Origin, migration pathways, and paleoenvironmental significance of Holocene ostracod records from the northeastern Black Sea shelf

Micropaleontological studies of the Black Sea, including ostracod records, have suggested that early Holocene salinity values were between ~5 and 10 practical salinity units (psu), contrasting with present values of 18–22 psu. However, more precise paleoenvironmental reconstructions based on ostracod assemblages require additional information related to their modern ecological affinities. This study uses modern species information collected from samples with living fauna to interpret the fossil Holocene assemblages of two sediment cores, Ak-2575 and Ak-521, collected from the northeastern outer shelf of the Black Sea. A total of 37 ostracod species are recorded in the fossil assemblages, with 2 related to freshwater/oligohaline environments, 23 from Caspian-type environments, and 12 from environments similar to the Mediterranean. Three distinct assemblage zones are identified from the Caspian type dominating in the early Holocene up to 7.4 cal ka BP, a mixed assemblage of Caspian type and Mediterranean type from 7.4 to 6.8 cal ka BP, and a progressive dominance of Mediterranean species from 6.8 cal ka BP. It is very likely that the dominant control of ostracod species occurrence during the period up to ~6.8 cal ka BP is salinity. A range of factors including temperature, biotope, and sedimentation rates influenced the species distribution over the last 6.8 cal ka BP

Effectiveness of Search for Unrelated Donor of Hematopoietic Stem Cells using Russian System Bone Marrow Donor Search: Experience of RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation

Background & Aims. The key condition for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the presence of HLA-compatible related or unrelated donor. If related donor is not found, further search is carried out in the Bone Marrow Donor Worldwide (BMDW) international data base, which is not effective enough (about 80–85 %), because of genotype specificity of Russian Federation residents. The recruitment procedure using BMDW takes a lot of time and is expensive. Therefore, there are good reasons to develop an alternative Russian data base, Bone Marrow Donor Search (BMDS), which includes data from Russian bone marrow donor registries and has a good potential. The aim is to evaluate the effectiveness of hematopoietic stem cell (HSC) donor search and transplant quality using the BMDS search system. Methods. 34 allo-HSCT recipients with malignancies and hematological diseases were enrolled in the study in RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation from November, 2012, to March, 2016. A HLA-compatible donor was found for each patient in the BMDS (www.bmds.info), which includes data from 13 Russian registries of HSC donors. Results. 34 allo-HSCTs were performed from unrelated donors recruited using Russian registries: 1 in 2012; 3 in 2013; 5 in 2014; 21 in 2015; and 4 in the 1st quarter of 2016. The greatest effectiveness of the BMDS search was in 2015 (14 %, n = 17). In 30 cases (88.2 %) a complete 10/10 compatibility for 5 HLA-gene loci was observed; in 4 cases (11.8 %) there was an incomplete compatibility (9/10). AB0 compatibility was only in 7 cases (20.6 %). In 15 cases (44.1 %) bone marrow was used for transplant harvesting; in 19 cases (55.9 %) peripheral blood stem cells were harvested by means of cytapheresis. The CD34+ count in the transplant was 1.2–12.0 x 106 CD34+ cell/kg (median: 5.0 x 106 CD34+ cell/kg). Engraftment was observed in 79.4 % of cases (n = 27), graft failure in 17.7 % of cases (n = 6), and early posttransplant mortality in 2.9 % of cases (n = 1). Conclusion. There was an increasing efficiency of search for a HLA-compatible unrelated HSC donor using a Russian BMDS search system for Russian residents with a graft quality similar to the one found in the international BMDW database

aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

Atypical protein kinase C (aPKC) is a key apical-basal polarity determinant and Par complex component. It is recruited by Par3/Baz (Bazooka in Drosophila) into epithelial apical domains through high-affinity interaction. Paradoxically, aPKC also phosphorylates Par3/Baz, provoking its relocalization to adherens junctions (AJs). We show that Par3 conserved region 3 (CR3) forms a tight inhibitory complex with a primed aPKC kinase domain, blocking substrate access. A CR3 motif flanking its PKC consensus site disrupts the aPKC kinase N lobe, separating P-loop/αB/αC contacts. A second CR3 motif provides a high-affinity anchor. Mutation of either motif switches CR3 to an efficient in vitro substrate by exposing its phospho-acceptor site. In vivo, mutation of either CR3 motif alters Par3/Baz localization from apical to AJs. Our results reveal how Par3/Baz CR3 can antagonize aPKC in stable apical Par complexes and suggests that modulation of CR3 inhibitory arms or opposing aPKC pockets would perturb the interaction, promoting Par3/Baz phosphorylation

Effect of arsenic-phosphorus interaction on arsenic-induced oxidative stress in chickpea plants

Arsenic-induced oxidative stress in chickpea was investigated under glasshouse conditions in response to application of arsenic and phosphorus. Three levels of arsenic (0, 30 and 60 mg kg−1) and four levels of P (50, 100, 200, and 400 mg kg−1) were applied to soil-grown plants. Increasing levels of both arsenic and P significantly increased arsenic concentrations in the plants. Shoot growth was reduced with increased arsenic supply regardless of applied P levels. Applied arsenic induced oxidative stress in the plants, and the concentrations of H2O2 and lipid peroxidation were increased. Activity of superoxide dismutase (SOD) and concentrations of non-enzymatic antioxidants decreased in these plants, but activities of catalase (CAT) and ascorbate peroxidase (APX) were significantly increased under arsenic phytotoxicity. Increased supply of P decreased activities of CAT and APX, and decreased concentrations of non-enzymatic antioxidants, but the high-P plants had lowered lipid peroxidation. It can be concluded that P increased uptake of arsenic from the soil, probably by making it more available, but although plant growth was inhibited by arsenic the P may have partially protected the membranes from arsenic-induced oxidative stress

Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia

Background & Aims. This paper presents the results of the observational study of ibrutinib in patients with chronic lymphocytic leukemia (CLL), conducted in SP Botkin Municipal Clinical Hospital. The main objective was the analysis of complications of ibrutinib and identification of factors, influencing the dosage regimen; the secondary objective was the estimation of the total response to treatment, event-free and overall survival. Materials & Methods. The study included 96 patients with CLL with indications for ibrutinib therapy. The median age was 64,9 years (range 32–91 years), the study population consisted of 69 (72 %) men and 27 (28 %) women. The condition of 25 (26 %) patients according to the ECOG scale was of > 3 points. The disease of stage C were diagnosed in 36 (37 %) patients . Deletion of 17p/TP53 mutations were detected in 29 (33 %) of 87 patients. Seventy patients had refractory CLL. The median of the number of the lines of the previous therapy was 3 (range 1–9). Adverse events were assessed in accordance with the CTCAE criteria, version 4.0; the bleeding severity was evaluated using ITP-specific bleeding score; hematological complications were classified according to the recommendations of IWCLL-2008. Results. Ibrutinib was administered at a dosage of 420 mg per day daily until progression or intolerable toxicity. The median duration of ibrutinib therapy was 10.3 months. Ibrutinib was shown to have moderate toxicity, mostly of grade I or II. The bleeding was the most frequent complication. Of the hematological complications, thrombocytopenia was the most common (35 %); neutropenia grade III) developed in 26 % of patients. The treatment response was assessed in 92 patients. The overall response to treatment was 89 %. Complete remission, partial remission and partial remission with lymphocytosis were achieved in 4 (4 %), 57 (62 %), and 21 (23 %) patients, respectively. The event-free survival and overall survival by the month 10 was 90 % and 91 %, respectively. For this observation period, ECOG status and the number of the lines of therapy prior to ibrutinib had the prognostic value. Conclusion. Ibrutinib was shown to have high efficiency in relapsed/refractory forms of CLL. The nature of the ibrutinib toxicity is fundamentally different from that of the conventional chemotherapy. The frequency of ibrutinib therapy complications and patients’ non-compliance depends on the intensity of the previous treatment of CLL. Despite a short observation period, it can be concluded that ibrutinib had the greatest impact on the patient’s quality of life when administered for the first relapse. The low toxicity of ibrutinib is likely to allow the combination with other antitumor agents

A Functional Role of RB-Dependent Pathway in the Control of Quiescence in Adult Epidermal Stem Cells Revealed by Genomic Profiling

Continuous cell renewal in mouse epidermis is at the expense of a pool of pluripotent cells that lie in a well defined niche in the hair follicle known as the bulge. To identify mechanisms controlling hair follicle stem cell homeostasis, we developed a strategy to isolate adult bulge stem cells in mice and to define their transcriptional profile. We observed that a large number of transcripts are underexpressed in hair follicle stem cells when compared to non-stem cells. Importantly, the majority of these downregulated genes are involved in cell cycle. Using bioinformatics tools, we identified the E2F transcription factor family as a potential element involved in the regulation of these transcripts. To determine their functional role, we used engineered mice lacking Rb gene in epidermis, which showed increased expression of most E2F family members and increased E2F transcriptional activity. Experiments designed to analyze epidermal stem cell functionality (i.e.: hair regrowth and wound healing) imply a role of the Rb-E2F axis in the control of stem cell quiescence in epidermis

Cryptic species in a well-known habitat: applying taxonomics to the amphipod genus Epimeria (Crustacea, Peracarida)

Taxonomy plays a central role in biological sciences. It provides a communication system for scientists as it aims to enable correct identification of the studied organisms. As a consequence, species descriptions should seek to include as much available information as possible at species level to follow an integrative concept of ‘taxonomics’. Here, we describe the cryptic species Epimeria frankei sp. nov. from the North Sea, and also redescribe its sister species, Epimeria cornigera. The morphological information obtained is substantiated by DNA barcodes and complete nuclear 18S rRNA gene sequences. In addition, we provide, for the first time, full mitochondrial genome data as part of a metazoan species description for a holotype, as well as the neotype. This study represents the first successful implementation of the recently proposed concept of taxonomics, using data from highthroughput technologies for integrative taxonomic studies, allowing the highest level of confidence for both biodiversity and ecological research

Identification and Characterization of Nucleolin as a COUP-TFII Coactivator of Retinoic Acid Receptor β Transcription in Breast Cancer Cells

The orphan nuclear receptor COUP-TFII plays an undefined role in breast cancer. Previously we reported lower COUP-TFII expression in tamoxifen/endocrine-resistant versus sensitive breast cancer cell lines. The identification of COUP-TFII-interacting proteins will help to elucidate its mechanism of action as a transcriptional regulator in breast cancer.FLAG-affinity purification and multidimensional protein identification technology (MudPIT) identified nucleolin among the proteins interacting with COUP-TFII in MCF-7 tamoxifen-sensitive breast cancer cells. Interaction of COUP-TFII and nucleolin was confirmed by coimmunoprecipitation of endogenous proteins in MCF-7 and T47D breast cancer cells. In vitro studies revealed that COUP-TFII interacts with the C-terminal arginine-glycine repeat (RGG) domain of nucleolin. Functional interaction between COUP-TFII and nucleolin was indicated by studies showing that siRNA knockdown of nucleolin and an oligonucleotide aptamer that targets nucleolin, AS1411, inhibited endogenous COUP-TFII-stimulated RARB2 expression in MCF-7 and T47D cells. Chromatin immunoprecipitation revealed COUP-TFII occupancy of the RARB2 promoter was increased by all-trans retinoic acid (atRA). RARβ2 regulated gene RRIG1 was increased by atRA and COUP-TFII transfection and inhibited by siCOUP-TFII. Immunohistochemical staining of breast tumor microarrays showed nuclear COUP-TFII and nucleolin staining was correlated in invasive ductal carcinomas. COUP-TFII staining correlated with ERα, SRC-1, AIB1, Pea3, MMP2, and phospho-Src and was reduced with increased tumor grade.Our data indicate that nucleolin plays a coregulatory role in transcriptional regulation of the tumor suppressor RARB2 by COUP-TFII