ISG15 Modulates Development of the Erythroid Lineage

Activation of erythropoietin receptor allows erythroblasts to generate erythrocytes. In a search for genes that are up-regulated during this differentiation process, we have identified ISG15 as being induced during late erythroid differentiation. ISG15 belongs to the ubiquitin-like protein family and is covalently linked to target proteins by the enzymes of the ISGylation machinery. Using both in vivo and in vitro differentiating erythroblasts, we show that expression of ISG15 as well as the ISGylation process related enzymes Ube1L, UbcM8 and Herc6 are induced during erythroid differentiation. Loss of ISG15 in mice results in decreased number of BFU-E/CFU-E in bone marrow, concomitant with an increased number of these cells in the spleen of these animals. ISG15-/- bone marrow and spleen-derived erythroblasts show a less differentiated phenotype both in vivo and in vitro, and over-expression of ISG15 in erythroblasts is found to facilitate erythroid differentiation. Furthermore, we have shown that important players of erythroid development, such as STAT5, Globin, PLC γ and ERK2 are ISGylated in erythroid cells. This establishes a new role for ISG15, besides its well-characterized anti-viral functions, during erythroid differentiation

Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion

Deciphering the pathogenesis of tendinopathy: a three-stages process

Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments

Glacial-to-Holocene sedimentation on the western slope of Great Bahama Bank

Thick, late Quaternary sediment sections were recovered at several sites on the leeward slope of Great Bahama Bank during Leg 166 of the Ocean Drilling Program. These sections have paleoceanographic records with potentially high temporal resolution. To make an initial assessment of the records corresponding to the Holocene highstand of sea level, we have identified and dated the sediments from the four upper slope sites (1004, 1005, 1008, and 1009) that were deposited during the period of time which spans the last glaciation through the Holocene. Age identifications are based upon the abundances of the Globorotalia menardii complex of planktonic foraminifera, the stable oxygen isotopic ratios of bulk sediment and the planktonic foraminifera Globogerinoides ruber, and AMS C-14 dating of bulk sediment. Comparison of these data with the sediment lithologic and geoacoustic properties shows that consistent stratigraphic relationships exist at each site: The uppermost interval of aragonite-rich sediments corresponds to the Holocene highstand of sea level (i.e. oxygen isotope stage 1) and these sediments are underlain by a relatively thin interval of aragonite-poor, partially lithified sediments which corresponds to the last glaciation when sea level was significantly lower than today (i.e. oxygen isotope stages 2-4). The Leg 166 upper slope sites possess carbonate accumulation and paleoceanographic proxy records with very high temporal resolution, with Sites 1004, 1008, and 1009 appearing to have the greatest stratigraphic integrity. Comparison of core and high-resolution seismic profile data establishes the Holocene nature of the uppermost seismic unit in the stratigraphic package of the western slope of Great Bahama Bank. © 2002 Elsevier Science B.V. All rights reserved