Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients

The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections

Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self-administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein-bound Cys concentrations while LS level was unchanged. Cocaine self-administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration

Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction

Glory in Russian poetic texts: metaphoric models

В статье рассматриваются реализации метафорических моделей, репрезентирующие лингвокультурный концепт «слава». Источником исследования являются фрагменты русских поэтических текстов XVIII-XX вв., включающие компаративные тропы с субъектом сопоставления «слава». Отмечено, что «слава» в компаративных конструкциях представлена главным образом в первом словарном значении (почетная известность как показатель признания заслуг, таланта). Типичными обладателями славы являются герои, поэты, в старой поэзии — цари и полководцы. Образ славы репрезентирован реализациями моделей, отражающих уподобление славы женщине, птице, напитку, растению и т. д. В русской поэзии слава представлена в движении, свете, звуках значительной интенсивности. Проявления славы позволяют говорить о ней как о могущественном существе, властном над людьми, пространством, временем. В поэзии XVIII-XX вв. слава, как правило, локализована в верхней области пространства. В современной поэзии традиционный образ славы видоизменяется, что проявляется в его прозаизации, приземленности, в наличии новых объектов сопоставления, в переплетении традиционного и нового и т. . The article is aimed at revealing the realization of metaphoric models, which represent linguacultural concept “glory”. The source of study is the extracts of Russian poetic texts of the XVIII-XX centuries. The extracts include comparative tropes with the subject of “glory”. It is established that “glory” in comparative constructions is usually presented by its first dictionary meaning (honorable prominence as a sign of credit and talent). Heroes, poets, tsars and battle captains become typical holders of glory. The image of glory is represented by models, which reflect the similarity of fame and a woman, a bird, a beverage, a plant and so on. Glory in Russian poetry is presented in movements, light and sounds in their great intensity. Manifestations of glory lead to the idea that it is a mighty matter, which has its great power over human beings, space and time. In the XVIII-XX century poetry glory as a rule is located in the upper space. In modern poetry, traditional image of glory is changing. It is getting down to earth, new subjects of comparison appear and they interrelate with traditional subjects

Phytomorphic metaphors in reflecting the concept “woman” in Russian poetry

В статье рассматриваются реализации метафорической модели «женщина-растение», объективирующие культурно значимый концепт «женщина». Материалом для исследования служит обширный корпус фрагментов русских поэтических текстов XVIII-XXI веков, в которых рассматриваются компаративные тропы, отражающие представления о женщине как элементе растительного мира. Основаниями традиционных сопоставлений являются признаки красоты, молодости, свежести, нежности, связь с весенним пробуждением природы. Наибольшей частотностью и распространенностью отличаются модели женщина/дева-роза и женщина/дева-лилия. На особенностях внешнего облика базируется уподобление женщин деревьям — с актуализацией тех или иных особенностей семантики соответствующих образов. Наиболее традиционным является образное представление о женщине как эстетическом объекте. В реализациях ряда моделей отражена слабость женщины, необходимость мужчины-опоры для ее полноценного существования. В поэзии XX-XXI веков происходит переосмысление и развитие традиционных моделей, обусловленных как корректировкой традиционных представлений о женщине, так и некоторыми тенденциями развития новой . The article considers the realization of the metaphorical model “womanplant”, reflecting the culturally significant concept of “woman”. The article is based on a wide corpus of extracts from Russian poetry XVIII-XXI centuries, where comparisons between a woman and a plant are used as figures of speech. The juxtaposition is based on the traditional characteristics of a woman such as beauty, youth, freshness, tenderness, spring renewal. The peculiarities of the outer image are based on comparing a woman with a tree, with certain semantics being actualized. The most traditional, however, is the imaginative representation of a woman as an aesthetic object. These models show a woman’s weakness, the need of a man’s support through life. Poetry of XX-XXI centuries reassesses and develops traditional models, determined by the alteration of the traditional image of a woman, as well as by the tendencies of new poetics movements