Rifting Kinematics Produced by Magmatic and Tectonic Stresses in the North Volcanic Zone of Iceland

In the North Volcanic Zone of Iceland, we studied with the greatest possible detail the complete structural architecture and kinematics of the whole Theistareykir Fissure Swarm (ThFS), an N-S-trending, 70 km long active rift. We made about 7500 measurements along 6124 post-Late Glacial Maximum (LGM) extension fractures and faults, and 685 pre-LGM structures. We have collected the data over the last 6 years, through extensive field surveys and with the aid of drone mapping with centimetric resolution. In the southern sector of the study area, extension fractures and faults strike mainly N10°-20°, the opening direction is about N110°, and the dilation amount is in the range 0.1–10 m. In the central sector, faults and extension fractures strike mainly N00-10°, the opening direction is N90-100°, and the dilation amount is 0.1–9 m. In the northern sector, extension fractures and faults strike N30-40°, the opening direction is about N125°, and the dilation amount is 0.1–8 m. The variations in strike are attributable to two processes: the interaction with the WNW-ESE-striking Husavik-Flatey transform fault and Grímsey Oblique Rift (Grímsey lineament), and the structural inheritance of older NNE- to NE-striking normal faults. Most extension fractures show a minor strike-slip component: a systematic right-lateral component can be accounted for by the interaction with the WNW-ESE-striking fault zones and the regional, oblique opening of the rift. We regard dyke propagation as a possible cause for the more complex strike-slip components measured at several other fractures. Cumulated dilation and fracture frequency decrease along the rift with distance away from the Theistareykir volcano, situated in the central sector of the ThFS. This is interpreted as a decrease in the number of dykes that are capable of reaching great distances after being injected from the magma chamber

Collaborative care for depression in general practice: overview of systematic reviews

n/

Fetiform teratoma in an Italian-Fresian calf: case report and literature review.

Introduction. Fetiform teratoma is a rare form of teratoma in animals and people that resembles a malformed fetus. This paper describes the first case of highly differentiated extragonadal fetiform teratoma with cranial connection in an Italian-Friesian calf. Case presentation. A 35-day-old male Italian-Friesian calf weighing 55 kg was referred because of a mass localized in the fronto-nasal region. The mass contained two lateral structures of similar size and conformation that were recognized as underdeveloped hind limbs, while at its center there was a small tail. The mass was surgically excised and sent to the pathologist for examination. Gross examination identified two femur-like rudimentary limbs and a sketch of bone located in between, morphologically referable to a rudimentary coxae-like bo ne. Some mucinous cysts, a virtual body cavity showing adipose and muscular tissues, some cartilaginous nuclei and a coelomatic body cavity were also noted. Histological examination showed differentiation into skin with dermal appendages, hair, adipose tissue, cartilage, bone, lymphoid tissue, neurovascular bundles, and a rudimentary tail. No neural tissue including spinal cord, brain matter, or gonadal differentiation was seen. On the basis of these findings, the mass was diagnosed as a highly differentiated extragonadal fetiform teratoma. Conclusion. Fetiform teratoma should be included among differential diagnoses in cases of neonatal malformation in bovine. Analyzing the available literature, the Friesian genetic strain seem to be predisposed to fetal malformation, but a systematic reporting of cases is needed, in order to investigate further the epidemiological, etiological, pathophysiological and therapeutic aspect of this kind of congenital disease

Golgi apparatus casein kinase phosphorylates bioactive Ser-6 of bone morphogenetic protein 15 and growth and differentiation factor 9

AbstractBone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9) are oocyte-secreted factors that play essential roles in human folliculogenesis and ovulation. Their bioactivity is tightly regulated through phosphorylation, likely to occur within the Golgi apparatus of the secretory pathway. Here we show that Golgi apparatus casein kinase (G-CK) catalyzes the phosphorylation of rhBMP-15 and rhGDF-9. rhBMP-15, in particular, is an excellent substrate for G-CK. In each protein a single residue is phosphorylated by G-CK, corresponding to the serine residue at the sixth position of the mature region of both rhBMP-15 and rhGDF-9, whose phosphorylation is required for biological activity

Astaxanthin Prevents Human Papillomavirus L1 Protein Binding in Human Sperm Membranes

Astaxanthin (Asta), red pigment of the carotenoid family, is known for its anti-oxidant, anti-cancer, anti-diabetic, and anti-inflammatory properties. In this study, we evaluated the effects of Asta on isolated human sperm in the presence of human papillomavirus (HPV) 16 capsid protein, L1. Sperm, purified by gradient separation, were treated with HPV16-L1 in both a dose and time-dependent manner in the absence or presence of 30 min-Asta pre-incubation. Effects of HPV16-L1 alone after Asta pre-incubation were evaluated by rafts (CTB) and Lyn dislocation, Tyr-phosphorylation (Tyr-P) of the head, percentages of acrosome-reacted cells (ARC) and endogenous reactive oxygen species (ROS) generation. Sperm membranes were also analyzed for the HPV16-L1 content. Results show that HPV16-L1 drastically reduced membrane rearrangement with percentage of sperm showing head CTB and Lyn displacement decreasing from 72% to 15.8%, and from 63.1% to 13.9%, respectively. Accordingly, both Tyr-P of the head and ARC decreased from 68.4% to 10.2%, and from 65.7% to 14.6%, respectively. Asta pre-incubation prevented this drop and restored values of the percentage of ARC up to 40.8%. No alteration was found in either the ROS generation curve or sperm motility. In conclusion, Asta is able to preserve sperm by reducing the amount of HPV16-L1 bound onto membranes

Catalase Takes Part in Rat Liver Mitochondria Oxidative Stress Defense

Highly purified rat liver mitochondria (RLM) when exposed to tert-butylhydroperoxide undergo matrix swelling, membrane potential collapse, and oxidation of glutathione and pyridine nucleotides, all events attributable to the induction of mitochondrial permeability transition. Instead, RLM, if treated with the same or higher amounts of H2O2 or tyramine, are insensitive or only partially sensitive, respectively, to mitochondrial permeability transition. In addition, the block of respiration by antimycin A added to RLM respiring in state 4 conditions, or the addition of H2O2, results in O2 generation, which is blocked by the catalase inhibitors aminotriazole or KCN. In this regard, H2O2 decomposition yields molecular oxygen in a 2:1 stoichiometry, consistent with a catalytic mechanism with a rate constant of 0.0346 s(-1). The rate of H2O2 consumption is not influenced by respiratory substrates, succinate or glutamate-malate, nor by N-ethylmaleimide, suggesting that cytochrome c oxidase and the glutathione-glutathione peroxidase system are not significantly involved in this process. Instead, H2O2 consumption is considerably inhibited by KCN or aminotriazole, indicating activity by a hemoprotein. All these observations are compatible with the presence of endogenous heme-containing catalase with an activity of 825 +/- 15 units, which contributes to mitochondrial protection against endogenous or exogenous H2O2. Mitochondrial catalase in liver most probably represents regulatory control of bioenergetic metabolism, but it may also be proposed for new therapeutic strategies against liver diseases. The constitutive presence of catalase inside mitochondria is demonstrated by several methodological approaches as follows: biochemical fractionating, proteinase K sensitivity, and immunogold electron microscopy on isolated RLM and whole rat liver tissue

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche

Membrane association of peroxiredoxin-2 in red cells is mediated by n-terminal cytoplasmic domain of band 3

Band 3(B3),the anion transporter, is an integral membrane protein that plays a key structural role by anchor in the plasmamembrane to the spectrin-based membrane skeleton in the red cell. In addition, it also plays a critical role in the assembly of glycolytic enzymes to regulate red cell metabolism. However, its ability to recruit proteins that can prevent membrane oxidation has not been previously explored. In this study, using a variety of experimental approaches including cross-linking studies, fluorescence and dichroic measurements,surface plasmon resonance analysis, and proteolytic digestion assays, we document that the antioxidant protein peroxiredoxin-2(PRDX2), the third most abundant cytoplasmic protein in RBCs, interacts with the cytoplasmic domain of B3. The surface electrostatic potential analysis and stoichiometry measurements revealed that the N-terminal peptide of B3 is involved in the interaction. PRDX2 underwent a conformational change upon its binding to B3 without losing its peroxidase activity. Hemichrome formation induced by phenylhydrazine of RBCs prevented membrane association of PRDX2, implying overlapping binding sites. Documentation of the absence of binding of PRDX2 to B3 Neapolis red cell membranes, in which the initial N-terminal 11 amino acids are deleted, enabled us to conclude that PRDX2 binds to the N-terminal cytoplasmic domain of B3 and that the first 11 amino acids of this domain are crucial for PRDX2 membrane association in intact RBCs. These findings imply yet another important role for B3 in regulating red cell membrane function

Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells

Lyn, a member of the Src family of kinases, is a key factor in the dys-regulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia

IN ChAc RED CELLS THE ABNORMALLY ACTIVATED LYN AFFECTS ANKYRIN MULTIPROTEIN COMPLEXES AND IS INHIBITED BY DASATINIB

Chorea-acanthocytosis (ChAc) is a hereditary-neurodegenerative disorder, one of the neuroacanthocytosis syndromes (NA). One of the hallmarks of NA is the presence of circulating acanthocytes, generation of which is still under investigation. Recently, we reported increased Tyr-phosphorylation state of the red blood cell (RBC) membrane proteins from ChAc patients, related to abnormal activation of Lyn, an Src family kinase (SFKs) (Blood 118; 5652; 2011). In the context of international collaboration, we further characterized Lyn signaling pathway in RBC from ChAc patients. In ChAc RBCs, we found a weakness of ankyrin - based multiprotein complex bridging the membrane to the cytoskeleton, contributing to the generation of acanthocytes. We then evaluated the state of Lyn (active-inactive) in the cytoplasmic fraction from RBC of ChAc patients. In ChAc RBCs we found higher levels of Phospho- Lyn-396, corresponding to active Lyn, compared to controls. We then evaluated whether classical Lyn inhibitors such as PP2 or Dasatinib, a pharmacological Lyn inhibitor, might block Lyn in ChAc RBCs. We found that both PP2 (0.1\u3bcM) or Dasatinib (0.1 \u3bcM) were able to efficiently inhibit Lyn in both ChAc and healthy RBCs. These data suggest that in ChAc (i) the abnormal activation of Lyn affects RBC membrane mechanical stability weakening both multiprotein complexes, bridging the membrane to the cytoskeleton; (ii) Lyn activity is inhibited by either PP2 or Dasatinib, suggesting Lyn as possible new therapeutic target in ChAc