Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1\u2013 300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na+-channel blocker. GLP-2 inhibitory effect was not affected by Nomega-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca2+-dependent K+ channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP7\u201328 (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a Gi/o protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by Gi protein

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

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils of polycythemia vera.

BACKGROUND: The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. DESIGN AND METHODS: We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63(+) basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. RESULTS: We found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63(+) basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63(+) basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. CONCLUSIONS: These data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells’ abnormal function and, putatively, in the pathogenesis of pruritus

Late Cenozoic tephrostratigraphy offshore the southern Central American Volcanic Arc: 2. Implications for magma production rates and subduction erosion

Pacific drill sites offshore Central America provide the unique opportunity to study the evolution of large explosive volcanism and the geotectonic evolution of the continental margin back into the Neogene. The temporal distribution of tephra layers established by tephrochonostratigraphy in Part 1 indicates a nearly continuous highly explosive eruption record for the Costa Rican and the Nicaraguan volcanic arc within the last 8 M.y. The widely distributed marine tephra layers comprise the major fraction of the respective erupted tephra volumes and masses thus providing insights into regional and temporal variations of large-magnitude explosive eruptions along the southern Central American Volcanic Arc (CAVA). We observe three pulses of enhanced explosive magmatism between 0-1 Ma at the Cordillera Central, between 1-2 Ma at the Guanacaste and at >3 Ma at the Western Nicaragua segments. Averaged over the long-term the minimum erupted magma flux (per unit arc length) is ∼0.017 g/ms. Tephra ages, constrained by Ar-Ar dating and by correlation with dated terrestrial tephras, yield time-variable accumulation rates of the intercalated pelagic sediments with four prominent phases of peak sedimentation rates that relate to tectonic processes of subduction erosion. The peak rate at >2.3 Ma near Osa particularly relates to initial Cocos Ridge subduction which began at 2.91±0.23 Ma as inferred by the 1.5 M.y. delayed appearance of the OIB geochemical signal in tephras from Barva volcano at 1.42 Ma. Subsequent tectonic re-arrangements probably involved crustal extension on the Guanacaste segment that favored the 2-1 Ma period of unusually massive rhyolite production

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias

Seismicity of the incoming plate and forearc near the Mariana Trench recorded by ocean bottom seismographs

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 21(4), (2020): e2020GC008953, doi:10.1029/2020GC008953.Earthquakes near oceanic trenches are important for studying incoming plate bending and updip thrust zone seismogenesis, yet are poorly constrained using seismographs on land. We use an ocean bottom seismograph (OBS) deployment spanning both the incoming Pacific Plate and the forearc to study seismicity near the Mariana Trench. The yearlong deployment in 2012–2013 consisted of 20 broadband OBSs and 5 suspended hydrophones, with an additional 59 short period OBSs and hydrophones recording for 1 month. We locate 1,692 earthquakes using a nonlinear method with a 3D velocity model constructed from active source profiles and surface wave tomography results. Events occurring seaward of the trench occur to depths of ~35 km below the seafloor, and focal mechanisms of the larger events indicate normal faulting corresponding to plate bending. Significant seismicity emerges about 70 km seaward from the trench, and the seismicity rate increases continuously towards the trench, indicating that the largest bending deformation occurs near the trench axis. These plate‐bending earthquakes occur along faults that facilitate the hydration of the subducting plate, and the lateral and depth distribution of earthquakes is consistent with low‐velocity regions imaged in previous studies. The forearc is marked by a heterogeneous distribution of low magnitude (<5 Mw) thrust zone seismicity, possibly due to the rough incoming plate topography and/or serpentinization of the forearc. A sequence of thrust earthquakes occurs at depths ~10 km below seafloor and within 20 km of the trench axis, demonstrating that the megathrust is seismically active nearly to the trench.We thank the captains, crew, and science teams on the R/V Thompson, Langseth and Melville, Dr. Patrick Shore for providing data management and technical support, and Ivan Komarov and Zhengyang Zhou for assistance with data analysis. We thank Ingo Grevemeyer and an anonymous reviewer for their comments to improve the manuscript. Instrumentation and technical support was provided by the PASSCAL program of the Incorporated Research Institutions in Seismology (IRIS) and the Woods Hole, Lamont‐Doherty, and Scripps facilities of the Ocean Bottom Seismograph Instrumentation Pool (OBSIP). Funding was provided by the MARGINS/GeoPRISMS program through NSF grant OCE‐0841074 (D.A.W.) and the Spencer T. and Ann W. Olin Fellowship program at Washington University in Saint Louis. Raw seismic data used in this study are available through the Data Management Center of the Incorporated Research Institutions for Seismology (http://www.iris.edu/dms/nodes/dmc) under network IDs XF and MI.2020-10-0

Pregnancy in patients with myelofibrosis: Mayo–Florence series of 24 pregnancies in 16 women

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