Late Little Ice Age palaeoenvironmental records from the Anzali and Amirkola Lagoons (south Caspian Sea): Vegetation and sea level changes

This is a postprint version of the article. The official published article can be found from the link below - Copyright @ 2011 Elsevier Ltd.Two internationally important Ramsar lagoons on the south coast of the Caspian Sea (CS) have been studied by palynology on short sediment cores for palaeoenvironmental and palaeoclimatic investigations. The sites lie within a small area of very high precipitation in a region that is otherwise dry. Vegetation surveys and geomorphological investigations have been used to provide a background to a multidisciplinary interpretation of the two sequences covering the last four centuries. In the small lagoon of Amirkola, the dense alder forested wetland has been briefly disturbed by fire, followed by the expansion of rice paddies from AD1720 to 1800. On the contrary, the terrestrial vegetation reflecting the diversity of the Hyrcanian vegetation around the lagoon of Anzali remained fairly complacent over time. The dinocyst and non-pollen palynomorph assemblages, revealing changes that have occurred in water salinity and water levels, indicate a high stand during the late Little Ice Age (LIA), from AD < 1620 to 1800–1830. In Amirkola, the lagoon spit remained intact over time, whereas in Anzali it broke into barrier islands during the late LIA, which merged into a spit during the subsequent sea level drop. A high population density and infrastructure prevented renewed breaking up of the spit when sea level reached its maximum (AD1995). Similar to other sites in the region around the southern CS, these two lagoonal investigations indicate that the LIA had a higher sea level as a result of more rainfall in the drainage basin of the CS.The coring and the sedimentological analyses were funded by the Iranian National Institute for Oceanography in the framework of a research project entitled “Investigation of the Holocene sediment along the Iranian coast of Caspian Sea: central Guilan”. The radiocarbon date of core HCGL02 was funded by V. Andrieu (Europôle Méditerranéen de l'Arbois, France) and that of core HCGA04 by Brunel University

BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34+ CD38− LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation

BCL6 is critical for the development of a diverse primary B cell repertoire

BCL6 protects germinal center (GC) B cells against DNA damage–induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7–dependent B cell precursors, we report that IL-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–Stat5 signaling is attenuated. At the transition from IL-7–dependent to –independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre–B cells from DNA damage–induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre–B cell self-renewal and the formation of a diverse polyclonal B cell repertoire

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

Nuclear import of UBL-domain protein Mdy2 is required for heat-induced stress response in Saccharomyces cerevisiae.

Ubiquitin (Ub) and ubiquitin-like (UBL) proteins regulate a diverse array of cellular pathways through covalent as well as non-covalent interactions with target proteins. Yeast protein Mdy2 (Get5) and its human homolog GdX (Ubl4a) belong to the class of UBL proteins which do not form conjugates with other proteins. Mdy2 is required for cell survival under heat stress and for efficient mating. As part of a complex with Sgt2 and Get4 it has been implicated in the biogenesis of tail-anchored proteins. Interestingly, in response to heat stress, Mdy2 protein that is predominantly localized in the nucleus co-localized with poly(A)-binding protein Pab1 to cytoplasmic stress granules suggesting that nucleocytoplasmic shuttling is of functional importance. Here we investigate the nuclear import of Mdy2, a process that is independent of the Get4/Sgt2 complex but required for stress response. Nuclear import is mediated by an N-terminal nuclear localization signal (NLS) and this process is essential for the heat stress response. In contrast, cells expressing Mdy2 lacking a nuclear export signal (NES) behave like wild type. Importantly, both Mdy2 and Mdy2-ΔNES, but not Mdy2-ΔNLS, physically interact with Pab1 and this interaction correlates with the accumulation in cytoplasmic stress granules. Thus, the nuclear history of the UBL Mdy2 appears to be essential for its function in cytoplasmic stress granules during the rapid cellular response to heat stress

Deletion of <i>GET4</i> or <i>SGT2</i> does not modify heat sensitivity or nuclear localization of Mdy2.

<p>(A) Temperature sensitivity of <i>mdy2</i>Δ cells. Equivalent to 0.4 OD₆₀₀ units of exponentially growing yeast cells diluted serially and spotted on YEPD agar plates. The plates were incubated at 28°C and 38°C for 2 days and pictures were taken. A representative experiment is shown. (B) Temperature sensitivity of <i>mdy2</i>Δ cells grown in liquid medium. Experiments were repeated three times with a similar outcome. The error bars represent standard error of the mean. (C) Mdy2 localizes mainly to the nucleus. Mdy2 in <i>mdy2</i>Δ, <i>get4</i>Δ, and <i>sgt2</i>Δ cells was localized by direct fluorescence of exponentially growing yeast cells using green fluorescence protein (GFP) (<i>green channel</i>). The mutant <i>mdy2</i>Δ was transformed with plasmid MDY2p-GFP-MDY2 (pZH152) or control vector. Nuclear DNA was stained by DAPI to indicate positions of nuclei (<i>blue channel</i>). Green fluorescence images of GFP-Mdy2 were recorded by a Zeiss Axioscope fluorescence microscope. Cells are shown by phase-contrast (PC) images and nuclear DNA by DAPA staining. Strains: WT (W303-1A), <i>mdy2</i>Δ (HZH686), <i>get4</i>Δ (HKA200), <i>sgt2</i>Δ (HLS2002), <i>mdy2</i>Δ <i>get4</i>Δ (HKA227), and <i>mdy2</i>Δ <i>sgt2</i>Δ (HLS2024).</p

Deletion of the N-terminal region Mdy2 affects GFP-Mdy2 nuclear localization and heat sensitivity.

<p>(A) Mdy2 and different C-, N-, and NC-terminal deletion fragments of Mdy2 open reading frame (see schematics) fused to the C-terminus of GFP protein expressed under the control of <i>GAL1</i> promoter in <i>mdy2</i>Δ (HZH686) cells. Temperature sensitivity recorded as indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052956#pone-0052956-g001" target="_blank">Figure 1A</a>. Representative experiments are shown. (B) Protein expression level of GFP-Mdy2 variants shows no difference in mutant cells. The left panel shows Western blot of total protein extracts from GFP-Mdy2, GFP-Mdy2- 1–149, GFP-Mdy2- 74–212, and GFP-Mdy2- 74–149 expressing yeast cells. GFP-Mdy2 was detected using anti-GFP antibody. Protein expression of actin as internal standard was performed using anti-actin antibody, clone C4/MAB1501 (left panel). Quantitative densitometry of protein expression showed no changes in the protein levels of GFP-Mdy2 variants. GFP-Mdy2 was set to 1 (right panel). (C) Visualization of exponentially growing indicated yeast cells was performed using fluorescence microscopy as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052956#pone-0052956-g001" target="_blank">Figure 1B</a>. (D) Quantitative and statistical analysis of the subcellular localization of GFP-Mdy2 variants. About 100 cells from three independent experiments were counted. The graphs show the percentage of cells demonstrating nuclear or cytosolic GFP-Mdy2 variant protein distribution.</p

Heat sensitivity of Mdy2 mutants with defective nuclear localization, Mdy2-ΔNLS, and nuclear export, Mdy2-ΔNES.

<p>(A) Protein expression level of GFP-Mdy2 and different putative NLS and NES constructs of Mdy2 is equal. Western blotting analysis of NLS and NES deletion constructs (<i>mdy2-</i>Δ<i>NLS</i> and <i>mdy2-</i>Δ<i>NES</i>, respectively) in CEN plasmids expressed under the control of <i>MDY2</i> promoter in <i>mdy2</i>Δ (HZH686) cells (left panel). Quantitative densitometry of protein expression showed no changes in GFP-Mdy2 variants. GFP-Mdy2 was set to 1 (right panel). (B) Temperature sensitivity of <i>mdy2</i>Δ cells carrying wild type Mdy2 (<i>MDY2</i>), empty vector (<i>mdy2</i>Δ), NLS and NES deletion constructs (<i>mdy2-</i>Δ<i>NLS</i> and <i>mdy2-</i>Δ<i>NES</i>, respectively) in CEN plasmids expressed under the control of <i>MDY2</i> promoter recorded as indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052956#pone-0052956-g001" target="_blank">Figure 1A</a>. Mdy2 mutants with a defect in nuclear localization <i>(mdy2-</i>Δ<i>NLS)</i> revealed an enhanced growth defect at elevated temperature (third row). Representative experiments are shown. (C) Temperature sensitivity of <i>mdy2</i> mutant cells grown in liquid medium.</p