In order to study the involvement of caspases in neuronal cell death, we have examined the effect... more In order to study the involvement of caspases in neuronal cell death, we have examined the effects of the viral caspase inhibitor p35 and peptide caspase inhibitors on sympathetic neurons isolated from the superior cervical ganglion (SCG). In these neurons, apoptosis can be induced by the withdrawal of nerve growth factor (NGF) and also by the addition of the kinase inhibitor staurosporine. p35 has been shown to be a broad spectrum inhibitor of the caspase family and promotes the survival of SCG neurons withdrawn from NGF. We show that p35 is also protective when apoptosis is induced by staurosporine. In addition, p35 inhibits a number of the morphological features associated with apoptosis, such as nuclear condensation, TUNEL labelling, and externalisation of phosphatidylserine. The tri-peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl)-fluoromethylketone (zVAD-fmk) was effective at inhibiting NGF withdrawal-induced and staurosporine-induced apoptosis of SCG neurons...
In order to study the involvement of caspases in neuronal cell death, we have examined the effect... more In order to study the involvement of caspases in neuronal cell death, we have examined the effects of the viral caspase inhibitor p35 and peptide caspase inhibitors on sympathetic neurons isolated from the superior cervical ganglion (SCG). In these neurons, apoptosis can be induced by the withdrawal of nerve growth factor (NGF) and also by the addition of the kinase inhibitor staurosporine. p35 has been shown to be a broad spectrum inhibitor of the caspase family and promotes the survival of SCG neurons withdrawn from NGF. We show that p35 is also protective when apoptosis is induced by staurosporine. In addition, p35 inhibits a number of the morphological features associated with apoptosis, such as nuclear condensation, TUNEL labelling, and externalisation of phosphatidylserine. The tri-peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl)-fluoromethylketone (zVAD-fmk) was effective at inhibiting NGF withdrawal-induced and staurosporine-induced apoptosis of SCG neurons...
A therapeutic antibody which is an antibody or antigen binding fragment and / or derivative there... more A therapeutic antibody which is an antibody or antigen binding fragment and / or derivative thereof that binds to β-amyloid peptide and CDRs comprising the following: CDRH1: dngma (SEQ ID NO: 1) CDRH2: FISNLAYSIDYADTVTG ( SEQ ID NO: 2) CDRH3: GTWFAY (SEQ ID NO: 3) within a frame of a variable region of human heavy chain originating from the VH3 family gene and: CDRL1: RVSQSLLHSNGYTYLH (SEC ID NO: 4) CDRL2: KVSNRFS (SEQ ID NO: 5) CDRL3: SQTRHVPYT (SEQ ID NO: 6) within a housing of a variable region of human light chain originates from amino acid sequence disclosed in SEQ ID NO: 24.
Background: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatme... more Background: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT)" randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention in the prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describe the procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. We also illustrate the main demographic and clinical characteristics of eligible screenees. Methods: The identification of PF&S was based on the co-occurrence of three defining elements: (1) reduced physical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) low muscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3) absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT was advertised through a variety of means. Site-specific case finding strategies were developed to accommodate the variability across centers in catchment area characteristics and access to the target population. A quick "participant profiling" questionnaire was devised to facilitate PF&S case finding. Results: During approximately 22 months, 12,358 prescreening interviews were completed in 17 SPRINTT sites resulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participating in the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidity burden. In most centers, project advertisement through mass media was the most rewarding case finding strategy. Conclusion: PF&S case finding in the community is a challenging, but feasible task. Although largely autonomous in daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity. This subset of the older population is therefore at high risk for disability and other negative health-related events. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass communication methods. a This site is no longer active.
In her News Feature “Out of bounds” (27 January p. [339][1]), A. McCook strove to present an obje... more In her News Feature “Out of bounds” (27 January p. [339][1]), A. McCook strove to present an objective narrative of the situation in which a student at Harvard University was forced to undergo a psychiatric evaluation and then filed a court order against scientist Dr. Lee Rubin. However, McCook failed to take into consideration Rubin's longstanding reputation as a scientist and a mentor. We are scientists who have worked with, been mentored by, or collaborated with Rubin. Some are current members of his laboratory, some have known him for many years, and a few have known him for more than 30 years. We could not let this story stand without adding our perspective. Rubin's scientific reputation can be readily appreciated simply by skimming through the list of his stellar publications. However, a dry bibliography fails to illuminate the quality of the scientist behind the science. Rubin has always upheld the highest standards of scientific and personal integrity. His kindness and concern for the personal well-being and professional development of his graduate students, and indeed everyone in his laboratory, has always been clearly evident. Rubin has always had our backs, whether as a mentor, a colleague, a boss, or a friend. He upholds the highest standards of scientific rigor while providing compassionate mentorship. His commitment to leading by example means we place the highest value on our friendship and connections with him. We have sought out his scientific counsel and, in several cases, engaged in collaborations that span many years. We feel fortunate to have had the opportunity to know and to work with him. It is our collective experience that besides being an outstanding scientist, he is a warm and caring scientific mentor who does not deserve to have the reputation he has built over 40 years or more besmirched. [1]: /lookup/doi/10.1126/science.355.6323.339
The invention antibodies, methods of treating a disease or disorder characterized by a β- amyloid... more The invention antibodies, methods of treating a disease or disorder characterized by a β- amyloid levels or β- amyloid deposits increase in the antibody, a pharmaceutical composition and manufacture thereof comprising the antibody binding to human β- amyloid peptide It relates to a method.
Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The develop... more Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The developmental relatedness of the two cell types is unresolved. alpha beta + T cells respond to specific pathogens by collaborating with immunoglobulin-producing B cells in distinct lymphoid organs such as the spleen and Peyer's patches. The precise influence of alpha beta + T cells on B cell development is poorly understood. To investigate the developmental effects of alpha beta + T cells on B cells and gamma delta + T cells, mice homozygous for a disrupted TCR alpha gene were generated. The homozygotes showed elimination of alpha beta + T cells and the loss of thymic medullae. Despite this, gamma delta + T cells developed in normal numbers, and there was an increase in splenic B cells.
Murine major histocompatibility complex class I genes are transcribed at high levels in placental... more Murine major histocompatibility complex class I genes are transcribed at high levels in placental tissues, lower levels in yolk-sac tissues and at barely detectable levels in the embryo at Day 13.5 of gestation. Genes are expressed at equivalent levels whether inherited maternally or paternally, and the genetic background has no effect on class I gene transcription. These results show that potential alloantigens are expressed in extra-embryonic tissues intimately associated with maternal tissues and blood supply and yet fail to induce immunological rejection.
In order to re-examine the sub-cellular location of the three influenza A/NT/60/68 polymerase pro... more In order to re-examine the sub-cellular location of the three influenza A/NT/60/68 polymerase proteins PB1, PB2 and PA in infected cells, specific antisera for each polymerase component have been prepared by immunizing rabbits with polymerase-beta-galactosidase fusion proteins synthesized in Escherichia coli. We show that polymerase PB1, PB2, and PA are predominantly associated with the nucleus of influenza-infected MDCK cells by immunocytochemical techniques. In the case of polymerase PB2 we investigate the possibility that nuclear accumulation is an intrinsic property of the PB2 protein. Using a vaccinia-PB2 recombinant virus, we show that PB2 accumulates intra-nuclearly in monkey CV-1 cells in the absence of any other influenza protein, suggesting it contains an intrinsic nuclear signal.
Advances in Experimental Medicine and Biology, 1995
Despite numerous studies, attributing function to the distinct T cell receptor (TCR) αβ+ and TCR ... more Despite numerous studies, attributing function to the distinct T cell receptor (TCR) αβ+ and TCR γδ+ IEL has proved difficult. TCR αβ+ cells are induced by the gut flora, have potent cytotoxic effector activity, and are capable of proliferation and elaborating lymphokines after stimulation in vitro.1-4 In contrast the biological function of TCR γδ+ cells is still largely unknown, although these cells do have weak cytotoxic activity.1-4 The stimulus which induces activity and the MHC restriction, if any, of TCR γδ+ IEL is unclear. Until now it has proved difficult to deplete IEL of all TCR αβ+ and yet retain sufficient TCR γδ+ IEL for functional assays at meaningful cell numbers. Several approaches have been taken with the aim of disrupting the T cell repertoire with varying degrees of success. The depletion of αβ T cells by injecting mice with antibodies to the αβ TCR, and the expression of prearranged TCR genes in transgenic mice are two examples.5,6 Instead, we have used the approach of genetically deleting the capacity of mice to make TCR αβ+ T cells using the technique of homologous recombination.7 This system yields the cleanest model mouse host for studying the biological function of TCR γδ+ cells and in particular the role of TCR γδ+ cells in mucosal immunity.
The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients res... more The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, a...
The mitogen-activated protein (MAP) kinases are a group of serine/threonine kinases that mediate ... more The mitogen-activated protein (MAP) kinases are a group of serine/threonine kinases that mediate intracellular signal transduction in response to environmental stimuli including stress, growth factors, and various cytokines. Of this family, the c-Jun N-terminal kinases (JNKs) are members which, depending on cell type, have been shown to activate the transcription of genes involved in the inflammatory response, apoptosis, and hypertrophy. Here we report the use Baculovirus/Sf9 cells to produce milligram quantities of recombinant JNK2beta2 substrate which could be purified to >90% as judged by SDS-PAGE. In addition, we report a novel method for the site-specific biotinylation for this enzyme and demonstrate that the biotinylated product is an authentic substrate of the upstream kinases MKK4 and 7 and can phosphorylate a downstream target, ATF-2. We also show that the phosphorylated product can be captured efficiently on streptavidin-coated beads for use in scintillation proximity a...
The signaling pathways that mediate the ability of NGF to support survival of dependent neurons a... more The signaling pathways that mediate the ability of NGF to support survival of dependent neurons are not yet completely clear. However previous work has shown that the c-Jun pathway is activated after NGF withdrawal, and blocking this pathway blocks neuronal cell death. In this paper we show that over-expression in sympathetic neurons of phosphatidylinositol (PI) 3-kinase or its downstream effector Akt kinase blocks cell death after NGF withdrawal, in spite of the fact that the c-Jun pathway is activated. Yet, neither the PI 3-kinase inhibitor LY294002 nor a dominant negative PI 3-kinase cause sympathetic neurons to die if they are maintained in NGF. Thus, although NGF may regulate multiple pathways involved in neuronal survival, stimulation of the PI 3-kinase pathway is sufficient to allow cells to survive in the absence of this factor.
In order to study the involvement of caspases in neuronal cell death, we have examined the effect... more In order to study the involvement of caspases in neuronal cell death, we have examined the effects of the viral caspase inhibitor p35 and peptide caspase inhibitors on sympathetic neurons isolated from the superior cervical ganglion (SCG). In these neurons, apoptosis can be induced by the withdrawal of nerve growth factor (NGF) and also by the addition of the kinase inhibitor staurosporine. p35 has been shown to be a broad spectrum inhibitor of the caspase family and promotes the survival of SCG neurons withdrawn from NGF. We show that p35 is also protective when apoptosis is induced by staurosporine. In addition, p35 inhibits a number of the morphological features associated with apoptosis, such as nuclear condensation, TUNEL labelling, and externalisation of phosphatidylserine. The tri-peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl)-fluoromethylketone (zVAD-fmk) was effective at inhibiting NGF withdrawal-induced and staurosporine-induced apoptosis of SCG neurons...
In order to study the involvement of caspases in neuronal cell death, we have examined the effect... more In order to study the involvement of caspases in neuronal cell death, we have examined the effects of the viral caspase inhibitor p35 and peptide caspase inhibitors on sympathetic neurons isolated from the superior cervical ganglion (SCG). In these neurons, apoptosis can be induced by the withdrawal of nerve growth factor (NGF) and also by the addition of the kinase inhibitor staurosporine. p35 has been shown to be a broad spectrum inhibitor of the caspase family and promotes the survival of SCG neurons withdrawn from NGF. We show that p35 is also protective when apoptosis is induced by staurosporine. In addition, p35 inhibits a number of the morphological features associated with apoptosis, such as nuclear condensation, TUNEL labelling, and externalisation of phosphatidylserine. The tri-peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl)-fluoromethylketone (zVAD-fmk) was effective at inhibiting NGF withdrawal-induced and staurosporine-induced apoptosis of SCG neurons...
A therapeutic antibody which is an antibody or antigen binding fragment and / or derivative there... more A therapeutic antibody which is an antibody or antigen binding fragment and / or derivative thereof that binds to β-amyloid peptide and CDRs comprising the following: CDRH1: dngma (SEQ ID NO: 1) CDRH2: FISNLAYSIDYADTVTG ( SEQ ID NO: 2) CDRH3: GTWFAY (SEQ ID NO: 3) within a frame of a variable region of human heavy chain originating from the VH3 family gene and: CDRL1: RVSQSLLHSNGYTYLH (SEC ID NO: 4) CDRL2: KVSNRFS (SEQ ID NO: 5) CDRL3: SQTRHVPYT (SEQ ID NO: 6) within a housing of a variable region of human light chain originates from amino acid sequence disclosed in SEQ ID NO: 24.
Background: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatme... more Background: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT)" randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention in the prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describe the procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. We also illustrate the main demographic and clinical characteristics of eligible screenees. Methods: The identification of PF&S was based on the co-occurrence of three defining elements: (1) reduced physical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) low muscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3) absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT was advertised through a variety of means. Site-specific case finding strategies were developed to accommodate the variability across centers in catchment area characteristics and access to the target population. A quick "participant profiling" questionnaire was devised to facilitate PF&S case finding. Results: During approximately 22 months, 12,358 prescreening interviews were completed in 17 SPRINTT sites resulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participating in the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidity burden. In most centers, project advertisement through mass media was the most rewarding case finding strategy. Conclusion: PF&S case finding in the community is a challenging, but feasible task. Although largely autonomous in daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity. This subset of the older population is therefore at high risk for disability and other negative health-related events. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass communication methods. a This site is no longer active.
In her News Feature “Out of bounds” (27 January p. [339][1]), A. McCook strove to present an obje... more In her News Feature “Out of bounds” (27 January p. [339][1]), A. McCook strove to present an objective narrative of the situation in which a student at Harvard University was forced to undergo a psychiatric evaluation and then filed a court order against scientist Dr. Lee Rubin. However, McCook failed to take into consideration Rubin's longstanding reputation as a scientist and a mentor. We are scientists who have worked with, been mentored by, or collaborated with Rubin. Some are current members of his laboratory, some have known him for many years, and a few have known him for more than 30 years. We could not let this story stand without adding our perspective. Rubin's scientific reputation can be readily appreciated simply by skimming through the list of his stellar publications. However, a dry bibliography fails to illuminate the quality of the scientist behind the science. Rubin has always upheld the highest standards of scientific and personal integrity. His kindness and concern for the personal well-being and professional development of his graduate students, and indeed everyone in his laboratory, has always been clearly evident. Rubin has always had our backs, whether as a mentor, a colleague, a boss, or a friend. He upholds the highest standards of scientific rigor while providing compassionate mentorship. His commitment to leading by example means we place the highest value on our friendship and connections with him. We have sought out his scientific counsel and, in several cases, engaged in collaborations that span many years. We feel fortunate to have had the opportunity to know and to work with him. It is our collective experience that besides being an outstanding scientist, he is a warm and caring scientific mentor who does not deserve to have the reputation he has built over 40 years or more besmirched. [1]: /lookup/doi/10.1126/science.355.6323.339
The invention antibodies, methods of treating a disease or disorder characterized by a β- amyloid... more The invention antibodies, methods of treating a disease or disorder characterized by a β- amyloid levels or β- amyloid deposits increase in the antibody, a pharmaceutical composition and manufacture thereof comprising the antibody binding to human β- amyloid peptide It relates to a method.
Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The develop... more Vertebrate T cells express either an alpha beta or gamma delta T cell receptor (TCR). The developmental relatedness of the two cell types is unresolved. alpha beta + T cells respond to specific pathogens by collaborating with immunoglobulin-producing B cells in distinct lymphoid organs such as the spleen and Peyer's patches. The precise influence of alpha beta + T cells on B cell development is poorly understood. To investigate the developmental effects of alpha beta + T cells on B cells and gamma delta + T cells, mice homozygous for a disrupted TCR alpha gene were generated. The homozygotes showed elimination of alpha beta + T cells and the loss of thymic medullae. Despite this, gamma delta + T cells developed in normal numbers, and there was an increase in splenic B cells.
Murine major histocompatibility complex class I genes are transcribed at high levels in placental... more Murine major histocompatibility complex class I genes are transcribed at high levels in placental tissues, lower levels in yolk-sac tissues and at barely detectable levels in the embryo at Day 13.5 of gestation. Genes are expressed at equivalent levels whether inherited maternally or paternally, and the genetic background has no effect on class I gene transcription. These results show that potential alloantigens are expressed in extra-embryonic tissues intimately associated with maternal tissues and blood supply and yet fail to induce immunological rejection.
In order to re-examine the sub-cellular location of the three influenza A/NT/60/68 polymerase pro... more In order to re-examine the sub-cellular location of the three influenza A/NT/60/68 polymerase proteins PB1, PB2 and PA in infected cells, specific antisera for each polymerase component have been prepared by immunizing rabbits with polymerase-beta-galactosidase fusion proteins synthesized in Escherichia coli. We show that polymerase PB1, PB2, and PA are predominantly associated with the nucleus of influenza-infected MDCK cells by immunocytochemical techniques. In the case of polymerase PB2 we investigate the possibility that nuclear accumulation is an intrinsic property of the PB2 protein. Using a vaccinia-PB2 recombinant virus, we show that PB2 accumulates intra-nuclearly in monkey CV-1 cells in the absence of any other influenza protein, suggesting it contains an intrinsic nuclear signal.
Advances in Experimental Medicine and Biology, 1995
Despite numerous studies, attributing function to the distinct T cell receptor (TCR) αβ+ and TCR ... more Despite numerous studies, attributing function to the distinct T cell receptor (TCR) αβ+ and TCR γδ+ IEL has proved difficult. TCR αβ+ cells are induced by the gut flora, have potent cytotoxic effector activity, and are capable of proliferation and elaborating lymphokines after stimulation in vitro.1-4 In contrast the biological function of TCR γδ+ cells is still largely unknown, although these cells do have weak cytotoxic activity.1-4 The stimulus which induces activity and the MHC restriction, if any, of TCR γδ+ IEL is unclear. Until now it has proved difficult to deplete IEL of all TCR αβ+ and yet retain sufficient TCR γδ+ IEL for functional assays at meaningful cell numbers. Several approaches have been taken with the aim of disrupting the T cell repertoire with varying degrees of success. The depletion of αβ T cells by injecting mice with antibodies to the αβ TCR, and the expression of prearranged TCR genes in transgenic mice are two examples.5,6 Instead, we have used the approach of genetically deleting the capacity of mice to make TCR αβ+ T cells using the technique of homologous recombination.7 This system yields the cleanest model mouse host for studying the biological function of TCR γδ+ cells and in particular the role of TCR γδ+ cells in mucosal immunity.
The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients res... more The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, a...
The mitogen-activated protein (MAP) kinases are a group of serine/threonine kinases that mediate ... more The mitogen-activated protein (MAP) kinases are a group of serine/threonine kinases that mediate intracellular signal transduction in response to environmental stimuli including stress, growth factors, and various cytokines. Of this family, the c-Jun N-terminal kinases (JNKs) are members which, depending on cell type, have been shown to activate the transcription of genes involved in the inflammatory response, apoptosis, and hypertrophy. Here we report the use Baculovirus/Sf9 cells to produce milligram quantities of recombinant JNK2beta2 substrate which could be purified to >90% as judged by SDS-PAGE. In addition, we report a novel method for the site-specific biotinylation for this enzyme and demonstrate that the biotinylated product is an authentic substrate of the upstream kinases MKK4 and 7 and can phosphorylate a downstream target, ATF-2. We also show that the phosphorylated product can be captured efficiently on streptavidin-coated beads for use in scintillation proximity a...
The signaling pathways that mediate the ability of NGF to support survival of dependent neurons a... more The signaling pathways that mediate the ability of NGF to support survival of dependent neurons are not yet completely clear. However previous work has shown that the c-Jun pathway is activated after NGF withdrawal, and blocking this pathway blocks neuronal cell death. In this paper we show that over-expression in sympathetic neurons of phosphatidylinositol (PI) 3-kinase or its downstream effector Akt kinase blocks cell death after NGF withdrawal, in spite of the fact that the c-Jun pathway is activated. Yet, neither the PI 3-kinase inhibitor LY294002 nor a dominant negative PI 3-kinase cause sympathetic neurons to die if they are maintained in NGF. Thus, although NGF may regulate multiple pathways involved in neuronal survival, stimulation of the PI 3-kinase pathway is sufficient to allow cells to survive in the absence of this factor.
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