Deficiencies of the Lipid-Signaling Enzymes Phospholipase D1 and D2 Alter Cytoskeletal Organization, Macrophage Phagocytosis, and Cytokine-Stimulated Neutrophil Recruitment

Cell migration and phagocytosis ensue from extracellular-initiated signaling cascades that orchestrate dynamic reorganization of the actin cytoskeleton. The reorganization is mediated by effector proteins recruited to the site of activity by locally-generated lipid second messengers. Phosphatidic acid (PA), a membrane phospholipid generated by multiple enzyme families including Phospholipase D (PLD), has been proposed to function in this role. Here, we show that macrophages prepared from mice lacking either of the classical PLD isoforms PLD1 or PLD2, or wild-type macrophages whose PLD activity has been pharmacologically inhibited, display isoform-specific actin cytoskeleton abnormalities that likely underlie decreases observed in phagocytic capacity. Unexpectedly, PA continued to be detected on the phagosome in the absence of either isoform and even when all PLD activity was eliminated. However, a disorganized phagocytic cup was observed as visualized by imaging PA, F-actin, Rac1, an organizer of the F-actin network, and DOCK2, a Rac1 activator, suggesting that PLD-mediated PA production during phagocytosis is specifically critical for the integrity of the process. The abnormal F-actin reorganization additionally impacted neutrophil migration and extravasation from the vasculature into interstitial tissues. Although both PLD1 and PLD2 were important in these processes, we also observed isoform-specific functions. PLD1-driven processes in particular were observed to be critical in transmigration of macrophages exiting the vasculature during immune responses such as those seen in acute pancreatitis or irritant-induced skin vascularization

CD73-Generated Extracellular Adenosine Promotes Resolution of Neutrophil-Mediated Tissue Injury and Restrains Metaplasia in Pancreatitis

Pancreatitis is currently the leading cause of gastrointestinal hospitalizations in the US. This condition occurs in response to abdominal injury, gallstones, chronic alcohol consumption or, less frequently, the cause remains idiopathic. CD73 is a cell surface ecto-5\u27-nucleotidase that generates extracellular adenosine, which can contribute to resolution of inflammation by binding adenosine receptors on infiltrating immune cells. We hypothesized genetic deletion of CD73 would result in more severe pancreatitis due to decreased generation of extracellular adenosine. CD73 knockout (CD7

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

A study of Johann Ulrich Steigleder’s Tablatur Buch darinnen daß Vatter unser (1627)

Johann Ulrich Steigleder’s Tabulatur Buch darinnen daß Vatter unser auff 2, 3, und 4 Stimmen Componirt, und Viertzig mal Variit würdt, auch bey ieder Variatio ein sonderlicher bericht zufinden. Auff Orgeln, und allen andern Musicalischen Instrumenten ordenlich zu appliciren was published in Strassburg in 1627. Exhibiting influence from the English and Netherlandish, North and South German, and Italian schools of composition, the collection includes the following genres: fantasia, toccata, fugue, canon, ornamented chorale, bicinium, and imitative and non-imitative cantus firmus settings. This encyclopedic and didactic collection of settings on Vater unser im Himmelreich is unique in its inclusion of performance indicative headings that point to the practice of collaborative performance between organ and voice and organ and a solo instrument. This thesis surveys Steigleder’s variations, with particular attention to the use of the chorale tune in motivic design.U of I OnlySchool of Music polic

“Un síntoma cuasi parapsicológico”… Palinopsia

La parapsicología se refiere al estudio de ciertostipos de fenómenos paranormales. Paranormal conciernea una experiencia que no parece ser explicable en términos del conocimiento científico o de nuestra comprensión de hechos cotidianos. La realidad científica del fenómeno parapsicológico y la validez científica de sus investigaciones,a menudo son áreas de frecuente disputa ycrítica. Hasta ahora la psicología formal la caracteriza como una pseudociencia. La palinopsia es un raro síntoma caracterizado por el fenómeno ilusorio de perseveracióny/o recurrencia de imágenes visuales luego de haber sido removido el estímulo excitatorio. Es una distorsión delprocesamiento de imágenes en el sistema visual causadopor lesiones unilaterales o bilaterales de variado origenque afectan las áreas posteriores de los hemisferioscerebrales, toxicidad o efectos colaterales de drogasterapéuticas, una extensa lista de condiciones misceláneasy aún en sujetos normales. A despecho de su rareza,existe abundante literatura al respecto posiblemente porsu carácter intrigante o por su naturaleza pseudoparapsicológica.Los autores presentan los casos de 6pacientes, dos de los cuales estaban recibiendotamoxifeno, una droga hasta el presente no reconocida como causa de este fenómeno.Palabras clave: Palinopsia; Poliopsia;Parapsicología. Meningioma; Metástasis cerebrales;Ilusiones visuales.SUMMARYParapsychology is the scientific study of certain typesof paranormal phenomena. The “paranormal” (besideor beyond the normal) refers to unusual experiences thatdo not seem to be explainable in terms of our everydayunderstanding or known scientific principles. The scientificreality of parapsychological phenomena and thevalidity of scientific parapsychological research is amatter of frequent dispute and criticism. The field isregarded by some critics as a pseudoscience.Palinopsia is a rare symptom characterized by the illusoryphenomenon of perseverance or recurrence of visualimages after removal of the exciting stimulus. It is adistortion of the processing in the visual system caused byunilateral o bilateral lesions of various kinds, such astoxicity or side effects of drugs, as well as an array ofmiscellaneous conditions, that affect posterior areas ofthe cerebral hemispheres in normal subjects. Despite itsrarity, there is abundance of literature on the subject,possibly because of the intriguing, quasiparapsychologicnature of the symptom. Six patients were identified withthe diagnosis of palinopsia o poliopsia of whom two weretaking the drug tamoxifen not previously described in theliterature.Key words: Palinopsia. Poliopsia. Parapsychology.Meningioma. Cerebral metastases. Visual illusions