A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

Avtors developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression patter

Evolutionary Dynamics of the Pericentromeric Heterochromatin in Drosophila virilis and Related Species

Pericentromeric heterochromatin in Drosophila generally consists of repetitive DNA, forming the environment associated with gene silencing. Despite the expanding knowledge of the impact of transposable elements (TEs) on the host genome, little is known about the evolution of pericentromeric heterochromatin, its structural composition, and age. During the evolution of the Drosophilidae, hundreds of genes have become embedded within pericentromeric regions yet retained activity. We investigated a pericentromeric heterochromatin fragment found in D. virilis and related species, describing the evolution of genes in this region and the age of TE invasion. Regardless of the heterochromatic environment, the amino acid composition of the genes is under purifying selection. However, the selective pressure affects parts of genes in varying degrees, resulting in expansion of gene introns due to TEs invasion. According to the divergence of TEs, the pericentromeric heterochromatin of the species of virilis group began to form more than 20 million years ago by invasions of retroelements, miniature inverted repeat transposable elements (MITEs), and Helitrons. Importantly, invasions into the heterochromatin continue to occur by TEs that fall under the scope of piRNA silencing. Thus, the pericentromeric heterochromatin, in spite of its ability to induce silencing, has the means for being dynamic, incorporating the regions of active transcription

Medicine and improvement in the Scots Magazine; and Edinburgh Literary Miscellany, 1804-17

Megan Coyer’s chapter engages with periodical print as a vehicle for an improving medical culture in Scotland, concentrating on the second series of the Scots Magazine. Coyer demonstrates how the Scottish press often complemented improving civic initiatives like the Edinburgh Lunatic Asylum campaign. She focuses attention on the distinctive national dynamics associated with medical improvement efforts in early nineteenth-century Scotland, with the Scots Magazine ‘providing a public forum for the expression of a national medical identity’. This identity, as Coyer shows, had an ideology of improvement at its core. This work recovers the cultural significance of the Scots Magazine as ‘the third major player in popular periodical culture in Romantic-era Scotland’; a status overshadowed by the recent critical attention devoted to the second Edinburgh Review and Blackwood’s in Scottish Romantic studies. Coyer also shows how the efforts of public health reformers highlight the complexity of improvement as both a material and moral process. She argues that print efforts dedicated to improving public health represent a ‘discursive strand in the magazine identifying a lack of cleanliness … as a moral and material blight on an otherwise improving Scottish society’. This bringing together of moral and practical aspects of improvement in the Scots also finds expression in the magazine’s series of Scottish medical biographies, whose narratives, Coyer notes, provide ‘ideal exemplars of lives dedicated to a culture of improvement’

Low level of expression of C-terminally truncated human FUS causes extensive changes in the spinal cord transcriptome of asymptomatic transgenic mice

A number of mutations in a gene encoding RNA-binding protein FUS have been linked to the development of a familial form of amyotrophic lateral sclerosis known as FUS-ALS. C-terminal truncations of FUS by either nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients bearing these highly pathogenic mutations the function of motor neurons is not noticeably compromised for at least a couple of decades, suggesting that until cytoplasmic levels of FUS lacking its C-terminal nuclear localisation signal reaches a critical threshold, motor neurons are able to tolerate its permanent production.In order to identify how the nervous system responds to low levels of pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low neuronal expression level of a highly aggregation-prone and pathogenic form of C-terminally truncated FUS. In contrast to mice that express substantially higher level of the same FUS variant and develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any clinical or histopathological signs of motor neuron deficiency even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice compared to their wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating for the potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective targets for therapy of FUS-ALS and possibly, other forms of ALS

ЗАСТОСУВАННЯ ЛАПАРОСКОПІЧНОЇ КИШКОВОЇ СИМПАТОЛІТИЧНОЇ БЛОКАДИ З МЕТОЮ ЗАПОБІГАННЯ СПАЙКОВОГО ПРОЦЕСУ

The results of the analysis of the developed method of adhesive peritoneal disease prevention are presented. The method is based on the performance of laparoscopic sympatholitic intestinal block, while performing adhesive disease surgery. The progress of the adhesive disease process in this case is prevented by the early restoration of the gastro-intestinal function, which has a positive effect on the postoperative course. Moreover, early mobilization is prompted by the adequate level of analgesia.Приведен анализ результатов использования разработанного способа предупреждения спаечной болезни брюшины. Метод основан на выполнении лапароскопической кишечной симпатолитической блокады во время вмешательств по поводу спаечной болезни. Прогрессирование спаечного процесса в послеоперационном периоде предупреждается путем раннего восстановления функции желудочно-кишечного тракта, что имеет положительный эффект на течение послеоперационного периода. Кроме того, ранней мобилизации больных способствует высокий уровень обезболивания.Наведено аналіз результатів використання розробленого способу запобігання спайкової хвороби очеревини. Метод базується на виконанні лапароскопічної кишкової симпатолітичної блокади під час втручань стосовно спайкової хвороби. Прогресування спайкового процесу у післяопераційному періоді запобігається шляхом раннього відновлення функції шлунково-кишкового тракту, що має позитивний ефект на перебіг післяопераційного періоду. Крім того, ранній мобілізації хворих сприяє високий рівень знеболення

Spontaneous gain of susceptibility suggests a novel mechanism of resistance to hybrid dysgenesis in Drosophila virilis.

Syndromes of hybrid dysgenesis (HD) have been critical for our understanding of the transgenerational maintenance of genome stability by piRNA. HD in D. virilis represents a special case of HD since it includes simultaneous mobilization of a set of TEs that belong to different classes. The standard explanation for HD is that eggs of the responder strains lack an abundant pool of piRNAs corresponding to the asymmetric TE families transmitted solely by sperm. However, there are several strains of D. virilis that lack asymmetric TEs, but exhibit a "neutral" cytotype that confers resistance to HD. To characterize the mechanism of resistance to HD, we performed a comparative analysis of the landscape of ovarian small RNAs in strains that vary in their resistance to HD mediated sterility. We demonstrate that resistance to HD cannot be solely explained by a maternal piRNA pool that matches the assemblage of TEs that likely cause HD. In support of this, we have witnessed a cytotype shift from neutral (N) to susceptible (M) in a strain devoid of all major TEs implicated in HD. This shift occurred in the absence of significant change in TE copy number and expression of piRNAs homologous to asymmetric TEs. Instead, this shift is associated with a change in the chromatin profile of repeat sequences unlikely to be causative of paternal induction. Overall, our data suggest that resistance to TE-mediated sterility during HD may be achieved by mechanisms that are distinct from the canonical syndromes of HD

Activity of heat shock genes' promoters in thermally contrasting animal species.

Heat shock gene promoters represent a highly conserved and universal system for the rapid induction of transcription after various stressful stimuli. We chose pairs of mammalian and insect species that significantly differ in their thermoresistance and constitutive levels of Hsp70 to compare hsp promoter strength under normal conditions and after heat shock (HS). The first pair includes the HSPA1 gene promoter of camel (Camelus dromedarius) and humans. It was demonstrated that the camel HSPA1A and HSPA1L promoters function normally in vitro in human cell cultures and exceed the strength of orthologous human promoters under basal conditions. We used the same in vitro assay for Drosophila melanogaster Schneider-2 (S2) cells to compare the activity of the hsp70 and hsp83 promoters of the second species pair represented by Diptera, i.e., Stratiomys singularior and D. melanogaster, which dramatically differ in thermoresistance and the pattern of Hsp70 accumulation. Promoter strength was also monitored in vivo in D. melanogaster strains transformed with constructs containing the S. singularior hsp70 ORF driven either by its own promoter or an orthologous promoter from the D. melanogaster hsp70Aa gene. Analysis revealed low S. singularior hsp70 promoter activity in vitro and in vivo under basal conditions and after HS in comparison with the endogenous promoter in D. melanogaster cells, which correlates with the absence of canonical GAGA elements in the promoters of the former species. Indeed, the insertion of GAGA elements into the S. singularior hsp70 regulatory region resulted in a dramatic increase in promoter activity in vitro but only modestly enhanced the promoter strength in the larvae of the transformed strains. In contrast with hsp70 promoters, hsp83 promoters from both of the studied Diptera species demonstrated high conservation and universality

Characteristic Features of the Transcriptome in A Rat Strain with Audiogenic Epilepsy

Audiogenic epilepsy (AE), developing in rodent strains in response to sound, is widely used as the model of generalized convulsive epilepsy, while the molecular mechanisms determining AE are currently poorly understood. The brain region that is crucial for AE development isthe inferior and superior colliculi (IC, SC). We compared IC-SC gene expression profiles in rats with different AE susceptibility using transcriptome analysis.The transcriptomes were obtained from the IC-SC of Wistar rats (with no AE), Krushinsky-Molodkina (KM) strain rats (100% AE susceptible), and ”0” strain rats (with no AE) selected from F2 KM x Wistar hybrids for AE absence. KM gene expression displayed characteristic differences inboth of the strains that were not susceptible to AE. There was increased expression of a number of genes responsible for positive regulation of the MAPK signaling cascade, as well as of genes responsible for the production of interferon and several other cytokines. An increase in the expression levels of theTTR gene was found in KM rats, as well as significantly lower expression of the Msh3 gene (involved in post-replicative DNA repair systems). AE was also describedin the 101/HY mouse strain with a mutation in the locus controlling DNA repair. The DNA repair system defects could be the primary factor leading to the accumulation of mutations, which, in turn, promote AE. Keywords: udiogenic seizure, KM strain, transcriptome, TTR gene, Msh3 gene, DNA repai

Adaptation of gene loci to heterochromatin in the course of Drosophila evolution is associated with insulator proteins

Pericentromeric heterochromatin is generally composed of repetitive DNA forming a transcriptionally repressive environment. Dozens of genes were embedded into pericentromeric heterochromatin during evolution of Drosophilidae lineage while retaining activity. However, factors that contribute to insusceptibility of gene loci to transcriptional silencing remain unknown. Here, we find that the promoter region of genes that can be embedded in both euchromatin and heterochromatin exhibits a conserved structure throughout the Drosophila phylogeny and carries motifs for binding of certain chromatin remodeling factors, including insulator proteins. Using ChIP-seq data, we demonstrate that evolutionary gene relocation between euchromatin and pericentric heterochromatin occurred with preservation of sites of insulation of BEAF-32 in evolutionarily distant species, i.e. D. melanogaster and D. virilis. Moreover, promoters of virtually all protein-coding genes located in heterochromatin in D. melanogaster are enriched with insulator proteins BEAF-32, GAF and dCTCF. Applying RNA-seq of a BEAF-32 mutant, we show that the impairment of BEAF-32 function has a complex effect on gene expression in D. melanogaster, affecting even those genes that lack BEAF-32 association in their promoters. We propose that conserved intrinsic properties of genes, such as sites of insulation near the promoter regions, may contribute to adaptation of genes to the heterochromatic environment and, hence, facilitate the evolutionary relocation of genes loci between euchromatin and heterochromatin.peerReviewe

Comparative analysis of the ovarian piRNA profiles between <i>P</i>-like strain <i>160</i> and both <i>M</i>- and neutral <i>(N)</i> strains studied.

<p>A) and B) Scatter plots represent the result of pairwise comparison of normalized piRNAs (23–29 nt) in <i>P</i>-strain <i>160</i> versus <i>M</i>-like strains <i>9</i> and <i>13</i>, and in <i>P</i>-strain <i>160</i> versus <i>N</i>-strains <i>140</i>, <i>Argentina</i>, <i>Magarach</i> and <i>101</i>, respectively. Diagonal lines indicate 10-fold levels of difference. All the TEs that exceed 10-fold line are marked as gray dots. The red dots indicate TEs that are shared between <i>M</i>-strains <i>9</i> and <i>13</i> in terms of their low expression levels in comparison with <i>P</i>-strain <i>160</i>. Spearman’s correlation (R) is shown. C) Venn diagram depicting differences and similarities in a number of TEs exhibiting 10-fold lower piRNA expression level in <i>M</i>-strains <i>9</i> and <i>13</i> in comparison with <i>P</i>-strain <i>160</i>. 10 families show the same pattern of deficit in strains <i>9</i> and <i>13</i>, relative to strain 160. D) Venn diagram demonstrates distribution of piRNAs to eight essential elements distinguishing neutral strains from <i>M</i>-like in terms of piRNA-mediated silencing among studied <i>N</i>-strains.</p