha line profile shows no core-to-wing anomaly like that found for cool Ap stars and therefore also may be used as a standard in comparative studies of the atmospheric structures of cool, slowly rotating Ap stars. HD 37594 shows a metal deficiency at the level of -0.3 dex for most elements and triangle-like cores of spectral lines. This star most probably belongs to the Delta Scuti group.Comment: 10 pages, 4 figure

Duality Invariant M-theory: Gauged supergravities and Scherk-Schwarz reductions

We consider the reduction of the duality invariant approach to M-theory by a U-duality group valued Scherk-Schwarz twist. The result is to produce potentials for gauged supergravities that are normally associated with non-geometric compactifications. The local symmetry reduces to gauge transformations with the gaugings exactly matching those of the embedding tensor approach to gauged supergravity. Importantly, this approach now includes a nontrivial dependence of the fields on the extra coordinates of the extended space.Comment: 22 pages Latex; v2: typos corrected and references adde

Субхроническая токсичность супрамолекулярного комплекса триклабендазола

Objective of research: Preclinical assessment of subchronic toxicity of the supramolecular complex of Triclabendazole applied on laboratory animals. Materials and methods: Investigations were conducted on 40 male rats with the body mass of 200-220 g. Animals were divided into 4 equal groups. The drug was given to rats of 1, 2 and 3 groups at the doses of 1/5 (2600 mg/kg), 1/10 (1300 mg/ kg) and 1/20 (650 mg/kg) of LD50 (13000 mg/kg), respectively, during 7 days daily orally into the stomach using the gastric tube. Animas from the 4th group received starch paste 1% and served as controls. During the experiment, we observed the general condition of animals, visible physiological functions (food and water intake, etc.), possible signs of intoxication; animals were weighted on the 1st, 3rd, 5th and 7th day of the experiment. On the 8th day of the experiment, animals were killed by decapitation. After killing rats and blood taking, laparotomy was conducted, mass of the main organs (heart, lungs, liver, spleen, brain, seminal glands, thymus, pancreas, and adrenal glands) was determined, their mass coefficients calculated, visible changes detected. Hematological and biochemical indices of rats from experimental and control groups were investigated using the automatic analyzer. Results and discussion: When using the drug in three test doses, general condition and behavior of animals were normal; no signs of intoxication were detected. Triclafascid did not induce an increase in body mass. The investigation of internal organs of experimental animals did not reveal abnormalities. Mass coefficients of internal organs of rats from experimental and control groups did not significantly differ from each other. The application of the drug at the doses of 1/5 and 1/10 of LD50 caused minor decrease in the hemoglobin level related to the controls. The number of erythrocytes, thrombocytes, leucocytes, erythrocyte sedimentation rate (ESR) showed no significant changes. In tested doses, Triclafascid had no significant effect on concentrations of total protein and glucose. Kidney function was estimated by urea and creatinine levels. Both values were equal to the controls. Activities of aspartate and alanine aminotransferase did not show any significant changes after application of the drug in the tested doses, which indicated the normal liver function.Цель исследования - доклиническая оценка субхронической токсичности супрамолекулярного комплекса триклабендазола на лабораторных животных. Материалы и методы. Исследования проводили на 40 крысах-самцах массой тела 200-220 г Животных разделили на 4 равные группы. Препарат вводили крысам 1, 2 и 3-й групп в дозах соответственно 1/5 (2600 мг/кг), 1/10 (1300 мг/кг) и 1/20 (650 мг/кг) от ЛД50 (13000 мг/кг) в течение 7 сут ежедневно перорально в желудок с помощью зонда. Животные 4-й группы получали 1%-ный крахмальный клейстер и служили контролем. В течение опыта проводили наблюдение за общим состоянием животных, видимыми физиологическими функциями (приемом корма, воды и т.д.), наличием признаков интоксикации; взвешивали животных на 1, 3, 5 и 7-е сутки опыта. На 8-е сутки животных всех групп убивали методом декапитации. После убоя крыс и забора крови проводили лапаротомию, определяли массу основных органов (сердца, легких, печени, почек, селезенки, мозга, семенников, тимуса, поджелудочной железы и надпочечников) и рассчитывали массовые коэффициенты, устанавливали наличие видимых изменений. Гематологические и биохимические показатели крови у крыс подопытных и контрольной групп исследовали на автоматическом анализаторе. Результаты и обсуждение. При введении препарата в трех тестируемых дозах общее состояние и поведение животных было в норме; признаки интоксикации отсутствовали. Триклафасцид не влиял на прирост массы тела. При исследовании внутренних органов опытных животных отклонений от нормы выявлено не было. Массовые коэффициенты внутренних органов у крыс опытных и контрольной группы достоверно не отличались друг от друга. При введении препарата в дозах 1/5 и 1/10 от ЛД50 наблюдали незначительное понижение уровня гемоглобина по отношению к контролю. Количество эритроцитов, тромбоцитов, лейкоцитов, СОЭ достоверных изменений не претерпели. В испытанных дозах триклафасцид не оказал значимого влияния на концентрацию общего белка, глюкозы. Функциональное состояние почек оценивали по уровню мочевины и креатинина. Оба показателя были на уровне с контролем. Активность аспартат- и аланинаминотрансфераз не подверглась значительным изменениям после введения препарата в тестируемых дозах, что говорит о том, что функциональное состояние печени остается в норме

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis