We have identified a novel protein, p22, required for "constitutive" exocytic membrane traffic. p22 belongs to the EF-hand superfamily of Ca2+-binding proteins and shows extensive similarity to the regulatory subunit of protein phosphatase 2B, calcineurin B. p22 is a cytosolic N-myristoylated protein that undergoes conformational changes upon binding of Ca2+. Antibodies against a p22 peptide block the targeting/fusion of transcytotic vesicles with the apical plasma membrane, but recombinant wild-type p22 overcomes that inhibition. Nonmyristoylated p22, or p22 incapable of undergoing Ca2+-induced conformational changes, cannot reverse the antibody-mediated inhibition. The data suggest that p22 may act by transducing cellular Ca2+ signals to downstream effectors. p22 is ubiquitously expressed, and we propose that its function is required for membrane trafficking events common to many cells.

The leucocyte common antigen, protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45, is a transmembrane glycoprotein, expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation. Disruption of the equilibrium between protein tyrosine kinase and phosphatase activity (from CD45 and others) can result in immunodeficiency, autoimmunity, or malignancy. CD45 is normally present on the cell surface, therefore it works upstream of a large signalling network which differs between cell types, and thus the effects of CD45 on these cells are also different. However, it is becoming clear that CD45 plays an essential role in the innate immune system and this is likely to be a key area for future research. In this review of PTPRC (CD45), its structure and biological activities as well as abnormal expression of CD45 in leukaemia and lymphoma will be discussed.

IRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to fludarabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed

SynopsisWinterkill lakes often have a characteristic fish community, presumably composed of species able to survive winter hypoxia. Our research on a small winterkill lake in northern Wisconsin indicates that fishes common in winterkill lakes have behavioral adaptations for tolerating or avoiding winter hypoxia. We examined the distribution of fishes within the lake during one winter (December through May), and fish migrations into and out of the lake for two consecutive years. As DO within the lake declined in late fall, adult-sized fishes of four species, brook stickleback, finescale date, redbelly date, and fathead minnow, moved to the ice-water interface where DO levels were highest. Stickleback, and to a lesser extent, fathead minnows, also moved toward the more highly oxygenated water near the inlet. During the first year, young-of-the-year fishes of blacknose shiner, Iowa darter, redbelly date, and fathead minnow, avoided hypoxic conditions by emigrating from the lake via the outlet stream in late fall and early winter while DO within the lake was still relatively high. Blacknose shiner, redbelly date, and fathead minnow returned to the lake in spring. Almost no fishes were trapped leaving the lake in the second fall-winter season. Central mudminnows neither moved to the ice-water interface nor emigrated from the lake as DO dropped. Mudminnows survive winter hypoxia by breathing oxygen-containing bubbles trapped beneath the ice. These relatively simple behavioral adaptations allow fishes to survive or avoid hypoxic conditions lethal to other species and may help explain the consistency in fish communities of winterkill lakes.

The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.

Factors affecting the distribution and abundance of animals are of substantial interest, and across most of their southern range, populations of moose (Alces alces (L., 1758)) are declining, presumably because of climate change. Conditions favouring moose population decline versus numerical increase in select areas of the range are not well understood. During 2006-2009, we tested the hypothesis that moose in southern Ontario formed a viable population near the species' southern range limit, despite occurrence of climate patterns apparently deleterious for population growth. Our study upheld each of our predictions: (i) high pregnancy rate (83.0%) and annual female survival rate (0.899 (0.859, 0.941; 95% CI)), indicating that the population was increasing (l = 1.16); (ii) female moose having blood-based condition indices within normal range, despite larger than expected home-range size; and (iii) levels of genetic differentiation indicating that the population was part of a larger metapopulation of moose in the region. We surmise that moose in southern Ontario currently are not subject to the prevalent continental decline, likely owing to favourable site-specific climatic conditions. Future research should elaborate on why select southern moose populations are increasing and whether they will ultimately succumb to die off as effects of climate change become increasingly pronounced.Résumé : Les facteurs qui affectent la distribution et l'abondance des animaux sont de grand intérêt. À travers l'ensemble du sud de leur aire de répartition, les populations d'orignaux (Alces alces (L., 1758)) sont en déclin, vraisemblablement à cause du changement climatique. Les conditions qui favorisent le déclin des populations d'orignaux, malgré les augmentations des nombres dans certaines régions particulières, restent mal comprises. Durant 2006-2009, nous avons testé l'hypothèse selon laquelle les orignaux du sud de l'Ontario forment une population viable près de la limite sud de l'aire de répartition de l'espèce, malgré la présence de patrons climatiques apparemment défavorables à la croissance de la population. Notre étude confirme chacune de nos prédictions : (i) un taux de grossesse (83,0 %) et un taux annuel de survie des femelles (0,899 (IC 95 % : 0,859-0,941) élevés, ce qui indique que la population est croissante (l = 1,16), (ii) des indices de condition basés sur le sang des femelles dans leur gamme normale, malgré un territoire vital plus grand que prévu et (iii) des degrés de différenciation génétique qui indiquent que la population appartient à une métapopulation plus grande d'orignaux dans la région. Nous soupçonnons que les orignaux du sud de l'Ontario ne sont pas affectés par le déclin qui prévaut à l'échelle du continent, vraisemblablement à cause de conditions climatiques favorables spécifiques au site. Des études futures devraient examiner pourquoi certaines populations du sud d'orignaux sont en croissance et voir si elles vont éventuelle-ment succomber au dépérissement à mesure que le changement climatique devi...

We present a new, valuable GEP-based signature for assessing prognosis in MDS. GEP-based signatures correlating with clinical outcome may significantly contribute to a refined risk classification of MDS.