General Information:

Id: 1,957
Diseases: Alzheimer disease - [OMIM]
Mammalia
review
Reference: Gibson GE et al.(2008) Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimers disease Ann. N. Y. Acad. Sci. 1147: 221-232 [PMID: 19076444]

Interaction Information:

Comment AD does not occur without a reduction in metabolism.
Formal Description
Interaction-ID: 15154

affects_activity of

in brain
Comment Reductions in metabolism correlate with apolipoprotein E (APOE) epsilon4 gene dose and are progressive in late-middle-aged persons.
Formal Description
Interaction-ID: 15166

gene/protein mutant

APOE (isoform E4)

affects_activity of

Comment Reductions in metabolism correlate with apolipoprotein E (APOE)epsilon4 gene dose and are progressive in late-middle-aged persons.
Formal Description
Interaction-ID: 15180

process

aging

decreases_activity of

Comment Oxidative stress is closely coupled to metabolism since disruptions in metabolism lead to increased free radical production and probably impair free radical removal (quenching).
Formal Description
Interaction-ID: 15181

affects_activity of

Comment Sources of oxidative stress in the brain: Free radicals or reactive oxygen species (ROS) include superoxide, hydroxyl radical, nitric oxide, peroxynitrite, and hydroperoxyl radicals.
Formal Description
Interaction-ID: 15183

drug/chemical compound

Reactive oxygen species

increases_activity of

Comment Sources of oxidative stress in the brain are free radicals or reactive oxygen species (ROS) include superoxide, hydroxyl radical, nitric oxide, peroxynitrite, and hydroperoxyl radicals.
Formal Description
Interaction-ID: 15184

drug/chemical compound

Free radical

increases_activity of

Comment Sources of oxidative stress in the brain are free radicals or reactive oxygen species (ROS) include superoxide, hydroxyl radical, nitric oxide, peroxynitrite, and hydroperoxyl radicals.
Formal Description
Interaction-ID: 15185

drug/chemical compound

O2-

increases_activity of

Comment Sources of oxidative stress in the brain are free radicals or reactive oxygen species (ROS) include superoxide, hydroxyl radical, nitric oxide, peroxynitrite, and hydroperoxyl radicals.
Formal Description
Interaction-ID: 15189

drug/chemical compound

NO

increases_activity of

Comment Sources of oxidative stress in the brain are free radicals or reactive oxygen species (ROS) include superoxide, hydroxyl radical, nitric oxide, peroxynitrite, and hydroperoxyl radicals.
Formal Description
Interaction-ID: 15194

drug/chemical compound

Peroxynitrite

increases_activity of

Comment Mitochondrial ROS can originate from multiple reactions in the tricarboxylic acid (TCA) cycle and/or the respiratory chain.
Formal Description
Interaction-ID: 15197

affects_quantity of

drug/chemical compound

Reactive oxygen species

in mitochondria
Comment Mitochondrial ROS can originate from multiple reactions in the tricarboxylic acid (TCA) cycle and/or the respiratory chain.
Formal Description
Interaction-ID: 15202

affects_quantity of

drug/chemical compound

Reactive oxygen species

in mitochondria
Comment Perturbations in metabolism generally exaggerate ROS production.
Formal Description
Interaction-ID: 15236

affects_quantity of

drug/chemical compound

Reactive oxygen species

Comment Antibodies to acrolein (a very reactive aldehyde product of lipid peroxidation) reveals oxidatively modified proteins around the areas of plaques and tangles and also in other areas.
Formal Description
Interaction-ID: 15237

drug/chemical compound

Acrolein

interacts (colocalizes) with

in AD patients
Comment Antibodies to acrolein (a very reactive aldehyde product of lipid peroxidation) reveals oxidatively modified proteins around the areas of plaques and tangles and also in other areas.
Formal Description
Interaction-ID: 15238

drug/chemical compound

Acrolein

interacts (colocalizes) with

in AD patients
Comment Lipoxygenase, a marker of oxidative stress, is increased in brains of AD patients.
Formal Description
Interaction-ID: 15239

affects_activity of

gene/protein

Lipoxygenase

Comment Lipoxygenase, a marker of oxidative stress, is increased in brains of AD patients.
Formal Description
Interaction-ID: 15240

gene/protein

Lipoxygenase

is localized in

tissue/cell line

brain

of AD patients
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15241

drug/chemical compound

2-Deoxy-D-glucose

decreases_activity of

process

energy metabolic process

(inhibition of energy metabolism) in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15244

complex/PPI

Insulin

decreases_activity of

process

energy metabolic process

(inhibition of energy metabolism) in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15245

drug/chemical compound

beta-Nitropropanoate

decreases_activity of

process

energy metabolic process

(inhibition of energy metabolism) in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15246

drug/chemical compound

Kainic acid

decreases_activity of

process

energy metabolic process

(inhibition of energy metabolism) in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15248

drug/chemical compound

2-Deoxy-D-glucose

increases_quantity of

gene/protein

BACE1

in Tg2576 transgenic mice
Drugbank entries Show/Hide entries for BACE1
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15249

complex/PPI

Insulin

increases_quantity of

gene/protein

BACE1

in Tg2576 transgenic mice
Drugbank entries Show/Hide entries for BACE1
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15250

drug/chemical compound

beta-Nitropropanoate

increases_quantity of

gene/protein

BACE1

in Tg2576 transgenic mice
Drugbank entries Show/Hide entries for BACE1
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15251

drug/chemical compound

Kainic acid

increases_quantity of

gene/protein

BACE1

in Tg2576 transgenic mice
Drugbank entries Show/Hide entries for BACE1
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15253

drug/chemical compound

2-Deoxy-D-glucose

increases_quantity of

in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15255

complex/PPI

Insulin

increases_quantity of

in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15257

drug/chemical compound

beta-Nitropropanoate

increases_quantity of

in Tg2576 transgenic mice
Comment Inhibition of energy metabolism by various pharmacological agents, such as insulin, 2-deoxyglucose, 3-nitropropionic acid (3-NP),or kainic acid, elevates beta-secretase levels and enhances plaque pathology in Tg2576 transgenic mice.
Formal Description
Interaction-ID: 15258

drug/chemical compound

Kainic acid

increases_quantity of

in Tg2576 transgenic mice
Comment Antibodies to acrolein (a very reactive aldehyde product of lipid peroxidation) reveals oxidatively modified proteins around the areas of plaques and tangles and also in other areas.
Formal Description
Interaction-ID: 15261

affects_activity of

in AD patients
Comment Antibodies to acrolein (a very reactive aldehyde product of lipid peroxidation) reveals oxidatively modified proteins around the areas of plaques and tangles and also in other areas.
Formal Description
Interaction-ID: 15263

process

lipid peroxidation

increases_quantity of

drug/chemical compound

Acrolein

lipid peroxidation affected the quantity of Acrolein in AD patients
Comment The activities of the enzymes of the TCA cycle change in brains from patients that died with autopsy-confirmed AD.
Formal Description
Interaction-ID: 15271

affects_activity of

in brain; of AD patients
Comment The activities of the pyruvate dehydrogenase complex (PDHC), isocitrate dehydrogenase complex (ICDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC) decline significantly in the brains of AD patients.
Formal Description
Interaction-ID: 15273

decreases_quantity of

complex/PPI

Pyruvate dehydrogenase complex

in brain; of AD patients
Comment The activities of the pyruvate dehydrogenase complex (PDHC), isocitrate dehydrogenase complex (ICDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC) decline significantly in the brains of AD patients.
Formal Description
Interaction-ID: 15274

decreases_quantity of

complex/PPI

Isocitrate dehydrogenase

in brain; of AD patients
Comment The activities of the pyruvate dehydrogenase complex (PDHC), isocitrate dehydrogenase complex (ICDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC) decline significantly in the brains of AD patients.
Formal Description
Interaction-ID: 15275

decreases_quantity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

in brain; of AD patients
Comment In the brains of AD patients activities of succinate dehydrogenase (SDH) (complex II) and malate dehydrogenase (MDH) are elevated.
Formal Description
Interaction-ID: 15276

increases_activity of

gene/protein

SDHA

Drugbank entries Show/Hide entries for SDHA
Comment In the brains of AD patients activities of succinate dehydrogenase (SDH) (complex II) and malate dehydrogenase (MDH) are elevated.
Formal Description
Interaction-ID: 15277

increases_activity of

gene/protein

MDH2

Drugbank entries Show/Hide entries for MDH2
Comment In brains from patients that died bearing the APP670/671 mutation, the protein levels of E1k and E2k are diminished.
Formal Description
Interaction-ID: 15294

gene/protein mutant

APP-p.KM670/671NL

decreases_quantity of

gene/protein

OGDH

in brain
Drugbank entries Show/Hide entries for OGDH
Comment In brains from patients that died bearing the APP670/671 mutation, the protein levels of E1k and E2k are diminished.
Formal Description
Interaction-ID: 15296

gene/protein mutant

APP-p.KM670/671NL

decreases_quantity of

gene/protein

DLST

in brain
Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite.
Formal Description
Interaction-ID: 15298

drug/chemical compound

Peroxynitrite

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite.
Formal Description
Interaction-ID: 15299

drug/chemical compound

NO

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite. KGDHC in intact mitochondria is inactivated by hydroxynonenal (HNE), a marker of oxidative stress that is elevated in brains of both AD patients and animals with impaired brain metabolism because of thiamine deficiency.
Formal Description
Interaction-ID: 15301

drug/chemical compound

Hydroxynonenal

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite. H2O2 diminishes KGDHC activity in synaptosomes, fibroblasts, and N2a cells.
Formal Description
Interaction-ID: 15303

drug/chemical compound

H2O2

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

in synaptosomes, fibroblasts, and N2a cells
Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite.
Formal Description
Interaction-ID: 15304

drug/chemical compound

chloroamine

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment KGDHC (alpha-ketoglutaric acid dehydrogenase complex) is inactivated by a variety of oxidants, including peroxynitrite, NO, hydroxynonenal, H2O2, chloroamine, and sodium hypochlorite.
Formal Description
Interaction-ID: 15305

drug/chemical compound

Sodium hypochlorite

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment Hydroxynonenal (HNE) is a marker of oxidative stress that is elevated in brains of both AD patients and animals with impaired brain metabolism because of thiamine deficiency.
Formal Description
Interaction-ID: 15306

affects_activity of

drug/chemical compound

Hydroxynonenal

Comment Hydroxynonenal (HNE) is a marker of oxidative stress that is elevated in brains of both AD patients and animals with impaired brain metabolism because of thiamine deficiency.
Formal Description
Interaction-ID: 15307

drug/chemical compound

Hydroxynonenal

is localized in

tissue/cell line

brain

of AD patients
Comment Hydroxynonenal (HNE) is a marker of oxidative stress that is elevated in brains of both AD patients and animals with impaired brain metabolism because of thiamine deficiency.
Formal Description
Interaction-ID: 15308

increases_quantity of

drug/chemical compound

Hydroxynonenal

Comment In brains from patients that died bearing the APP670/671 mutation, the protein levels of E1k and E2k are diminished.
Formal Description
Interaction-ID: 15309

gene/protein mutant

APP-p.KM670/671NL

affects_activity of

gene/protein

APP

Drugbank entries Show/Hide entries for APP
Comment PDHC, ICDHC, and KGDHC - these enzymes are the entry steps of substrates into the TCA cycle and form the first half of theTCA cycle.
Formal Description
Interaction-ID: 15310

complex/PPI

Pyruvate dehydrogenase complex

affects_activity of

Comment PDHC, ICDHC, and KGDHC - these enzymes are the entry steps of substrates into the TCA cycle and form the first half of theTCA cycle.
Formal Description
Interaction-ID: 15311

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

affects_activity of

Comment In brains from patients that died bearing the APP670/671 mutation, the protein levels of E1k and E2k are diminished. KGDHC is a multi-enzyme complex that consists of an ordered array of multiple copies of three proteins: alpha-ketoglutarate dehydrogenase (E1k, EC 1.2.4.2), dihydrolipoyl succinyltransferase (E2k, EC 2.3.1.61), and dihydrolipoyl dehydrogenase (E3, EC 1.8.1.4).
Formal Description
Interaction-ID: 15313

gene/protein

OGDH

affects_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

in brain
Drugbank entries Show/Hide entries for OGDH
Comment In brains from patients that died bearing the APP670/671 mutation, the protein levels of E1k and E2k are diminished. KGDHC is a multi-enzyme complex that consists of an ordered array of multiple copies of three proteins: alpha-ketoglutarate dehydrogenase (E1k, EC 1.2.4.2), dihydrolipoyl succinyltransferase (E2k, EC 2.3.1.61), and dihydrolipoyl dehydrogenase (E3, EC 1.8.1.4).
Formal Description
Interaction-ID: 15314

gene/protein

DLST

affects_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

in brain
Comment PDHC, ICDHC, and KGDHC - these enzymes are the entry steps of substrates into the TCA cycle and form the first half of theTCA cycle.
Formal Description
Interaction-ID: 15315

complex/PPI

Isocitrate dehydrogenase

affects_activity of

Comment KGDHC is a multi-enzyme complex that consists of an ordered array of multiple copies of three proteins: alpha-ketoglutarate dehydrogenase (E1k, EC 1.2.4.2), dihydrolipoyl succinyltransferase (E2k, EC 2.3.1.61), and dihydrolipoyl dehydrogenase (E3, EC 1.8.1.4).
Formal Description
Interaction-ID: 15316

gene/protein

DLD

affects_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Drugbank entries Show/Hide entries for DLD
Comment Treatment of KGDHC with increasing concentrations of GSSG progressively enhances glutathionylation of E1k, E2k, and E3.
Formal Description
Interaction-ID: 15317

drug/chemical compound

Glutathione disulfide

affects_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

with increasing concentrations of GSSG
Comment KGDHC is regulated by glutathione.
Formal Description
Interaction-ID: 15318

drug/chemical compound

Glutathione

affects_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Drugbank entries Show/Hide entries for Glutathione
Comment Treatment of KGDHC with increasing concentrations of GSSG progressively enhances glutathionylation of E1k, E2k, and E3.
Formal Description
Interaction-ID: 15319

drug/chemical compound

Glutathione disulfide

affects_processing of

gene/protein

OGDH

glutathionylation of E1k
Drugbank entries Show/Hide entries for OGDH
Comment Treatment of KGDHC with increasing concentrations of GSSG progressively enhances glutathionylation of E1k, E2k, and E3.
Formal Description
Interaction-ID: 15320

drug/chemical compound

Glutathione disulfide

affects_processing of

gene/protein

DLST

glutathionylation of E2k
Comment Treatment of KGDHC with increasing concentrations of GSSG progressively enhances glutathionylation of E1k, E2k, and E3.
Formal Description
Interaction-ID: 15322

drug/chemical compound

Glutathione disulfide

affects_processing of

gene/protein

DLD

glutathionylation of E3
Drugbank entries Show/Hide entries for DLD
Comment The H2O2-induced increase in ROS and cell death is greater in cells with diminished E2k than in controls.
Formal Description
Interaction-ID: 15323

gene/protein

DLST

affects_quantity of

drug/chemical compound

Reactive oxygen species

Comment The H2O2-induced increase in ROS and cell death is greater in cells with diminished E2k than in controls.
Formal Description
Interaction-ID: 15325

drug/chemical compound

H2O2

affects_quantity of

drug/chemical compound

Reactive oxygen species

Comment The H2O2-induced increase in ROS and cell death is greater in cells with diminished E2k than in controls.
Formal Description
Interaction-ID: 15326

drug/chemical compound

H2O2

affects_activity of

process

neuron death

Comment The H2O2-induced increase in ROS and cell death is greater in cells with diminished E2k than in controls.
Formal Description
Interaction-ID: 15327

drug/chemical compound

Reactive oxygen species

affects_activity of

process

neuron death

Comment Under reducing conditions KGDHC is the primary source of H2O2 in mitochondria.
Formal Description
Interaction-ID: 15494

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

affects_quantity of

drug/chemical compound

H2O2

in mitochondria
Comment MDH activity varies with the E2k levels in cells with variable Ek2 protein levels.
Formal Description
Interaction-ID: 15495

gene/protein

DLST

affects_activity of

gene/protein

MDH

Drugbank entries Show/Hide entries for MDH
Comment Cellular calcium dynamics are altered in cells from patients with AD.
Formal Description
Interaction-ID: 15496

affects_activity of

Comment Fibroblasts from AD patients or from presenilin-1 transgenic mice have exaggerated ER calcium stores.
Formal Description
Interaction-ID: 15497

affects_activity of

in fibroblasts; from AD patients or from presenilin-1 transgenic mice
Comment Fibroblasts from AD patients or from presenilin-1 transgenic mice have diminished mitochondrial calcium uptake.
Formal Description
Interaction-ID: 15498

decreases_activity of

in fibroblasts; from AD patients or from presenilin-1 transgenic mice
Comment A selective inhibitor of KGDHC is alpha-keto-beta-methyl valerate (KMV).
Formal Description
Interaction-ID: 15503

drug/chemical compound

Alpha-keto-beta-methyl valerate

decreases_activity of

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

Comment Inhibitors of KGDHC release cytochrome C from the mitochondria to the cytosol, activate caspases and alter ER calcium stores before they cause a decline the mitochondrial membrane potentials (a measure of mitochondrial function).
Formal Description
Interaction-ID: 15508

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

affects_activity of

to the cytosol
Comment A selective inhibitor of KGDHC is alpha-keto-beta-methyl valerate (KMV), Inhibitors of KGDHC activate caspases.
Formal Description
Interaction-ID: 15509

drug/chemical compound

Alpha-keto-beta-methyl valerate

decreases_activity of

Comment A selective inhibitor of KGDHC is alpha-keto-beta-methyl valerate (KMV), Inhibitors of KGDHC alter ER calcium stores before they cause a decline the mitochondrial membrane potentials (a measure of mitochondrial function).
Formal Description
Interaction-ID: 15510

drug/chemical compound

Alpha-keto-beta-methyl valerate

affects_activity of

Comment A selective inhibitor of KGDHC is alpha-keto-beta-methyl valerate (KMV), Inhibitors of KGDHC alter ER calcium stores before they cause a decline the mitochondrial membrane potentials (a measure of mitochondrial function).
Formal Description
Interaction-ID: 15512

drug/chemical compound

Alpha-keto-beta-methyl valerate

decreases_activity of

Comment Malondialdehyde, a common measure of oxidative stress, is elevated in the brains of Dld+/- mice.
Formal Description
Interaction-ID: 15527

increases_quantity of

drug/chemical compound

Malonaldehyde

in brain; of Dld+/- mice
Drugbank entries Show/Hide entries for
Comment Malondialdehyde, a common measure of oxidative stress, is elevated in the brains of Dld+/- mice.
Formal Description
Interaction-ID: 15528

affects_quantity of

drug/chemical compound

Malonaldehyde

Drugbank entries Show/Hide entries for
Comment A reduction in KGDHC activity can impair memory in the emotional domain.
Formal Description
Interaction-ID: 15529

complex/PPI

Alpha-ketoglutarate dehydrogenase complex

affects_activity of