Transcriptional repression of Hox genes by C. elegans HP1/HPL and H1/HIS-24.

Elucidation of the biological role of linker histone (H1) and heterochromatin protein 1 (HP1) in mammals has been difficult owing to the existence of a least 11 distinct H1 and three HP1 subtypes in mice. Caenorhabditis elegans possesses two HP1 homologues (HPL-1 and HPL-2) and eight H1 variants. Remarkably, one of eight H1 variants, HIS-24, is important for C. elegans development. Therefore we decided to analyse in parallel the transcriptional profiles of HIS-24, HPL-1/-2 deficient animals, and their phenotype, since hpl-1, hpl-2, and his-24 deficient nematodes are viable. Global transcriptional analysis of the double and triple mutants revealed that HPL proteins and HIS-24 play gene-specific roles, rather than a general repressive function. We showed that HIS-24 acts synergistically with HPL to allow normal reproduction, somatic gonad development, and vulval cell fate decision. Furthermore, the hpl-2; his-24 double mutant animals displayed abnormal development of the male tail and ectopic expression of C. elegans HOM-C/Hox genes (egl-5 and mab-5), which are involved in the developmental patterning of male mating structures. We found that HPL-2 and the methylated form of HIS-24 specifically interact with the histone H3 K27 region in the trimethylated state, and HIS-24 associates with the egl-5 and mab-5 genes. Our results establish the interplay between HPL-1/-2 and HIS-24 proteins in the regulation of positional identity in C. elegans males

Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis

In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.Bio-organic Synthesi

НОВЕ МІСЦЕЗНАХОДЖЕННЯ ДВОСТУЛКОВИХ МОЛЮСКІВ ЗОВНІШНИХ КАРПАТ ПОЛЬЩІ

The peculiar Oligocene bivalve fauna typical of the Solenovian stage of the Paratethys has been found in the Outer Carpathians, Poland. It includes nine species, six of which are characteristic Paratethyan endemics known from the Solenovian Sea (second part of the Rupelian) with brackishwater conditions.Своеобразный комплекс двустворчатых моллюсков, характерных для соленовского уровня опреснения бассейна Паратетис, впервые найден во Внешних Карпатах Польши. Он содержит девять видов, из которых шесть являются специфичными солоноватоводными эндемиками Паратетиса, известными для соленовского времени опреснения бассейна позднего рюпеля.Своєрідний комплекс двостулкових молюсків, характерних для солонівського рівня опріснення басейну Паратетіс, вперше знайдено в Зовнішніх Карпатах Польщі. Він містить дев’ять видів, з яких шість є специфічними солонуватоводними ендеміками Паратетісу, відомими для солонівського часу опріснення басейну пізнього рюпелю

Oligocene bivalve faunas from the Silesian Nappe, Polish Outer Carpathians: Evidence for the early history of the Paratethys

The study is focused on the taxonomic inventory of an intriguing bivalve fauna from the Lower Oligocene Menilite Beds (Dynów Marls) within the Silesian Nappe, Polish Outer Carpathians. Sixteen bivalve species have been identified within the material collected in two small quarries in Jabłonica Polska near Krosno. Stratigraphic and geographic distributions of all recognized species are considered. This assemblage, the first of this kind in Poland and one of three recognized in the Outer Carpathians, shows clear affinities to coeval typical Solenovian faunas from Ukraine to Kazakhstan, with particular comparison made to bivalve faunas from the Menilite Formation (Subchert Member) within the Boryslav-Pokuttya Nappe, Ukrainian Outer Carpathians. Moreover, this study presents an overview of the main aspects and definitions of the date of the Paratethys origin. The main criterion used to define the time of the Paratethys birth is the distinct faunal turnover from the moderately diverse boreal or Tethyan bivalve faunas populating particular basins of the Northern Peri-Tethys in the earliest Oligocene to the uniform, highly endemic fauna inhabiting the newly formed semi-closed basin. This vast inland sea, named Paratethys, was populated by representatives of eight euryhaline bivalve families. They are characterized by extinct Paratethyan genera, such as Bessia Kojumdgieva et Sapungieva, Merklinicardium Popov, Korobkoviella Merklin, Urbnisia Goncharova, Ergenica G. Popov and Janschinella Merklin

FoCo: a simple and robust quantification algorithm of nuclear foci

BACKGROUND: The number of γH2AX foci per nucleus is an accepted measure of the number of DNA double-strand breaks in single cells. One of the experimental techniques for γH2AX detection in cultured cells is immunofluorescent labelling of γH2AX and nuclei followed by microscopy imaging and analysis. RESULTS: In this study, we present the algorithm FoCo for reliable and robust automatic nuclear foci counting in single cell images. FoCo has the following advantages with respect to other software packages: i) the ability to reliably quantify even densely distributed foci, e.g., on images of cells subjected to radiation doses up to 10 Gy, ii) robustness of foci quantification in the sense of suppressing out-of-focus background signal, and iii) its simplicity. FoCo requires only 5 parameters that have to be adjusted by the user. CONCLUSIONS: FoCo is an open-source user-friendly software with GUI for individual foci counting, which is able to produce reliable and robust foci quantifications even for low signal/noise ratios and densely distributed foci. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-015-0816-5) contains supplementary material, which is available to authorized users

Miodobory – środkowomioceński system rafowy, jego zróżnicowanie biologiczne i litofacje

The unique Middle Miocene reef belt formed within the Paratethyan realm constitutes at present the Medobory Hills in western Ukraine and northernmost Moldova. Not only is the size of this structure (almost 300 km long) quite unusual, but also the development of peculiar facies and their spatial distribution. Two distinct reef generations appear in Medobory (Late Badenian and Early Sarmatian), both separated by a sharp erosional boundary. Two Upper Badenian calcareous lithofacies dominate – organodetrital and biohermal (with coralline-algae as main framework builders accompanied by a rich invertebrate assemblage). The Lower Sarmatian strata, although megascopically very similar to Upper Badenian ones, differ drastically when studied closely. The main reef components here are serpulids and microbialites, usually with ubiquitous, but taxonomically highly impoverished fauna. Differences in lithofacies and biotic communities between both reef systems unveil open-marine environment during formation of Upper Badenian reefs and a drastic change of conditions at the Badenian/Sarmatian boundary (including emersion and intense weathering). The Early Sarmatian basin was established soon after and highly restricted conditions prevailed in it (e.g. with mesohaline waters and intense evaporation occurring simultaneously); its deposits are the last record of Middle Miocene sedimentation within the Medobory area.Wzgórza Miodoborów, rozciągające się na przestrzeni niemal 300 km na obszarze zachodniej Ukrainy i północnej Mołdawii, założone są na pasie raf miocenu środkowego, uformowanych w obrębie północno-wschodnich peryferii Paratetydy. Znaczne zróżnicowanie litofacjalne, jak i zmienność zespołów biotycznych wśród utworów rafowych jest rezultatem obecności dwóch generacji raf (późnobadeńskiej i wczesnosarmackiej) oddzielonych wyraźną powierzchnią erozyjną. Wśród wapiennych osadów górnego badenu dominują litofacje organodetrytyczne i biohermalne. Ich głównym składnikiem skałotwórczym są krasnorosty, którym towarzyszą bogate taksonomicznie zespoły bezkręgowców, obejmujące m.in. korale, mięczaki, szkarłupnie. Rafy sarmatu dolnego budowane są przez mikrobiality, w obrębie których występują serpule (i podrzednie mszywioły). Silnie zubożona taksonomicznie fauna zamieszkująca rafy sarmackie zdominowana jest przez mięczaki. Różnice bio- i litofacjalne w obrębie wymienionych generacji raf są efektem drastycznej zmiany warunków sedymentacji, połączonej z emersją i intensywnym wietrzeniem, do której doszło na przełomie badenu i sarmatu w efekcie przebudowy basenu przedkarpackiego. W jej wyniku pełnomorski zbiornik późnobadeński został zastąpiony przez silnie izolowany basen wczesnego sarmatu, zaś powstałe w tym ostatnim osady wieńczą sukcesję utworów miocenu w tej części zapadliska przedkarpackiego

Proteasome dysfunction disrupts adipogenesis and induces inflammation via ATF3.

OBJECTIVE: Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and associated regulators, who suffer from proteasome-associated autoinflammatory syndromes (PRAAS). These patients display lipodystrophy and fevers, which may be partly related to adipocyte malfunction and abnormal thermogenesis in adipose tissue. However, the cell-intrinsic pathways that could underlie these symptoms are unclear. Here, we investigate the impact of two proteasome subunits implicated in PRAAS, Psmb4 and Psmb8, on differentiation, function and proteostasis of brown adipocytes. METHODS: In immortalized mouse brown pre-adipocytes, levels of Psmb4, Psmb8, and downstream effectors genes were downregulated through reverse transfection with siRNA. Adipocytes were differentiated and analyzed with various assays of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration. RESULTS: Loss of Psmb4, but not Psmb8, disrupted proteostasis and adipogenesis. Proteasome function was reduced upon Psmb4 loss, but partly recovered by the activation of Nuclear factor, erythroid-2, like-1 (Nfe2l1). In addition, cells displayed higher levels of surrogate inflammation and stress markers, including Activating transcription factor-3 (Atf3). Simultaneous silencing of Psmb4 and Atf3 lowered inflammation and restored adipogenesis. CONCLUSIONS: Our study shows that Psmb4 is required for adipocyte development and function in cultured adipocytes. These results imply that in humans with PSMB4 mutations, PRAAS-associated lipodystrophy is partly caused by disturbed adipogenesis. While we uncover a role for Nfe2l1 in the maintenance of proteostasis under these conditions, Atf3 is a key effector of inflammation and blocking adipogenesis. In conclusion, our work highlights how proteasome dysfunction is sensed and mitigated by the integrated stress response in adipocytes with potential relevance for PRAAS patients and beyond