Analysis Tools
mortality/aging
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• most homozygotes die at 10-14 days after birth, with few surviving past weaning
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growth/size/body
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• at 2-3 days after birth, homozygotes display an absence of fat deposits in the body trunk
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• although apparently normal at birth, homozygotes are smaller than control littermates at 2-3 days after birth
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• homozygotes display progressive wasting starting at 2-3 days after birth
• at the time of death, mutant body weights are only 20-50% of those in wild-type littermates
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adipose tissue
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• at 2-3 days after birth, homozygotes display an absence of fat deposits in the body trunk
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muscle
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• at 2-3 days after birth, homozygotes display reduced muscle mass relative to wild-type controls
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immune system
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• when cultured at 37C for 20 hrs in the absence of cytotoxic stimuli, mutant CD4+CD8+ thymocytes display an increase in spontaneous apoptosis relative to untreated wild-type cells
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• mutant thymuses are extremely atrophic
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• homozygotes display granulocytosis relative to wild-type controls
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• homozygotes display lymphopenia of both T and B lymphocytes in peripheral blood
• in contrast, erythrocyte counts are normal
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• homozygotes display a reduction in the total number of thymocytes
• around the terminal stage, mutant thymocytes become devoid of CD4+CD8+ double-positive T cells
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• homozygotes show a reduction of B cell precursors (B220+CD43-) in the bone marrow
• however, B cell development is not completely blocked
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• around the terminal stage, mutant thymocytes become devoid of CD4+CD8+ double-positive T cells
• however, thymocytes derived from younger homozygotes or fetal thymic organ cultures display a normal profile of surface markers, indicating normal thymocyte development
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• mutant spleens are extremely atrophic
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• homozygotes lack secondary germinal centers in spleen
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• at 2-3 weeks of age, homozygotes display clearly detectable serum TNF levels whereas wild-type and heterozygous control mice do not
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• homozygotes lack secondary germinal centers in lymph nodes
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• homozygotes display lymphoid depletion in thymus and spleen
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hematopoietic system
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• when cultured at 37C for 20 hrs in the absence of cytotoxic stimuli, mutant CD4+CD8+ thymocytes display an increase in spontaneous apoptosis relative to untreated wild-type cells
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• mutant thymuses are extremely atrophic
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• homozygotes display granulocytosis relative to wild-type controls
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• homozygotes display lymphopenia of both T and B lymphocytes in peripheral blood
• in contrast, erythrocyte counts are normal
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• homozygotes display a reduction in the total number of thymocytes
• around the terminal stage, mutant thymocytes become devoid of CD4+CD8+ double-positive T cells
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• homozygotes show a reduction of B cell precursors (B220+CD43-) in the bone marrow
• however, B cell development is not completely blocked
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• around the terminal stage, mutant thymocytes become devoid of CD4+CD8+ double-positive T cells
• however, thymocytes derived from younger homozygotes or fetal thymic organ cultures display a normal profile of surface markers, indicating normal thymocyte development
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• mutant spleens are extremely atrophic
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• homozygotes lack secondary germinal centers in spleen
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homeostasis/metabolism
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• at 2-3 weeks of age, homozygotes display clearly detectable serum TNF levels whereas wild-type and heterozygous control mice do not
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cellular
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• upon induction with mouse TNF (mTNF), mutant MEFs exhibit a nearly normal yet delayed NF-kappaB activation; however, by 90 min after mTNF treatment, the proportion of activated NF-kappaB is similar to that in control MEFs, with no differences in the supershift pattern, as determined by using specific antibodies to different NF-kappaB family members
• unlike wild-type cells, mutant MEFs fail to show a peak in JNK/SAPK activation at ~ 10-15 min after mTNF treatment
• however, other stress signals (e.g. anisomycin, UV irradiation, and heat shock) are still able to activate JNK/SAPK in mutant MEFs, indicating that this defect is specific to the TNF signaling pathway
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• in culture, mutant CD4+CD8+ double-positive thymocytes show increased sensitivity to cell death induced by mTNF (10 ng/ml) alone or in combination with cycloheximide relative to control (wild-type and heterozygous) thymocytes
• mutant hematopoietic precursors are highly sensitive to TNF-induced death: only very few or no erythroid and myeloid colonies develop from mutant fetal livers, whereas colonies from control fetal livers are only mildly suppressed
• mutant thymocytes are more sensitive than control cells to human TNF- or anti-TNFR1-induced cell death in the presence of cycloheximide
• whereas wild-type MEFs are resistant to treatment with mTNF plus cycloheximide, similarly-treated mutant MEFs start dying as early as 6 hrs, with only 15%-40% surviving by 24 hrs after treatment
• notably, treatment with anti-Fas antibody or dexamethasone reduces the viability of mutant thymocytes to a similar extent as in wild-type thymocytes
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• when cultured at 37C for 20 hrs in the absence of cytotoxic stimuli, mutant CD4+CD8+ thymocytes display an increase in spontaneous apoptosis relative to untreated wild-type cells
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endocrine/exocrine glands
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• when cultured at 37C for 20 hrs in the absence of cytotoxic stimuli, mutant CD4+CD8+ thymocytes display an increase in spontaneous apoptosis relative to untreated wild-type cells
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• mutant thymuses are extremely atrophic
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• homozygotes display a reduction in the total number of thymocytes
• around the terminal stage, mutant thymocytes become devoid of CD4+CD8+ double-positive T cells
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