Neurons cyclin dependent kinase 5. Medical search. Frequent questions

Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. (wikipedia.org)
Cdk5 is a proline-directed serine/threonine kinase, which was first identified as a CDK family member due to its similar structure to CDC2/CDK1 in humans, a protein that plays a crucial role in the regulation of the cell cycle. (wikipedia.org)
Even though Cdk5 has a similar structure to other cyclin-dependent kinases, its activators are highly specific (CDK5R1 and CDK5R2). (wikipedia.org)
The Cdk5 kinase has an original design as well. (wikipedia.org)
Cdk5 belongs to the eukaryotic protein kinases (ePKs). (wikipedia.org)
Recently Cdk5 has emerged as an essential kinase in sensory pathways. (wikipedia.org)
Unlike other cyclin-dependent kinases, CDK5 does not also require phosphorylation on the T loop. (wikipedia.org)
Cdk5 is abundant and mainly expressed in neurons, where it phosphorylates protein polymers with a high molecular weight called neurofilaments, and microtubule-associated protein tau, which are abundant in the CNS (Central Nervous System). (wikipedia.org)
The main role of Cdk5 when it comes to neurons is to assure proper neuronal migration. (wikipedia.org)
Neurons will send out both dendrites and axons to form connections with other neurons in order to transmit information, and Cdk5 regulates this process. (wikipedia.org)
In order to perform, Cdk5 needs to be activated by p35 (these 3 amino acids, Asp-259, Asn-266, and Ser-270, are involved in the formation of hydrogen bonds with Cdk5) or p39 (the isoform of p35), which are two of its neuron-specific regulatory subunits. (wikipedia.org)
The protein encoded by this gene is a neuron-specific activator of CDK5 kinase. (nih.gov)
It associates with CDK5 to form an active kinase. (nih.gov)
This protein and neuron-specific CDK5 activator CDK5R1/p39NCK5A both share limited similarity to cyclins, and thus may define a distinct family of cyclin-dependent kinase activating proteins. (nih.gov)
GSK3β and Cdk5 are the two kinases in the center of research on Alzheimer's disease (AD), involved in the pathological symptoms of AD, Aβ plaque formation, tau hyperphosphorylation and neurodegeneration. (frontiersin.org)
So far, both kinases have mostly been examined in isolation, leading to a schism of the research field into defenders of the GSK3β-versus the Cdk5 hypotheses of AD. (frontiersin.org)
Cdk5 is named after its structural similarity to members of the serine/threonine cyclin-dependent kinase family. (frontiersin.org)
Besides sharing both up- and downstream pathways, Cdk5 and GSK3β are linked more directly in neurons. (frontiersin.org)
using cultured neurons: Their investigations to determine a regulatory pathway for kinesin-driven motility in axons revealed that Cdk5 is neccessary for kinesin-driven motility within the axon but cannot directly phosphorylate kinesin. (frontiersin.org)
Inhibition of Cdk5 by olomoucine enhanced phosphorylation of kinesin, suggesting that the effect was mediated by negative regulation of other kinases. (frontiersin.org)
Here, we investigated the mechanism by which cyclin I safeguards against apoptosis and found that cyclin I bound and activated cyclin-dependent kinase 5 (Cdk5) in isolated mouse podocytes and neurons. (jci.org)
Cdk5 activity was reduced in glomeruli and brain lysates from cyclin I-deficient mice, and inhibition of Cdk5 increased in vitro the susceptibility to apoptosis in response to cellular damage. (jci.org)
Taken together, these data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in terminally differentiated cells that functions via MAPK signaling to modulate levels of the prosurvival proteins Bcl-2 and Bcl-XL. (jci.org)
Cyclin I-Cdk5 preferentially phosphorylates tau. (jci.org)
A ) HEK293 cells were transfected with HA-Cdk5, then cotransfected with either myc-p35 or myc-cyclin I. Following an IP to the myc epitope tag on either p35 or cyclin I, in vitro kinase assays were performed using either histone H1 (HH1) or tau as substrates. (jci.org)
In contrast, cyclin I-Cdk5 preferentially phosphorylated tau (lane 6) rather than histone H1 (lane 2). (jci.org)
No kinase activity was detected in the presence of a kinase-inactive dominant negative Cdk5 mutant (HA-D145N-Cdk5, lane 3, 7) or in the absence of either Cdk5 (lanes 1, 5) or p35/cyclin I (lanes 4, 8). (jci.org)
B ) To compare the kinase kinetics by which cyclin I-Cdk5 phosphorylates tau in comparison with p35-Cdk5, a time-course experiment was performed in HEK293 cells cotransfected with myc-p35 and HA-Cdk5 or myc-cyclin I and HA-Cdk5. (jci.org)
Cyclin I-Cdk5 showed phosphorylation kinetics similar to those of p35-Cdk5. (jci.org)
3 We previously described that deregulation of cyclin-dependent kinase 5 (Cdk5) activity induced by mutant huntingtin increases the susceptibility of striatal neurons to dopamine via D1 receptor activation. (bmj.com)
Cyclin-dependent kinase 5 (Cdk5) /p35 is involved in many developmental processes of the central nervous system. (biomedcentral.com)
These results indicated that Cdk5/p35 in excitatory neurons is important for the hippocampal synaptic plasticity and associative memory retention. (biomedcentral.com)
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that belongs to the CDK family and is expressed primarily in the central nervous system. (biomedcentral.com)
Cdk5 is activated by complexing with neuron-specific activator molecules such as p35 and p39. (biomedcentral.com)
Using behavioral and electrophysiological analyses, we investigate whether the p35/Cdk5 activity is involved in associative memory learning in excitatory or inhibitory neurons. (biomedcentral.com)
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, and its activity is dependent upon an association with a neuron-specific activating subunit. (elsevierpure.com)
p39 −/− mice in which forebrain GABAergic neurons have lost their Cdk5 kinase activity. (elsevierpure.com)
These results indicate that Cdk5 is required for the formation of the ventral striatum in a cell-autonomous manner, and loss of the kinase activity of Cdk5 causes GABAergic neuronal death in the developing mouse forebrain. (elsevierpure.com)
Cyclin-dependent kinase 5 (CDK5) affects the tumor microenvironment, which may influence the efficacy of TKI+IO. (e-crt.org)
Our study elucidates cyclin dependent kinase 5 (Cdk5) as an essential player in the development of lymphatic vessels. (oncotarget.com)
On the mechanistic level, we show that Cdk5 phosphorylates the forkhead transcription factor Foxc2 which regulates Foxc2-dependent transcription. (oncotarget.com)
Our recent study elucidates the serine-threonine kinase cyclin dependent kinase 5 (Cdk5) as the missing link in the regulation of Foxc2 in the lymphatic endothelium [ 12 ]. (oncotarget.com)
The "neuronal kinase" Cdk5 has been supposed to be neuron-specific for a long time due to its essential function in CNS development, function and disease. (oncotarget.com)
Sema 3A mediated retraction appears to be related to its binding to Npn 1 and Plxn A2 receptors, thus activating the downstream Fyn tyrosine kinase pathway that promotes the threonine-serine kinase cyclin-dependent kinase 5, CDK5, phosphorylation at the Tyr15 residue and the CDK5 processing to generate the active fragment p35. (biomedcentral.com)
Ashok B. Kulkarni, Ph.D., has spent years studying a protein called cyclin-dependent kinase 5 (Cdk5). (medlineplus.gov)

Kinases are enzymes that catalyze reactions of phosphorylation. (wikipedia.org)
Phosphorylation of tau was already evident after 5 minutes and reached a plateau after 40-50 minutes. (jci.org)
However, a kinase responsible for Foxc2 phosphorylation has not been identified. (oncotarget.com)
Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. (biomedcentral.com)

Therefore, binding with the activator is sufficient to activate the kinase. (wikipedia.org)
Cyclin-dependent kinase 5 and its activator p35 disrupt Munc18a-syntaxin 1 binding, thereby promoting synaptic vesicle fusion during exocytosis. (eur.nl)
The cyclin-dependent kinase activator, Spy1A, is targeted for degradation by the ubiquitin ligase NEDD4. (antikoerper-online.de)

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. (bmj.com)
Synaptic Signals from Glutamate-Treated Neurons Induce Aberrant Post-Synaptic Signals in Untreated Neuronal Networks. (uml.edu)
Tau-positive neuronal inclusions in neurons of the substantia nigra (no alpha synuclein-positive inclusions, as are found in Parkinson disease). (medscape.com)
In this study, they focused on the analysis of neuronal positioning of GABAergic neurons in the forebrain. (elsevierpure.com)
Neuronal connections are made with exquisite accuracy between specific types of neurons. (stanford.edu)
This may imply that an insult due to Sema 3A overexpression during the early phases of neuronal development might compromise neuronal organization and connectivity and make neurons perhaps more vulnerable to other insults across their lifespan. (biomedcentral.com)
Liang SL*;Liao W;Chen RS, 2023.03, 'Perinatal blockade of neuronal glutamine transport sex-differentially alters glutamatergic synaptic transmission and organization of neurons in the ventrolateral ventral media hypothalamus of adult rats, ' Journal of Neuroendocrinology, pp.1-15. (nccu.edu.tw)
Additionally, an aberrant response of microglia to Aβ deposits and degenerating neurons can lead to inflammatory states that further contribute to neuronal damage [ 3 ] Thus, finding ways to preferentially enhance microglial phagocytosis of toxic deposits such as Aβ without degradation of healthy synapses or exaggerated inflammatory responses could be an effective preventive and therapeutic strategy in NDDs, such as AD (Fig. 1 ). (biomedcentral.com)
It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. (biomedcentral.com)
MARK3 was localized to a subset of the GVD-containing neurons and also had a weak general cytoplasmic neuronal staining in both NDE and AD. (biomedcentral.com)

Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) has become the first-line treatment for advanced renal cell carcinoma, despite the lack of prognostic biomarkers. (e-crt.org)
Recently, clinical trials of immune checkpoint inhibitor plus vascular endothelial growth factor receptor-tyrosine kinase inhibitor (TKI) for mRCC have exhibited outstanding efficacies [ 3 - 5 ]. (e-crt.org)
An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin. (biomedcentral.com)
The cyclin-dependent kinase inhibitor, p21 cip1/waf1 (p21), maintains hematopoietic stem cell quiescence, and we evaluated its role in the regenerative response of neural tissue after ischemic injury using the mice deficient in p21. (rupress.org)
Furthermore, a cyclin-dependent kinase-2 inhibitor suppressed the toxic actions of cisplatin on SGN-like cells in otic organoids. (elsevierpure.com)

The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. (cancerindex.org)

Assignment of CDK5R2 coding for the cyclin-dependent kinase 5, regulatory subunit 2 (NCK5AI protein) to human chromosome band 2q35 by fluorescent in situ hybridization. (nih.gov)
This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. (cancerindex.org)

Voytenko and Galazyuk, 2006 ), a process regulated by the number of excitatory vs. inhibitory (E/I) contacts received by a single neuron. (frontiersin.org)
Since these mice had p35 deletion in all cells, it was impossible to separate and analyze its functions in excitatory and inhibitory neurons. (biomedcentral.com)
In the present study, we created mice in which the p35 gene was deleted in hippocampal excitatory neurons (CaMKII-Cre p35cKO) or GABAergic inhibitory neurons (Dlx-Cre p35cKO). (biomedcentral.com)
neurons to the excitatory actions of ior and mental function. (lu.se)

Here, we present our analysis of p35 conditional KO mice (p35cKO) in hippocampal pyramidal neurons or forebrain GABAergic neurons using electrophysiological and behavioral methods. (biomedcentral.com)

Besides formation of neurofibrillary tangles and neuron loss, the Alzheimer's disease brain is characterized by neuritic plaques consisting of β-amyloid peptide deposits and impaired neurotransmission. (eur.nl)
It is characterized by loss/dysfunction of cholinergic neurons, and formation of amyloid plaques, and formation of neurofibrillary tangles, among other changes, due to hyperphosphorylation of tau-protein. (researcher.life)

Some investigations have reported that the active states of protein kinases structurally differ from each other in order to preserve the geometry of its machinery so that catalytic output works properly. (wikipedia.org)

Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of G q -protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca 2+ /proline-rich tyrosine kinase 2/cJun N -terminal kinase pathway. (jneurosci.org)

In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. (biomedcentral.com)

4Paoletti P, Vila I, Rifé M, Lizcano JM, Alberch J, Ginés S. Dopaminergic and glutamatergic signaling crosstalk in Huntington's disease neurodegeneration: the role of p25/cyclin dependent kinase 5. (bmj.com)

Even though the P2X3 receptor desensitizes rapidly (and, thus, self-limits its function), it can elicit fast, strong sensory neuron depolarization and firing which are actually enhanced in pathological pain states [ 4 - 8 ]. (biomedcentral.com)

Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease. (bmj.com)
The functionality of striatal neurons is tightly controlled by various metabotropic receptors. (jneurosci.org)
Whereas the G s /G i -protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G q -protein-dependent signals remain poorly understood. (jneurosci.org)

Excitability of individual neurons dictates the overall excitation in specific brain circuits. (frontiersin.org)
Proteomic studies of the molecular components of the highly complex mammalian postsynaptic machinery point to an ancestral molecular machinery in unicellular organisms - the protosynapse - that existed before the evolution of metazoans and neurons, and hence challenges existing views on the origins of the brain. (nature.com)
Figure 5: MASC signalling diversity within the brain. (nature.com)
I am interested in understanding how neurons in our brain are connected. (stanford.edu)
However, it is clear that this pattern of expression is essential for brain development and to maintain neurons healthy in adulthood. (biomedcentral.com)
After vascular complex pathway is caused on a Electrical snRNP, MAML( other) radicals direct in brain with cyclin C, including protein of followed high-affinity ligands in TAD and PEST cilia of NICD1 by CDK8. (evakoch.com)
A drug that acts directly on the sensory neurons in the face rather than by suppressing pain signaling in the brain could offer a more direct, effective, and safer way to treat facial pain, Dr. Yamada said. (medlineplus.gov)

Additionally, we detected increased levels of active glycogen synthase kinase 3 β, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. (biomedcentral.com)
Contact with these chemicals altered the enzymatic activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta, and protein phosphatase-2A. (researcher.life)

In addition, levels of the prosurvival proteins Bcl-2 and Bcl-XL were reduced in podocytes and neurons from cyclin I-deficient mice, and restoration of Bcl-2 or Bcl-XL expression prevented injury-induced apoptosis. (jci.org)
For these studies we use neurons that are maintained in cell culture as well as genetically-modified strains of mice that are at increased risk for developing neurodegenerative conditions analogous to those observed in humans. (uml.edu)
Furthermore, NMDAR-dependent long-term depression (LTD) induction by low-frequency stimuli in hippocampal slices from CamkII-p35cKO mice was impaired compared to that in control mice. (biomedcentral.com)
CreER-p35cKO mice show reduced dendritic spine density in CA1 pyramidal neurons and impaired LTD induction in the hippocampus with impairment in spatial learning and memory and reduced anxiety-like behavior [ 11 ]. (biomedcentral.com)
In the cortex of transgenic Tg2576 mice over-expressing human β-amyloid precursor protein with the Swedish mutation known to lead to familial Alzheimer's disease, which have substantial levels of β-amyloid peptide but lack neurofibrillary tangles and neuron loss, no alterations of protein levels were detected. (eur.nl)
Liao W*;Lee KZ;Su SH;Luo Y, 2020.03, 'Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice, ' bioRxiv, Vol.2020, No.3, pp.1-37. (nccu.edu.tw)
Jhang CL;Huang TN;Hsueh YP;Liao W*, 2017.07, 'Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors, ' Human Molecular Genetics, Vol.26, No.20, pp.3922-3934. (nccu.edu.tw)

One of the earliest phosphorylated sites on tau is Ser 262 that is preferentially phosphorylated by microtubule affinity regulating kinase (MARK), of which four isoforms exist. (biomedcentral.com)

We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. (biomedcentral.com)
The molecular mechanism underlying the NPR-A dependent inhibition of TG P2X3 receptor function remains unclear. (biomedcentral.com)
These diverse actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which belongs to the nuclear receptor superfamily and functions as a hormone-dependent transcription factor. (brainimmune.com)
Receptor-interacting protein kinase 1 (RIPK1), a key molecule mediating necroptosis and regulated by transforming growth factor β-activated kinase 1 (TAK1), was reported to be associated with cognitive impairment in several neurodegenerative diseases. (imperial.ac.uk)
5. Carlezon, W.A. Jr. & Wise, R.A. Rewarding actions drug to its receptor, but rather by the rats, treatments associated with aversive of phencyclidine and related drugs in nucleus ac- failure of an expected drug injection to states such as severe drug withdrawal cumbens shell and frontal cortex. (lu.se)
A ubiquitous, cytoplasmic protein found in mature OLFACTORY RECEPTOR NEURONS of all VERTEBRATES. (bvsalud.org)

The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. (cancerindex.org)

We investigated protein levels of the signaling pathway: p35, cyclin-dependent kinase 5, Munc18a, syntaxin 1A and 1B, Munc18-interacting protein 1 and Munc18-interacting protein 2 in Alzheimer's disease cortex and found that this pathway was up-regulated in the Alzheimer's disease parietal and occipital cortex. (eur.nl)
These data suggest that the pathway is enhanced in dying or surviving neurons and might serve a protective role by compensating for decreased neurotransmission and decreasing β-amyloid peptide levels early during the progression of Alzheimer's disease. (eur.nl)
To analyze this effect anatomically, we manipulated G q -protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. (jneurosci.org)
Acute G q -protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. (jneurosci.org)
In contrast, sustained G q -protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. (jneurosci.org)

The presence of cortical Lewy bodies is confirmed by the finding of alpha synuclein positive rounded cytoplasmic inclusion in neurons. (medscape.com)

The molecule belongs to the cyclin-dependent kinase family. (wikipedia.org)

Jhang CL;Lee HY;Chen JC;Liao W*, 2020.06, 'Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder, ' Human Molecular Genetics, Vol.29, No.14, pp.2408-2419. (nccu.edu.tw)

Huntington's disease (HD) is characterised by motor disturbances associated to dysfunction and degeneration of the medium spiny neurons within the striatum. (bmj.com)

Neuron, 2019 Nov 6. (nih.gov)

In this manner the neurons strike a "balance" that allows for neurons to become activated and convey discrete synaptic signals, while preventing excessive excitation. (frontiersin.org)

The strength of individual synapses is modulated to compensate for changes in other synapses, on the same neuron, that would otherwise alter overall cellular activity. (frontiersin.org)

Cerebral cortex with ballooned neuron. (medscape.com)
Tau positive tangles in neurons of the cortex. (medscape.com)

The hippocampal precursors migrated and differentiated into a higher number of neurons after injury. (rupress.org)

Cyclin I is an atypical cyclin because it is most abundant in postmitotic cells. (jci.org)

There are other acetyltransferases of cheap enzymes signaling available( clathrin-dependent), lymphoblastic and online( sterol). (evakoch.com)

The connectivity of a neuron (its unique constellation of synaptic inputs and outputs) is essential for its function. (stanford.edu)

This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. (cancerindex.org)
Variants in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in nerve cells ( neurons ). (medlineplus.gov)

The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods. (biomedcentral.com)

We previously showed that cyclin I does not regulate proliferation, but rather controls survival of podocytes, terminally differentiated epithelial cells that are essential for the structural and functional integrity of kidney glomeruli. (jci.org)
[5] It represents about 8% of the total DNA in human cells. (wikidoc.org)
The spiral ganglion of the cochlea is essential for hearing and contains primary bipolar neurons that relay action potentials generated by mechanosensory hair cells. (elsevierpure.com)
Injury to spiral ganglion neurons (SGNs) causes permanent hearing loss because these cells have limited regenerative capacity. (elsevierpure.com)

Spy1, a unique cell cycle regulator, alters viability in ALS motor neurons and cell lines in response to mutant SOD1-induced DNA damage. (antikoerper-online.de)

ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. (biomedcentral.com)

This common neurodegenerative disease is clinically characterized by a progressive and gradual cognitive impairment, synapse loss, and substantial loss of neurons in later stages. (biomedcentral.com)

The cyclin-like protein Spy1/RINGO promotes mammary transformation and is elevated in human breast cancer. (antikoerper-online.de)

also called PCTK1 and cyclin-dependent kinase 16 (Cdk16)) is an associate from the PCTAIRE family members a branch of kinases linked to the Cdk family members which include PCTAIRE1 2 and 3. (healthdisparitiesks.org)

Anatomy32

Organisms8

Diseases3

Chemicals and Drugs142

Analytical, Diagnostic and Therapeutic Techniques and Equipment17

Phenomena and Processes50

Disciplines and Occupations2

Information Science3

Cdk545

Phosphorylation4

Activator3

Neuronal10

Inhibitor5

Serine1

Subunit2

Excitatory4

Forebrain GABAergic neurons1

Formation of neurofibrillary tangles2

Protein kinases1

Tyrosine1

Vitro1

Neurodegeneration1

Sensory neuron1

Striatal neurons3

Brain7

Glycogen2

Mice7

Preferentially phosphorylated1

Receptor6

Regulatory1

Pathway5

Cytoplasmic1

Molecule1

Deficiency1

Dysfunction1

20191

Synaptic signals1

Synapses1

Cortex2

Hippocampal1

Abundant1

Enzymes1

Constellation1

Activity2

Pathological1

Cells4

Mutant1

Stimuli1

Cognitive impairment1

Promotes1

Family1