Semen analysis of G olden R etriever healthy dogs and those affected by muscular dystrophy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106077/1/and12079.pd

Prenatal and Neonatal Adaptations with a Focus on the Respiratory System

Contents Among the modifications that occur during the neonatal period, pulmonary development is the most critical. The neonate's lungs must be able to perform adequate gas exchange, which was previously accomplished by the placenta. Neonatal respiratory distress syndrome is defined as insufficient surfactant production or pulmonary structural immaturity and is specifically relevant to preterm newborns. Prenatal maternal betamethasone treatment of bitches at 55days of gestation leads to structural changes in the neonatal lung parenchyma and consequently an improvement in the preterm neonatal respiratory condition, but not to an increase in pulmonary surfactant production. Parturition represents an important challenge to neonatal adaptation, as the uterine and abdominal contractions during labour provoke intermittent hypoxia. Immediately after birth, puppies present venous mixed acidosis (low blood pH and high dioxide carbon saturation) and low but satisfactory Apgar scores. Thus, the combination of physiological hypoxia during birth and the initial effort of filling the pulmonary alveoli with oxygen results in anaerobiosis. As a neonatal adaptation follow-up, the Apgar analysis indicates a tachypnoea response after 1h of life, which leads to a shift in the blood acidbase status to metabolic acidosis. One hour is sufficient for canine neonates to achieve an ideal Apgar score; however, a haemogasometric imbalance persists. Dystocia promotes a long-lasting bradycardia effect, slows down Apgar score progression and aggravates metabolic acidosis and stress. The latest data reinforce the need to accurately intervene during canine parturition and offer adequate medical treatment to puppies that underwent a pathological labour

Frictional properties of subduction input sediments at an erosive convergent continental margin and related controls on décollement slip modes - the Costa Rica Seismogenesis Project (CRISP)

The spectrum of slip modes occurring along shallow portions of the plate boundary décollement in subduction zones includes aseismic slip, slow slip, and seismogenic slip. The factors that control slip modes directly influence the hazard potential of subduction zones for generating large magnitude earthquakes and tsunamis. We conducted an experimental study of the frictional behaviour of subduction input sediments, recovered from two IODP expeditions to the erosive subduction margin offshore Costa Rica (Exp. 334, 344),employing rotary shear under hydrothermal conditions. The velocity dependence of friction was explored, using simulated gouges prepared from all major lithologies, covering a wide range of conditions representative for the initial stages of subduction. Temperature, effective normal stress, and pore fluid pressure were varied systematically up to 140 °C, 110 MPa and 120 MPa respectively. Sliding velocities up to 100 μm/s, relevant for earthquake rupture nucleation and slow slip, were investigated. The only sediment type that produced frictional instabilities (i.e. laboratory earthquakes) was the calcareous ooze carried by the incoming Cocos Plate, which by virtue of its slip weakening behaviour is also a likely candidate for triggering slow slip events. We evaluate this mechanism of producing unstable slip and consider alternatives. Therefore, locking and unlocking of plate boundary megathrusts are not only related to variations in pore fluid pressure, but may also depend on the presence of pelagic carbonate‐rich lithologies. Subduction systems containing such input are likely low‐latitude, where extensive deposition of carbonates takes place above the CCD

Hydrogeological system of erosional convergent margins and its influence on tectonics and interplate seismogenesis

[1] Fluid distribution in convergent margins is by most accounts closely related to tectonics. This association has been widely studied at accretionary prisms, but at half of the Earth's convergent margins, tectonic erosion grinds down overriding plates, and here fluid distribution and its relation to tectonics remain speculative. Here we present a new conceptual model for the hydrological system of erosional convergent margins. The model is based largely on new data and recently published observations from along the Middle America Trench offshore Nicaragua and Costa Rica, and it is consistent with observations from other erosional margins. The observations indicate that erosional margins possess previously unrecognized distinct hydrogeological systems: Most fluid contained in the sediment pores and liberated by early dehydration reactions drains from the plate boundary through a fractured upper plate to seep at the seafloor across the slope, rather than migrating along the décollement toward the deformation front as described for accretionary prisms. The observations indicate that the relative fluid abundance across the plate-boundary fault zone and fluid migration influence long-term tectonics and the transition from aseismic to seismogenic behavior. The segment of the plate boundary where fluid appears to be more abundant corresponds to the locus of long-term tectonic erosion, where tectonic thinning of the overriding plate causes subsidence and the formation of the continental slope. This correspondence between observations indicates that tectonic erosion is possibly linked to the migration of overpressured fluids into the overriding plate. The presence of overpressured fluids at the plate boundary is compatible with the highest flow rates estimated at slope seeps. The change from aseismic to seismogenic behavior along the plate boundary of the erosional margin begins where the amount of fluid at the fault declines with depth, indicating a control on interplate earthquakes. A previously described similar observation along accreting plate boundaries strongly indicates that fluid abundance exerts a first-order control on interplate seismogenesis at all types of subduction zones. We hypothesize that fluid depletion with depth increases grain-to-grain contact, increasing effective stress on the fault, and modifies fault zone architecture from a thick fault zone to a narrower zone of localized slip

A Structurally Simple Vaccine Candidate Reduces Progression and Dissemination of Triple-Negative Breast Cancer

The Tn antigen is a well-known tumor-associated carbohydrate determinant, often incorporated in glycopeptides to develop cancer vaccines. Herein, four copies of a conformationally constrained mimetic of the antigen TnThr (GalNAc-Thr) were conjugated to the adjuvant CRM197, a protein licensed for human use. The resulting vaccine candidate, mime[4]CRM elicited a robust immune response in a triple-negative breast cancer mouse model, correlated with high frequency of CD4+ T cells and low frequency of M2-type macrophages, which reduces tumor progression and lung metastasis growth. Mime[4]CRM-mediated activation of human dendritic cells is reported, and the proliferation of mime[4]CRM-specific T cells, in cancer tissue and peripheral blood of patients with breast cancer, is demonstrated. The locked conformation of the TnThr mimetic and a proper presentation on the surface of CRM197 may explain the binding of the conjugate to the anti-Tn antibody Tn218 and its efficacy to fight cancer cells in mice

A Highly Sensitive Quantitative Real-Time PCR Assay for Determination of Mutant JAK2 Exon 12 Allele Burden

Mutations in the Janus kinase 2 (JAK2) gene have become an important identifier for the Philadelphia-chromosome negative chronic myeloproliferative neoplasms. In contrast to the JAK2V617F mutation, the large number of JAK2 exon 12 mutations has challenged the development of quantitative assays. We present a highly sensitive real-time quantitative PCR assay for determination of the mutant allele burden of JAK2 exon 12 mutations. In combination with high resolution melting analysis and sequencing the assay identified six patients carrying previously described JAK2 exon 12 mutations and one novel mutation. Two patients were homozygous with a high mutant allele burden, whereas one of the heterozygous patients had a very low mutant allele burden. The allele burden in the peripheral blood resembled that of the bone marrow, except for the patient with low allele burden. Myeloid and lymphoid cell populations were isolated by cell sorting and quantitative PCR revealed similar mutant allele burdens in CD16+ granulocytes and peripheral blood. The mutations were also detected in B-lymphocytes in half of the patients at a low allele burden. In conclusion, our highly sensitive assay provides an important tool for quantitative monitoring of the mutant allele burden and accordingly also for determining the impact of treatment with interferon-α-2, shown to induce molecular remission in JAK2V617F-positive patients, which may be a future treatment option for JAK2 exon 12-positive patients as well

Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are ∼99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17% these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation

Repercussion of megakaryocyte-specific Gata1 Loss on megakaryopoiesis and the hematopoietic precursor compartment

During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cK-OMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches. © 2016 Meinders et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited