Kevin Wang - Academia.edu (original) (raw)
Papers by Kevin Wang
We report Cooper minima-induced Franck-Condon breakdown for N2 2sigma_u-1 photoionization. The me... more We report Cooper minima-induced Franck-Condon breakdown for N2 2sigma_u-1 photoionization. The measurements are over an extended energy range (230 eV), and we find that the v^+= 2/v^+= 0 and v^+= 1/v^+= 0 vibrational branching ratios vary strongly over a 100 eV range. This is a dramatic deviation from Franck-Condon predictions, and calculations show that this coupling between vibrational and electronic
Rotationally resolved photoelectron spectra can provide much insight into the underlying dynamics... more Rotationally resolved photoelectron spectra can provide much insight into the underlying dynamics of molecular photoionization, one of the simplest of molecular fragmentation processes. With the recent development of zero-kinetic-energy (ZEKE) photoelectron spectroscopy based on pulsed-field ionization of very high Rydberg states, it is now possible to exploit the narrow bandwidth of laser radiation to achieve sub-wave-number resolution in ion rovibronic
Neurochemical Research, 1999
Maitotoxin is a potent toxin that activates voltage and receptor-mediated Ca2+ channels, resultin... more Maitotoxin is a potent toxin that activates voltage and receptor-mediated Ca2+ channels, resulting in Ca2+ overload and rapid cell death. We report that maitotoxin-induced cell death is associated with activation of calpain but not caspase-3 proteases in septo-hippocampal cell cultures. Calpain and caspase-3 activation were examined by accumulation of protease-specific breakdown products to a-spectrin. Cell death manifested exclusively necrotic-like characteristics
Advances in dermatology, 2008
Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed... more Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed interest in the effect of dietary interventions on acne, the elucidation of the involvement of TLR and MMPs in acne pathogenesis, and a more detailed functional understanding of various treatment modalities at the molecular level are all promising indications that advances in therapeutics are sure to follow. Health utilities will serve not only as powerful outcome measures of treatment effects but also as clinical decision-making aids in everyday practice. It is hoped that future advances will further uncover additional molecular and cellular details of pathophysiology, leading to rational targeted design of medications, and advance clinical management through improved understanding of the psychosocial impact of acne on patients.
Trends in cell biology, 2009
Hox genes encode transcription factors that specify embryonic positional identity in cells and gu... more Hox genes encode transcription factors that specify embryonic positional identity in cells and guide tissue differentiation. Recent advances have greatly increased our understanding of the epigenetic mechanisms that ensure the faithful expression of Hox genes in adult cells and which involve the interplay of histone methylation, demethylation and intergenic transcription of long non-coding RNAs. The transcriptional memory of Hox genes poses both an opportunity and a challenge for regenerative medicine. Matching the positional identity of transplanted stem cells with that of the host environment, as reflected by their respective Hox profiles, is likely to be required to achieve regenerative healing. Strategies to manipulate the plasticity of Hox gene expression will probably become a major focus in regenerative medicine.
Ear, nose, & throat journal, 2010
A retrospective study was conducted to assess outcomes of reconstruction of the oral cavity with ... more A retrospective study was conducted to assess outcomes of reconstruction of the oral cavity with the platysma myocutaneous flap, in terms of flap survival, complications, and quality of life. Included were 10 patients with squamous cell carcinoma (stage T1 to T4; nodal status N0 to N2) of the oral cavity who were treated between 2002 and 2006. Each patient underwent tumor resection, modified radical neck dissection, and primary reconstruction with a platysma myocutaneous flap. Operating time, length of stay, time to swallow, and complications were assessed, and the University of Washington Quality of Life questionnaire was administered. Mean operating time was <4 hours, mean length of stay was 11 days, and mean time to swallow was 9 days. One patient had distal flap necrosis and one had wound dehiscence. No total flap failures or fistulas occurred. The authors conclude that the platysma myocutaneous flap provides thin, pliable, reliable tissue for use in the oral cavity. The addi...
Current opinion in otolaryngology & head and neck surgery, 2011
This article reviews literature pertaining to advances in oromandibular reconstruction in the con... more This article reviews literature pertaining to advances in oromandibular reconstruction in the context of a 30-year background of microvascular free tissue transfer, which still represents the current standard of care. Most literature reiterates established patterns of reconstruction. Notable exceptions address these key areas: the use of computer-assisted modeling to more closely and efficiently design the excision of the mandible, to produce the template and to contour the fibula bone to fit the defect; the evolution of plating techniques to maximize the bony repair; distraction osteogenesis; tissue engineering; and optimal techniques for dealing with osteonecrosis, from both radiation and bisphosphonate use. Osteocutaneous free flaps remain the standard of care. The fibula flap has emerged as the accepted favorite among these flaps. Evolution of fibula flap reconstruction constitutes a major portion of the current literature. Improvements upon free tissue transfer are currently el...
PloS one, 2014
The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain ... more The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody als...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014
Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported... more Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cor...
Toxicological sciences : an official journal of the Society of Toxicology, 2014
Detection of compound-related neurodegeneration is currently limited to brain histopathology in v... more Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic ac...
Neural regeneration research, 2014
The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide.... more The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other biochemical drug-based approaches to ameliorate these disorders. Unfortunately, we are still facing many obstacles that are rendering current neurotherapies ineffective in clinical trials for reasons that are yet to be discovered. That is why we should start by fully understanding the complex mechanisms of neurogenesis and the factors that affect it, or else, all our suggested therapies would fail since they would not be targeting the essence of the neurological disorder but rather the symptoms. One possible paradigm shift is to switch from neuroprotectant therapies towards neurodegeneration/neurorestorative approaches. In addition, other and our laboratories are increasingly focusing on combining the use of pharmacological agents (such as Rho-associated kinase (ROCK) inhib...
Genes & development, Jan 15, 2014
Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step ... more Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene ...
eLife, 2015
Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect th... more Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these...
Journal of Neurochemistry, 2002
Abstract: We characterized the activation of interleukin-1β-converting enzyme (ICE)-like protease... more Abstract: We characterized the activation of interleukin-1β-converting enzyme (ICE)-like proteases (caspases) in human neuroblastoma cells (SH-SY5Y) following challenge with staurosporine, an established agent known to induce apoptosis. Time course analyses of lactate dehydrogenase release detected a significant increase in cell death as early as 6 h that continued at least until 24 h following staurosporine treatment. Western blot analyses using anti-poly(ADP-ribose) polymerase (anti-PARP) and anti-CPP32 antibodies revealed proteolytic processing of CPP32 (an ICE homologue) as well as fragmentation of PARP as early as 3 h following staurosporine challenge. Furthermore, the hydrolysis of the CPP32 substrate acetyl-DEVD-7-amido-4-methylcoumarin was detected as early as 3 h and became maximal at 6 h after staurosporine challenge, suggesting a delayed and sustained period of CPP32-like activation. In addition, we used the first immunohistochemical examination of CPP32 and PARP in cells following an apoptotic challenge. The localization of CPP32 in untreated SH-SY5Y cells was exclusively restricted to the cytoplasm. Following staurosporine challenge there was a condensing of CPP32 immunofluorescence from the cytoplasm to a region adjacent to the plasma membrane. In contrast, PARP immunofluorescence was evenly distributed in the nucleus in untreated SH-SY5Y cells and on staurosporine challenge was found to be associated with condensed chromatin. It is important that a pan ICE inhibitor [carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene] was able to attenuate lactate dehydrogenase release and PARP and CPP32 cleavage and altered immunohistochemical staining patterns for PARP and CPP32 following staurosporine challenge.
Journal of Neurochemistry, 2002
Abstract: Caspase activation has been shown to be a critical step in several models of neuronal a... more Abstract: Caspase activation has been shown to be a critical step in several models of neuronal apoptosis such as staurosporine treatment of human neuroblastoma SH-SY5Y cells and potassium deprivation of rat cerebellar granule neurons. One common event is the appearance of caspase-mediated 120-kDa nonerythroid α-spectrin breakdown product (SBDP120). Second, inhibitors of the caspase family are effective blockers of such neuronal death. In this study, we report the appearance of caspase-mediated SBDP120 in excitotoxin-challenged fetal rat cerebrocortical neurons [N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate] and rat cerebellar granule neurons (NMDA and kainate). A general caspase inhibitor, carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-D-DCB), blocked the formation of SBDP120 under these conditions and attenuated the observed NMDA-induced lactate dehydrogenase (LDH) release in both cell types. Furthermore, hydrolytic activity toward a caspase-3-preferred synthetic peptide substrate, acetyl-DEVD-7-amido-4-methylcoumarin, was significantly elevated in NMDA-treated granule neurons. Lastly, oxygen-glucose deprivation (OGD)-challenged cerebrocortical cultures also showed the appearance of SBDP120. Again, Z-D-DCB blocked the SBDP120 formation as well as attenuated the LDH release from the OGD-challenged neurons. Taken together, the presence of caspase-specific SBDP120 and the neuroprotective effects of Z-D-DCB strongly suggest that caspase activation contributes at least in part to excitotoxin- and OGD-induced neuronal death.
SSRN Electronic Journal, 2000
Motivated by investor disagreement and corporate disclosure literatures, we examine how stock pri... more Motivated by investor disagreement and corporate disclosure literatures, we examine how stock price shocks in the absence of public announcement of firm specific news affect future stock returns. We find that both large short term price drops and hikes are followed by negative abnormal returns over the subsequent twelve months. The asymmetric drifts, return continuation for negative price shocks versus return reversal for positive ones, are in sharp contrast to the general findings of symmetric drifts in corporate event studies.
Current Protocols in Protein Science, 2001
SSRN Electronic Journal, 2000
ABSTRACT Multifactor asset pricing models play an important role in evaluation of anomalies and m... more ABSTRACT Multifactor asset pricing models play an important role in evaluation of anomalies and managed portfolios. In empirical studies, however, the researchers' prior often includes a rich set of competing models which all seem plausible, but none is conclusively dominant. In this paper we propose a unified approach to model selection and inference for application and evaluation of factor pricing models. We run horse races among a set of high profile models to select winners according to predictive ability and then utilize White's (2000) reality check methodology to test the top performers. We provide empirical results on testing multifactor explanations of industry momentum, and present a test of the three moment CAPM.
SSRN Electronic Journal, 2000
We report Cooper minima-induced Franck-Condon breakdown for N2 2sigma_u-1 photoionization. The me... more We report Cooper minima-induced Franck-Condon breakdown for N2 2sigma_u-1 photoionization. The measurements are over an extended energy range (230 eV), and we find that the v^+= 2/v^+= 0 and v^+= 1/v^+= 0 vibrational branching ratios vary strongly over a 100 eV range. This is a dramatic deviation from Franck-Condon predictions, and calculations show that this coupling between vibrational and electronic
Rotationally resolved photoelectron spectra can provide much insight into the underlying dynamics... more Rotationally resolved photoelectron spectra can provide much insight into the underlying dynamics of molecular photoionization, one of the simplest of molecular fragmentation processes. With the recent development of zero-kinetic-energy (ZEKE) photoelectron spectroscopy based on pulsed-field ionization of very high Rydberg states, it is now possible to exploit the narrow bandwidth of laser radiation to achieve sub-wave-number resolution in ion rovibronic
Neurochemical Research, 1999
Maitotoxin is a potent toxin that activates voltage and receptor-mediated Ca2+ channels, resultin... more Maitotoxin is a potent toxin that activates voltage and receptor-mediated Ca2+ channels, resulting in Ca2+ overload and rapid cell death. We report that maitotoxin-induced cell death is associated with activation of calpain but not caspase-3 proteases in septo-hippocampal cell cultures. Calpain and caspase-3 activation were examined by accumulation of protease-specific breakdown products to a-spectrin. Cell death manifested exclusively necrotic-like characteristics
Advances in dermatology, 2008
Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed... more Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed interest in the effect of dietary interventions on acne, the elucidation of the involvement of TLR and MMPs in acne pathogenesis, and a more detailed functional understanding of various treatment modalities at the molecular level are all promising indications that advances in therapeutics are sure to follow. Health utilities will serve not only as powerful outcome measures of treatment effects but also as clinical decision-making aids in everyday practice. It is hoped that future advances will further uncover additional molecular and cellular details of pathophysiology, leading to rational targeted design of medications, and advance clinical management through improved understanding of the psychosocial impact of acne on patients.
Trends in cell biology, 2009
Hox genes encode transcription factors that specify embryonic positional identity in cells and gu... more Hox genes encode transcription factors that specify embryonic positional identity in cells and guide tissue differentiation. Recent advances have greatly increased our understanding of the epigenetic mechanisms that ensure the faithful expression of Hox genes in adult cells and which involve the interplay of histone methylation, demethylation and intergenic transcription of long non-coding RNAs. The transcriptional memory of Hox genes poses both an opportunity and a challenge for regenerative medicine. Matching the positional identity of transplanted stem cells with that of the host environment, as reflected by their respective Hox profiles, is likely to be required to achieve regenerative healing. Strategies to manipulate the plasticity of Hox gene expression will probably become a major focus in regenerative medicine.
Ear, nose, & throat journal, 2010
A retrospective study was conducted to assess outcomes of reconstruction of the oral cavity with ... more A retrospective study was conducted to assess outcomes of reconstruction of the oral cavity with the platysma myocutaneous flap, in terms of flap survival, complications, and quality of life. Included were 10 patients with squamous cell carcinoma (stage T1 to T4; nodal status N0 to N2) of the oral cavity who were treated between 2002 and 2006. Each patient underwent tumor resection, modified radical neck dissection, and primary reconstruction with a platysma myocutaneous flap. Operating time, length of stay, time to swallow, and complications were assessed, and the University of Washington Quality of Life questionnaire was administered. Mean operating time was <4 hours, mean length of stay was 11 days, and mean time to swallow was 9 days. One patient had distal flap necrosis and one had wound dehiscence. No total flap failures or fistulas occurred. The authors conclude that the platysma myocutaneous flap provides thin, pliable, reliable tissue for use in the oral cavity. The addi...
Current opinion in otolaryngology & head and neck surgery, 2011
This article reviews literature pertaining to advances in oromandibular reconstruction in the con... more This article reviews literature pertaining to advances in oromandibular reconstruction in the context of a 30-year background of microvascular free tissue transfer, which still represents the current standard of care. Most literature reiterates established patterns of reconstruction. Notable exceptions address these key areas: the use of computer-assisted modeling to more closely and efficiently design the excision of the mandible, to produce the template and to contour the fibula bone to fit the defect; the evolution of plating techniques to maximize the bony repair; distraction osteogenesis; tissue engineering; and optimal techniques for dealing with osteonecrosis, from both radiation and bisphosphonate use. Osteocutaneous free flaps remain the standard of care. The fibula flap has emerged as the accepted favorite among these flaps. Evolution of fibula flap reconstruction constitutes a major portion of the current literature. Improvements upon free tissue transfer are currently el...
PloS one, 2014
The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain ... more The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody als...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014
Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported... more Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cor...
Toxicological sciences : an official journal of the Society of Toxicology, 2014
Detection of compound-related neurodegeneration is currently limited to brain histopathology in v... more Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic ac...
Neural regeneration research, 2014
The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide.... more The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other biochemical drug-based approaches to ameliorate these disorders. Unfortunately, we are still facing many obstacles that are rendering current neurotherapies ineffective in clinical trials for reasons that are yet to be discovered. That is why we should start by fully understanding the complex mechanisms of neurogenesis and the factors that affect it, or else, all our suggested therapies would fail since they would not be targeting the essence of the neurological disorder but rather the symptoms. One possible paradigm shift is to switch from neuroprotectant therapies towards neurodegeneration/neurorestorative approaches. In addition, other and our laboratories are increasingly focusing on combining the use of pharmacological agents (such as Rho-associated kinase (ROCK) inhib...
Genes & development, Jan 15, 2014
Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step ... more Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene ...
eLife, 2015
Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect th... more Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these...
Journal of Neurochemistry, 2002
Abstract: We characterized the activation of interleukin-1β-converting enzyme (ICE)-like protease... more Abstract: We characterized the activation of interleukin-1β-converting enzyme (ICE)-like proteases (caspases) in human neuroblastoma cells (SH-SY5Y) following challenge with staurosporine, an established agent known to induce apoptosis. Time course analyses of lactate dehydrogenase release detected a significant increase in cell death as early as 6 h that continued at least until 24 h following staurosporine treatment. Western blot analyses using anti-poly(ADP-ribose) polymerase (anti-PARP) and anti-CPP32 antibodies revealed proteolytic processing of CPP32 (an ICE homologue) as well as fragmentation of PARP as early as 3 h following staurosporine challenge. Furthermore, the hydrolysis of the CPP32 substrate acetyl-DEVD-7-amido-4-methylcoumarin was detected as early as 3 h and became maximal at 6 h after staurosporine challenge, suggesting a delayed and sustained period of CPP32-like activation. In addition, we used the first immunohistochemical examination of CPP32 and PARP in cells following an apoptotic challenge. The localization of CPP32 in untreated SH-SY5Y cells was exclusively restricted to the cytoplasm. Following staurosporine challenge there was a condensing of CPP32 immunofluorescence from the cytoplasm to a region adjacent to the plasma membrane. In contrast, PARP immunofluorescence was evenly distributed in the nucleus in untreated SH-SY5Y cells and on staurosporine challenge was found to be associated with condensed chromatin. It is important that a pan ICE inhibitor [carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene] was able to attenuate lactate dehydrogenase release and PARP and CPP32 cleavage and altered immunohistochemical staining patterns for PARP and CPP32 following staurosporine challenge.
Journal of Neurochemistry, 2002
Abstract: Caspase activation has been shown to be a critical step in several models of neuronal a... more Abstract: Caspase activation has been shown to be a critical step in several models of neuronal apoptosis such as staurosporine treatment of human neuroblastoma SH-SY5Y cells and potassium deprivation of rat cerebellar granule neurons. One common event is the appearance of caspase-mediated 120-kDa nonerythroid α-spectrin breakdown product (SBDP120). Second, inhibitors of the caspase family are effective blockers of such neuronal death. In this study, we report the appearance of caspase-mediated SBDP120 in excitotoxin-challenged fetal rat cerebrocortical neurons [N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate] and rat cerebellar granule neurons (NMDA and kainate). A general caspase inhibitor, carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-D-DCB), blocked the formation of SBDP120 under these conditions and attenuated the observed NMDA-induced lactate dehydrogenase (LDH) release in both cell types. Furthermore, hydrolytic activity toward a caspase-3-preferred synthetic peptide substrate, acetyl-DEVD-7-amido-4-methylcoumarin, was significantly elevated in NMDA-treated granule neurons. Lastly, oxygen-glucose deprivation (OGD)-challenged cerebrocortical cultures also showed the appearance of SBDP120. Again, Z-D-DCB blocked the SBDP120 formation as well as attenuated the LDH release from the OGD-challenged neurons. Taken together, the presence of caspase-specific SBDP120 and the neuroprotective effects of Z-D-DCB strongly suggest that caspase activation contributes at least in part to excitotoxin- and OGD-induced neuronal death.
SSRN Electronic Journal, 2000
Motivated by investor disagreement and corporate disclosure literatures, we examine how stock pri... more Motivated by investor disagreement and corporate disclosure literatures, we examine how stock price shocks in the absence of public announcement of firm specific news affect future stock returns. We find that both large short term price drops and hikes are followed by negative abnormal returns over the subsequent twelve months. The asymmetric drifts, return continuation for negative price shocks versus return reversal for positive ones, are in sharp contrast to the general findings of symmetric drifts in corporate event studies.
Current Protocols in Protein Science, 2001
SSRN Electronic Journal, 2000
ABSTRACT Multifactor asset pricing models play an important role in evaluation of anomalies and m... more ABSTRACT Multifactor asset pricing models play an important role in evaluation of anomalies and managed portfolios. In empirical studies, however, the researchers' prior often includes a rich set of competing models which all seem plausible, but none is conclusively dominant. In this paper we propose a unified approach to model selection and inference for application and evaluation of factor pricing models. We run horse races among a set of high profile models to select winners according to predictive ability and then utilize White's (2000) reality check methodology to test the top performers. We provide empirical results on testing multifactor explanations of industry momentum, and present a test of the three moment CAPM.
SSRN Electronic Journal, 2000