2,971 research outputs found
The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis
No full textRodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
Seminal contributions of Timothy J. Crow
Full text link© The Author(s), 2025. Published by Cambridge
University Press. This is an Open Access article,
distributed under the terms of the Creative
Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0), which
permits unrestricted re-use, distribution and
reproduction, provided the original article is
properly cited.We recall the life and work of Timothy J. Crow, whose contributions provided great insights into the pathophysiology of schizophrenia and continue to shape many questions in the field. We compile his key works relating to psychotic disorders, focusing on the trajectory of his theoretical stance. Our account is interlaced with our own interpretation of the evidence that influenced Crow's arguments over the years as well as his scientific method. Crow has had a significant impact on the neuroscience of schizophrenia. Many of his observations are still valid and several questions he raised remain unanswered to date.https://www.cambridge.org/core/journals/psychological-medicine/article/seminal-contributions-of-timothy-j-crow/25B0EA70F496D0D3351937E44ADDD45
Tools for evolutionary acquisition : a study of Multi-Attribute Tradespace Exploration (MATE) applied to the Space Based Radar (SBR)
No full textThesis (S.M.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2003.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Statement of responsibility on t.p. reads: 2nd Lieutenant Timothy J. Spaulding, USAF.Includes bibliographical references (p. 139-142).by Timothy J. Spaulding.S.M
Low-frequency earthquakes beneath Tullu Moye volcano, Ethiopia, reveal fluid pulses from shallow magma chamber
Full text linkThe active magmatic processes beneath volcanoes in continental rifts is poorly understood. For example, until recently in the East African rift (EAR), the majority of the young volcanoes were thought to be inactive. More recent studies have shown that numerous volcanoes in the EAR are seismically active and deforming rapidly. However, an unambiguous sign of actively degassing magma hosted in shallow magma bodies has eluded most investigators. Here we present detailed analysis of the first low-frequency (LF) earthquake swarms to be observed in the Main Ethiopian Rift. The earthquakes locate to beneath Tullu Moye volcano and are directly related to the presence of a shallow magma body with a high fluid content. Using spectral modelling we show that the LF earthquakes appear to have low stress-drops (1–50 kPa) which we interpret in terms of low rupture velocities and high pore-fluid pressure. Careful relocation of the LF earthquakes place them approximately 4 km below the surface within one of two possible clusters. However, analysis of the correlation between earthquake waveforms show that each swarm contains a range of earthquake families and as such a diversity of earthquake source mechanisms. To explain these observations, we propose the seismicity is induced by H2O/CO2 fluid pulses from the shallow magma body into a highly fractured region. Fluid pulses cause high pore fluid pressures, which also cause the low rupture velocities
Local seismicity near the actively deforming Corbetti volcano in the Main Ethiopian Rift
Full text linkCorbetti is currently one of the fastest uplifting volcanoes globally, with strong evidence from geodetic and gravity data for a subsurface inflating magma body. A dense network of 18 stations has been deployed around Corbetti and Hawassa calderas between February 2016 and October 2017, to place seismic constraints on the magmatic, hydrothermal and tectonic processes in the region. We locate 122 events of magnitudes between 0.4 and 4.2 using a new local velocity model. The seismicity is focused in two areas: directly beneath Corbetti caldera and beneath the city of Hawassa. The shallower 0–5 km depth below sea level (b.s.l.) earthquakes beneath Corbetti are mainly focused in EW- to NS-elongated clusters at Urji and Chabbi volcanic centres. This distribution is interpreted to be mainly controlled by a northward propagation of hydrothermal fluids away from a cross-rift pre-existing fault. Source mechanisms are predominantly strike-slip and different to the normal faulting away from the volcano, suggesting a local rotation of the stress-field. These observations, along with a low Vp/Vs ratio, are consistent with the inflation of a gas-rich sill, likely of silicic composition, beneath Corbetti. In contrast, the seismicity beneath Hawassa extends to greater depth (16 km b.s.l.). These earthquakes are focused on 8–10 km long segmented faults, which are active in seismic swarms. One of these swarms, in August 2016, is focused between 5 and 16 km depth b.s.l. along a steep normal fault beneath the city of Hawassa, highlighting the earthquake hazard for the local population.</p
Corrigendum to “High-pressure adsorptive storage of hydrogen in MIL-101 (Cr) and AX-21 for mobile applications: Cryocharging and cryokinetics” [Mater & Des 89 (2016) 1086–1094]
No full textRefers To Nuno Bimbo, Wesley Xu, Jessica E. Sharpe, Valeska P. Ting, Timothy J. Mays High-pressure adsorptive storage of hydrogen in MIL-101 (Cr) and AX-21 for mobile applications: Cryocharging and cryokinetics Materials & Design, Volume 89, 5 January 2016, Pages 1086-1094 The authors regret to inform that….. The Supplementary Information should have been included in the original paper and is now provided with this corrigendum. All the data and figures, contained in the manuscript and supporting information, are available and can be accessed free of charge at http://dx.doi.org/10.15125/BATH-00099. Any questions related to the data should be addressed to the corresponding author. Authors would like to apologize for the inconvenience caused
A simulation-based concurrent engineering approach for assembly system design
No full textThesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering; in conjunction with the Leaders for Manufacturing Program at MIT, 2002.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Includes bibliographical references (p. 81-82).by Timothy J. Sweitzer.S.M.M.B.A
Exploiting Domain Knowledge in Making Delegation Decisions
Full text link@inproceedings{conf/admi/EmeleNSP11, added-at = {2011-12-19T00:00:00.000+0100}, author = {Emele, Chukwuemeka David and Norman, Timothy J. and Sensoy, Murat and Parsons, Simon}, biburl = {http://www.bibsonomy.org/bibtex/20a08b683088443f1fd36d6ef28bf6615/dblp}, booktitle = {ADMI}, crossref = {conf/admi/2011}, editor = {Cao, Longbing and Bazzan, Ana L. C. and Symeonidis, Andreas L. and Gorodetsky, Vladimir and Weiss, Gerhard and Yu, Philip S.}, ee = {http://dx.doi.org/10.1007/978-3-642-27609-5_9}, interhash = {1d7e7f8554e8bdb3d43c32e02aeabcec}, intrahash = {0a08b683088443f1fd36d6ef28bf6615}, isbn = {978-3-642-27608-8}, keywords = {dblp}, pages = {117-131}, publisher = {Springer}, series = {Lecture Notes in Computer Science}, timestamp = {2011-12-19T00:00:00.000+0100}, title = {Exploiting Domain Knowledge in Making Delegation Decisions.}, url = {http://dblp.uni-trier.de/db/conf/admi/admi2011.html#EmeleNSP11}, volume = 7103, year = 2011
p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis
No full textHepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. We show that human hepatic myofibroblasts co-express p75(NTR) (p75 neurotrophin receptor) and sortilin, thus facilitating differential responses to mature and pro nerve growth factor (proNGF). Although mature NGF is proapoptotic, proNGF protects human hepatic myofibroblasts from apoptosis. Moreover, in recovery from experimental liver fibrosis, the decrease in proNGF parallels loss of hepatic myofibroblasts by apoptosis. Macrophage-derived matrix metalloproteinase 7 (MMP7) cleaves proNGF in a concentration-dependent manner, and its expression in the liver coincides with falling proNGF levels. To define the dominant effect of p75(NTR)-mediated events in experimental liver fibrosis, we have used a mouse lacking the p75(NTR) ligand-binding domain but expressing the intracellular domain. We show that absence of p75(NTR) ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75(NTR) limits hepatocyte and oval cell proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Conclusion: NGF species have a differential effect on hepatic myofibroblast survival. Our data suggest that cleavage of proNGF by MMP7 during the early phase of recovery from liver fibrosis alters the pro/mature NGF balance to facilitate hepatic myofibroblast loss. Whereas fibrosis develops in the absence of p75(NTR) signaling, the dominant effects of loss of p75(NTR) ligand-mediated events are the retardation of liver fibrosis resolution via regulation of hepatic myofibroblast proliferation and apoptosis, and the reduction of hepatocyte and oval cell proliferation
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