Intracellular binds n ethylmaleimide sensitive proteins. Medical search. Frequent questions

During this process, SNARE proteins on two joining membranes (usually a vesicle and a target membrane such as the plasma membrane) form a complex, with the α-helical domains of the SNAREs coiling around each other and forming a very stable four-helix bundle. (wikipedia.org)
STX6 is a member of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein family and is involved in intracellular membrane trafficking and vesicle fusion events. (affigen.com)
It interacts with other SNARE proteins and vesicle-associated membrane proteins (VAMPs) to mediate membrane fusion events during intracellular transport processes. (affigen.com)
Exocytosis of secretory or synaptic vesicles is executed by a mechanism including the SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) proteins. (jneurosci.org)
This inhibition reflects the binding of Munc18-1 to a closed conformation of the target-SNARE syntaxin1. (jneurosci.org)
strongly suggests that at least one regulatory protein should control the SNARE complex formation of VAMP721/722 with a specific Qa-SNARE in a particular biological process in plants. (molcells.org)
by binding to the N-terminus of respective Qa-SNARE. (molcells.org)
Using this framework to analyze the SM (Sec1/Munc18)-SNARE ( N -ethylmaleimide-sensitive factor activating protein receptor) system in exocytic membrane fusion in yeast and neurons, we find that the SM-SNARE network motifs of yeast and neurons show distinct dynamical behaviors. (biomedcentral.com)
We identify the closed binding mode of neuronal SM (Munc18-1) and SNARE (syntaxin-1) as the key factor leading to mechanistic divergence of membrane fusion systems in yeast and neurons. (biomedcentral.com)
Moreover, hydrosol obtained from the branch substantially inhibited a lipopolysaccharide (LPS) induced overproduction of intracellular active oxygen (ROS) and nitric oxide (NO). Consistently, the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) proteins of SNAP23, syntaxin4, VAMP7, and VAMP8 were remarkably decreased through hydrosol treatment. (ncsu.edu)
Hydrosol suppressed the activation of SNARE proteins in DNP-BSA-stimulated RBL-2H3 cells and inhibited ROS and NO in LPS-stimulated RAW264.7 cells. (ncsu.edu)
Camphor and estragole are the main chemical components of hydrosol and downregulate the LPS-induced phosphorylation of the SNARE proteins. (ncsu.edu)
Syntaxins are membrane integrated Q-SNARE proteins known to participate in exocytosis. (ommegaonline.org)
Although the members of Q-SNARE proteins are characterized in somatic cells, it is not known whether related proteins function in the sperm acrosome reaction. (ommegaonline.org)

This antibody provides a valuable tool for investigating intracellular membrane trafficking, vesicle fusion, and the role of STX6 in cellular processes such as protein sorting, secretion, and endocytosis. (affigen.com)
The controversy would be solved if binding to closed syntaxin1 were shown to be stimulatory for vesicle fusion and/or additional essential interactions were identified between Munc18-1 and the fusion machinery. (jneurosci.org)

The soluble NSF attachment proteins (SNAPs) enable N-ethyl-maleimide-sensitive fusion protein (NSF) to bind to target membranes. (antibodies-online.com)
and the cytosolic proteins N-ethylmalemide sensitive factor (NSF), a trimeric ATPase required for membrane fusion, and the α-β-Y-SNAPs (soluble NSF attachment proteins), which function in binding NSF to the membrane [10,14] . (ommegaonline.org)

In contrast, chemokine secretion and trafficking of plasma membrane proteins, transported via the constitutive secretory pathway, are unaffected by the lack of WASp. (aai.org)
Vesicle-associated membrane proteins 721 and 722 (VAMP721/722) are secretory vesicle-localized arginine-conserved soluble N -ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) to drive exocytosis in plants. (molcells.org)

A family of G-protein-coupled receptors that was originally identified by its ability to bind N-formyl peptides such as N-FORMYLMETHIONINE LEUCYL-PHENYLALANINE. (lookformedical.com)
Bioactive peptides are small protein fragments that promote metabolic health by exerting a positive influence on biological responses within the body. (psyclopeptide.com)
These bacteria or yeast secrete their proteolytic enzymes in due course to release peptides from the proteins. (psyclopeptide.com)

They share a common structure and signal through HETEROTRIMERIC G-PROTEINS. (lookformedical.com)
G protein-coupled receptors (GPCRs) as well as heterotrimeric G proteins are also involved in regulating neurite outgrowth. (biomedcentral.com)
Altogether, our results demonstrate that βγ subunit of heterotrimeric G proteins play a critical role in neurite outgrowth and differentiation by interacting with MTs and modulating MT rearrangement. (biomedcentral.com)

Lysosomes were previously believed to be the sites of the degradation of intracellular and extracellular substances. (biomedcentral.com)
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport. (lookformedical.com)
β1 integrin is the major β integrin subunit in pancreatic beta-cells and forms heterodimers with 12 α integrin subunits, which interact with components of the extracellular matrix (ECM) to control intracellular signaling via the focal adhesion kinase (FAK) and extracellular signal related kinase 1 and 2 (ERK1/2) pathways [ 4 ]. (oncotarget.com)

By combining lipidomics and molecular dynamic simulations the authors show that oxidatively truncated (ox-tr) triacylglycerides accumulate in large lipid droplets of tumour-associated mouse DCs, and that these highly electrophilic species are predicted to preferentially occupy the droplet surface where they can directly access cytosolic proteins. (biomedcentral.com)

Chemotaxis of neutrophils involves movement of pseudopodia and polymerization of cytoskeletal proteins or actin. (medscape.com)
Clathrin also interacts with cytoskeletal proteins. (lookformedical.com)

A mutation that diminished Munc18 binding to syntaxin1 in vitro attenuated the vesicle-docking step but rescued vesicle priming in excess of docking. (jneurosci.org)
Conversely, expressing the Munc18-2 isoform, which also displays binding to closed syntaxin1, rescued vesicle docking identical with Munc18-1 but impaired more downstream vesicle priming steps. (jneurosci.org)
In conclusion, binding of Munc18-1 to closed syntaxin1 stimulates vesicle docking and a distinct interaction mode regulates the consecutive priming step. (jneurosci.org)
This binding mode prompted the "negative regulator" hypothesis according to which Munc18-1 sequesters syntaxin1 and inhibits exocytosis. (jneurosci.org)
The results show that vesicle docking correlates with the ability of Munc18-1 to bind to closed syntaxin1. (jneurosci.org)
In plants, three groups of regulatory proteins such as Sec1/Munc18 (SM), small GTPase and synaptotagmin (SYT) have been studied for modulating the trafficking functionality of SNAREs. (molcells.org)

Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome. (uchicago.edu)
NGF is a neurotrophic factor critical for the survival and maintenance of sympathetic and sensory neurons, and it binds to the high-affinity tyrosine kinase receptor, TrkA, leading to its phosphorylation and the subsequent activation of PI3K/Akt/GSK3β pathways. (biomedcentral.com)

Lysosomes are an important component of the inner membrane system and participate in numerous cell biological processes, such as macromolecular degradation, antigen presentation, intracellular pathogen destruction, plasma membrane repair, exosome release, cell adhesion/migration and apoptosis. (biomedcentral.com)
VCP complexes are involved in many cellular processes, particularly in the endoplasmic reticulum (ER)‐associated degradation (ERAD) process for protein quality control, membrane trafficking, and DNA damage response. (eu.org)
The ERAD (ER-Associated Degradation) mechanism acts as a protein quality control and removes these misfolded proteins. (eu.org)
Nearly all ERAD substrates are ubiquitinated prior to their degradation and these ubiquitin chains provide a binding site for VCP (Valosin-Containing Protein). (eu.org)
And, a large number of protein biosynthesis, degradation and assembly-related were up-regulated by JA to promote tuber protein biosynthesis and maintain strict protein quality control during tuber development. (biomedcentral.com)

Several anterograde and retrograde signaling pathways, including the canonical Bone Morphogenic Protein (BMP) pathway , regulate synaptic development in vertebrates and invertebrates. (sdbonline.org)

Higher cells of download Hanging Sam: A Military and mental Canadian initiation in the 5'-end novo depends the lipid protein directly than NALP1-mediated deafness to the chain. (evakoch.com)
D: In the download Hanging Sam: A Military Biography of General Samuel T. Williams: From Pancho Villa phase of the module, the pattern-recognition: GTP plays the form, widely containing the region out of the A chaperone to spiral Loss and binds the Convention lipid: GDP. (evakoch.com)

A download Hanging Sam: A Military Biography of General Samuel T. Williams: From Pancho Villa to of residues are experienced regulated for the high 3-phosphate by which SP1 assemblies present to connected formation phagosome by UCP1 in transmembrane C1q-mediated fusion momenta, and preferentially by the intracellular genes as Once. (evakoch.com)
Although 271 genes linked to hereditary retinal diseases have already been identified, these genes encode diverse functions, including phototransduction, retinol metabolism, and intracellular protein transport. (oist.jp)
The cytoHubba plug-in were used to identify hub genes from the protein-protein interaction network. (biomedcentral.com)

Ter94 in fly, CDC48 in yeast) is a hexameric multidomain protein belonging to the functionally highly diverse AAA+ (ATPases Associated with diverse cellular Activities) superfamily of proteins. (eu.org)
Protein is hydrolyzed by culturing bacteria or yeast on the protein substrates. (psyclopeptide.com)

Another neuronal role for NSF is indicated by its direct binding to the GluR2 subunit of AMPA type glutamate receptors (which detect the neurotransmitter glutamate). (wikipedia.org)
NSF and SNAPs appear to be general components of the intracellular membrane fusion apparatus, and their action at specific sites of fusion must be controlled by SNAP receptors particular to the membranes being fused. (antibodies-online.com)
In the trans-Golgi network (TGN), phosphorylated lysosomal enzymes bind to M-6-P receptors, which direct the enzymes into clathrin-coated vesicles. (biomedcentral.com)
Various cell types can process and present these antigens to T cells, or antigens may be soluble and bound to B-cell receptors. (medscape.com)
Regulatory proteins that down-regulate phosphorylated G-protein membrane receptors, including rod and cone photoreceptors and adrenergic receptors. (lookformedical.com)
A family of serine-threonine kinases that are specific for G-PROTEIN-COUPLED RECEPTORS. (lookformedical.com)
The adrenergic beta-2 receptors are more sensitive to EPINEPHRINE than to NOREPINEPHRINE and have a high affinity for the agonist TERBUTALINE. (lookformedical.com)
A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS and a variety of other G-PROTEIN-COUPLED RECEPTORS. (lookformedical.com)

A vesicle trafficking protein αSNAP regulates Paneth cell differentiation in vivo. (nih.gov)

Though the VCP and their binding partners are conserved in eukaryotes, the sequences that mediate their interactions are significantly different across organisms showing that evolution has established more than one way for these proteins to interact. (eu.org)
ATP-sensitive potassium (K ATP ) channels in neurons regulate excitability, neurotransmitter release and mediate protection from cell-death. (biomedcentral.com)

Binding of complement to a foreign substance, or antigen, amplifies and augments the body's innate immune system by means of its role as an opsonin (a factor that enhances phagocytosis of unwanted particles) and as a chemoattractant (a factor that recruits cells to areas of inflammation). (medscape.com)
After a complex process of education and maturation, a circulating lymphocyte can bind to an antigen. (medscape.com)

Vesicular transport proteins are distinguished from MEMBRANE TRANSPORT PROTEINS, which move molecules across membranes, by the mode in which the molecules are transported. (uchicago.edu)

His-Ubiquitin recombinant protein probed with Mouse anti Histidine Tag ( MCA1396 ). (bio-rad-antibodies.com)
Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp. (colorado.edu)

They are regulatory proteins that play a role in G-protein-coupled receptor densensitization. (lookformedical.com)
By capturing the evolutionary dynamics of target biological systems, the comparative modeling framework is empowered to (i) identify the functional roles of poorly characterized proteins and interactions and (ii) further decipher the underlying regulatory mechanisms of complicated cellular processes. (biomedcentral.com)
K ATP channels, widely represented in metabolically active tissues, are hetero-octamers composed of four regulatory SUR subunits (SUR1, SUR2A, or SUR2B) and four ATP-sensitive pore-forming inwardly rectifying potassium channel (Kir6.x) subunits (Kir6.1 or Kir6.2) [ 20 ]. (biomedcentral.com)

Thus, conditional temperature-sensitive mutations in the Drosophila melanogaster gene for NSF lead to a comatose behaviour at the restrictive temperature (and hence the gene is called comatose), presumably because neuronal functions are blocked. (wikipedia.org)
Neuronal loss of the serine-threonine protein kinase Tao , a regulator of the Hippo signaling pathway, results in supernumerary boutons, each of which contain a normal number of active zones. (sdbonline.org)

much 75 cytosol of pairing substrates are in 1500 220 KDa proteins with IGFBP3 and ALS. (evakoch.com)
Here we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed 'Site #1', can also bind additional LRRK2 substrates, Rab8A and Rab10. (stanford.edu)

[ 1 ] Neutrophils move to the site of invasion by means of chemotaxis, which occurs in response to microbial products, activated complement proteins, and cytokines. (medscape.com)

Orthologous to human NAPA (NSF attachment protein alpha). (nih.gov)

Intercellular adhesion molecule 5, which binds to and activates integrins, may be a direct target of perisynaptic MMP proteolysis during LTP. (nature.com)
Because we have shown earlier that prenylation and subsequent methylation/demethylation of γ subunits are required for the Gβγ-MTs interaction in vitro , small-molecule inhibitors (L-28 and L-23) targeting prenylated methylated protein methyl esterase (PMPMEase) were tested in the current study. (biomedcentral.com)

Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. (shengsci.com)

Opsonins are often antibodies or components of the complement pathway that bind to the surface of target organisms to facilitate this phagocytosis. (medscape.com)
In this study, we demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an essential component of the cytokine secretory pathway in CD4 + T cells. (aai.org)
The download Hanging Sam: A Military Biography of General of Insulin like Growth Factor Binding Proteins( IGFBPs) phase 50 response pathway good research with reviewed N cell and C formation enzymes binding for conjugating Insulin like Growth Factors I and II( IGF I and IGF II). (evakoch.com)
Key interacting proteins of the plasma membrane, the cytosol and the vesicle membrane which function in the membrane fusion pathway, have been identified in a variety of cell types and characterized at the molecular level [10-14] . (ommegaonline.org)

N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSF gene. (wikipedia.org)
This gene encodes soluble NSF attachment protein gamma. (antibodies-online.com)
Na(+) influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation. (nih.gov)
Mutations of a gene sequence can modify the interfaces or domains of its protein product and lead to the emergence of new or loss of existing protein interaction patterns [ 11 ]. (biomedcentral.com)

The Endoplasmic Reticulum (ER) is an important eukaryotic cell organelle that has various functions, including the synthesis of proteins for export and quality control of nascent proteins. (eu.org)
Some cell wall polysaccharide synthesis and cytoskeleton formation-related proteins were up-regulated by JA to promote tuber cell expansion. (biomedcentral.com)
We focus on zebrafish mutants, in which photoreceptor degeneration is caused by defects in protein synthesis in ER, protein transport from ER to the apical photoreceptive membrane region, and phototransduction. (oist.jp)

New insights into protein secretion: TANGO1 runs rings around the COPII coat. (uchicago.edu)

However, support for the third model is missing at the physiological level, and it is unclear which role the two suggested binding modes play in the exocytotic cascade. (jneurosci.org)
The expression of Insulin and Pancreatic and duodenal homeobox-1 mRNA was significantly reduced in MIPβ1KO islets, along with reductions in insulin exocytotic proteins. (oncotarget.com)

N-ethylmaleimide sensitive fusion protein has been shown to interact with NAPA. (wikipedia.org)
As for many essential biological processes, intracellular membrane fusion is mediated by interactions among a series of evolutionarily conserved proteins. (biomedcentral.com)
These diverse functions performed by the acrosomal segment during fertilization reveal the importance of identifying the specific signaling events and protein constituents which initiate and regulate the membrane fusion process of the acrosome reaction and prepare spermatozoa to fuse with the egg. (ommegaonline.org)

In Dictyostelium discoideum amoebae, similar mutations lead to a cessation of cell movement at the restrictive temperature, indicating a role for intracellular membrane transport in migration. (wikipedia.org)
Emerging evidence suggests that lysosomes may also be the cellular center for intracellular transport (Fig. 1 ), signaling (Fig. 2 ), and metabolism. (biomedcentral.com)
Lysosomes play a crucial role in intracellular transport. (biomedcentral.com)
The main structural coat protein of COATED VESICLES which play a key role in the intracellular transport between membranous organelles. (lookformedical.com)
Vesicular Transport Proteins" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (uchicago.edu)
A broad category of proteins involved in the formation, transport and dissolution of TRANSPORT VESICLES. (uchicago.edu)
They play a role in the intracellular transport of molecules contained within membrane vesicles. (uchicago.edu)
This graph shows the total number of publications written about "Vesicular Transport Proteins" by people in this website by year, and whether "Vesicular Transport Proteins" was a major or minor topic of these publications. (uchicago.edu)
Below are the most recent publications written about "Vesicular Transport Proteins" by people in Profiles. (uchicago.edu)
We also study the NPC1 protein that is essential for cholesterol transport in humans and can lead to Niemann Pick C disease when mutated. (stanford.edu)

Although it is highly homologous to G-PROTEIN-COUPLED RECEPTOR KINASE 2, it is not considered to play an essential role in regulating myocardial contractile response. (lookformedical.com)
A G-protein-coupled receptor kinase subtype that is primarily expressed in the MYOCARDIUM and may play a role in the regulation of cardiac functions. (lookformedical.com)

In the last few years dramatic advances have been achieved towards elucidating some of the molecular events involved, and a previously unsuspected complexity of proteins that selectively interact directly or indirectly with individual AMPA receptor subunits have been identified. (portlandpress.com)
Several isoforms of the protein with molecular sizes of 47 kDa and 52 kDa exist due to multiple ALTERNATIVE SPLICING. (lookformedical.com)
The long term goal of our research is to elucidate the molecular mechanisms by which proteins are targeted to specific and distinct compartments. (stanford.edu)

The SHP box forms a short, antiparallel β-strand that interacts by β-augmentation with the β-sheet of the C-terminal part of the NTD subdomain of VCP at a site distinct from that to which other VCP ligands bind. (eu.org)
The N-terminal loop region of the SHP motif interacts with the first pocket, while the central β strand of the motif makes key interactions with the second binding pocket. (eu.org)

The AffiAB® Goat Anti-STX6 Polyclonal IgG Antibody is an antibody derived from goats that specifically targets and binds to STX6, also known as Syntaxin 6. (affigen.com)
Enables syntaxin binding activity. (nih.gov)

Eye proteins are the biological molecules that make up the various structures of the eye and are essential for its proper function. (lookformedical.com)
Many of the biological processes mediated by protein interaction networks are highly evolutionarily conserved or related across species. (biomedcentral.com)

Integrating the dynamics across species is particularly important in modeling cellular processes through protein interaction networks. (biomedcentral.com)
The results revealed that the levels of a number of proteins involved in various cellular processes were regulated by JA during tuber development. (biomedcentral.com)

Therefore this study provides a new method to solve the discrepancies and to generalize the functional role of SM proteins. (biomedcentral.com)

Find NAPG Proteins for a variety of species such as anti-Human NAPG, anti-Arabidopsis thaliana NAPG, anti-Mouse NAPG. (antibodies-online.com)

they identified NSF after observing that a cytoplasmic factor, required for membrane fusions, was inactivated by treatment with N-ethylmaleimide. (wikipedia.org)
Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. (bvsalud.org)
The M-type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (TSHD7A), and neural epidermal growth factor-like 1 protein (NELL-1) are major autoantigens against podocyte antigens in idiopathic membranous nephropathy (IMN) [ 1 ]. (biomedcentral.com)

The resulting molecules show superior functional properties for their respective applications and demonstrate the generalizable potential of the described protein design approach. (bvsalud.org)
Here I present an overview of some of the main interacting proteins, and describe what we know about how these may fit into cellular pathways that control AMPA receptor targeting, trafficking and functional expression. (portlandpress.com)
A total of 257 differentially expressed proteins (DEPs) were identified by iTRAQ, which provided a comprehensive overview on the functional protein profile changes of tuber development regulated by JA. (biomedcentral.com)

A beta-hairpin comprising the nuclear localization sequence sustains the self-associated states of nucleosome assembly protein 1. (colorado.edu)

The C-terminal region of the motif is stabilized by a loop-loop interaction at the third binding pocket. (eu.org)
interaction( Hh) is a bound transfer that is very proteins in modifications resulting past plasma mRNA, fibril-associated information DNA, isoform kinase and activity( characterised in Hui and Angers, 2011). (evakoch.com)

Three motifs known to bind to the N-terminal domain of VCP are the SHP box, VIM (VCP-Interacting Motif), and VBM (VCP-Binding Motif) and they help direct VCP into different cellular pathways. (eu.org)

A pure form of proteolytic enzyme is used to hydrolyze the protein to produce short peptide sequences. (psyclopeptide.com)

They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid, N -ethylmaleimide or p -chloromercuribenzoate. (embl.de)
These are the ' zinc-binding cellular acid ' sugar and the ' genome resulting ' history. (evakoch.com)

However, the use of mutant expression in the presence of endogenous protein left it unclear how the observed effects were related to the defect of vesicle docking in (M)unc18-1 knock-outs. (jneurosci.org)

The helical VIM and VBM motifs bind to the same groove but through different key residues. (eu.org)

A purplish-red, light-sensitive pigment found in RETINAL ROD CELLS of most vertebrates. (lookformedical.com)
Although the members of these protein families are widely distributed among various types of somatic cells [10,11] , it is not known whether related proteins function in the acrosome reaction. (ommegaonline.org)
In the renal glomeruli, VEGFA is mainly expressed in and secreted from podocytes and tubular epithelial cells, which induces renal injury through binding to the receptor VEGFR, mainly VEGFR2, which is expressed on the surface of endothelial cells [ 8 ]. (biomedcentral.com)

De novo protein design can readily address these challenges. (bvsalud.org)

SNARE14

Vesicle fusion2

Soluble NSF attachment proteins2

Membrane proteins2

Peptides3

HETEROTRIMERIC G-PROTEI3

Extracellular3

Cytosolic proteins1

Cytoskeletal proteins2

Munc186

Phosphorylation2

Degradation5

Synaptic1

Lipid2

Genes3

Yeast2

Receptors8

Vivo1

Mediate2

Antigen2

Membranes1

Recombinant2

Regulatory3

Neuronal2

Substrates2

Cytokines1

Attachment protein alpha1

Molecule2

Tyrosine kinase1

Pathway4

Gene4

Synthesis3

Secretion1

Exocytotic2

Fusion3

Transport10

Receptor Kinase2

Molecular3

Interacts2

Syntaxin2

Biological2

Cellular processes2

Role1

Arabidopsis1

Factor3

Functional3

Localization1

Interaction2

Pathways1

Sequences1

Acid2

Unclear1

Helical1

Cells3

Novo1