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One way for cells to respond appropriately to current physiological conditions is to sense and integrate more than one signal. A good example comes from glycogenolysis, the hydrolysis of glycogen to yield glucose 1-phosphate. In Chapter 13, we saw that a rise in cAMP induced by epinephrine stimulation of $\beta$ -adre... | {
"Header 1": "INTEGRATION OF SIGNALS AND GENE CONTROLS",
"Header 2": "Integration of Multiple Second Messengers Regulates Glycogenolysis",
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In the regulation of glycogenolysis, neural and hormonal signals regulate the same key multimeric enzyme. In contrast, the maintenance of normal blood glucose concentrations depends on the balance between two hormones that elicit different cell responses. During periods of stress, the epinephrine-induced increase in gl... | {
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"Header 2": "Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level",
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HIF-1 is a dimer composed of two subunits, $\alpha$ and $\beta$ . The $\beta$ subunit is abundant in the cytosol under high or low oxygen conditions but, when oxygen is plentiful, the $\alpha$ subunit (HIF $\alpha$ ) is ubiquitinated and degraded in proteasomes (Chapter 3). Ubiquitination is promoted by the von H... | {
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This allows each transgenic fly line to survive, even if the activation of the gene will prove lethal in the progeny of the cross.

#### **(c) Creating mosaic tissues with clones of cells that lack a gene function**
Yeast FLP recombinase, acting upon FRT sequences inserted near the cen... | {
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This structure develops from a group of epidermal vulval precursor cells (VPCs) whose fates are controlled by an inductive signal from a nearby cell called the anchor cell. All the VPCs have the potential to become any of three different cell types: 1 and 2, which refer to different vulval cell types, and 3, which is a... | {
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These early patterning events set the stage for the later development and proper placement of different tissues (e.g., muscle, nerve, epidermis) and body parts, as well as the shapes of the appendages and the organization of cell types within them. Because the early embryo is initially symmetric side to side, the creat... | {
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Thus the signaling has come full circle: Gurken ligand produced dorsally in oocyte → activation of its EGF-like receptor on dorsal follicle cells, and then back through the protease cascade on the ventral side → Spätzle ligand → activation of its receptor, Toll, on the ventral side of the embryo. The net effect is to c... | {
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For example, *bicoid* mRNA is trapped at the most anterior region, or anterior pole, of the early fly embryo (Figure 15-19). The anterior localization of

▲ **EXPERIMENTAL FIGURE 15-19 Maternally derived** *bicoid* **mRNA is localized to the anterior region of early** *Drosophila* **emb... | {
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elegans.* Even more intriguing is the discovery that Bicoid protein binds

▲ **FIGURE 15-21 Role of Nanos protein in excluding maternally derived Hunchback (Hb) protein from the posterior region of** *Drosophila* **embryos.** (a) Both *nanos* (red) and *hunchback (hb)* (blue) mRNAs deriv... | {
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The sequence similarity between gap proteins and nuclear receptors suggests that gap genes may have evolved from genes whose transcription was controlled by signals that could cross membranes, such as the steroid hormones. The use of such signal-controlled genes, rather than transcription cascades, could explain how ea... | {
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Because some segment-polarity genes encode components of cell–cell signaling systems, they are discussed in Section 15.5.
Figure 15-24a schematically depicts the distribution of some key regulators in the *Drosophila* embryo during the first few hours after fertilization. When all the segmentation genes have been tur... | {
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**Floral Organs** A flower comprises four different organs called sepals, petals, stamens, and carpels, which are arranged in concentric circles called whorls. Whorl 1 is the outermost; whorl 4, the innermost. *Arabidopsis* has a complete set of floral organs, including four sepals in whorl 1, four petals in whorl 2,... | {
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#### **Boundary Creation by Extracellular Signals 15.5**
As the syncytial fly embryo becomes cellular and undergoes gastrulation, the movement of proteins and mRNAs through the common cytoplasm of a syncytium is over. Further cellfate specification is controlled primarily by cells communicating with one another thr... | {
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Findings from genetic studies in *Drosophila* indicate that two membrane proteins, Smoothened (Smo) and Patched (Ptc), are required to receive and transduce a Hedgehog signal to the cell interior. Smoothened has 7 membrane-spanning $\alpha$ helices, similarly to G protein–coupled receptors (Chapter 13). Patched is pr... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
As noted previously, the *Drosophila* segment-polarity gene wingless encodes a protein that belongs to the Wnt family of secreted signals. Inactivation of wingless causes segment-polarity defects very similar to those caused by the loss of hedgehog function. This observation is logical because Hedgehog and Wingless for... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
In the dorsal region, BMP proteins secreted from the overlying ectoderm cells act in a similar fashion to create dorsal cell fates. [See
T. M. Jessell, 2000, *Nature Rev. Genet.* **1**:20.]
#### **Cell-Surface Proteoglycans Influence Signaling by Some Pathways**
How do signals move through or around cells embedde... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
In *ephrin-B2* knockout mice, angiogenesis is blocked at the primary plexus stage. The absence of ephrin-B2 thus interrupts the development of both arteries and veins. (c) Formation of intercalating arteries and veins results from interactions between developing arterial and venous endothelial cells mediated by ephrin-... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
(b) Initially, *achaete (ac)* and other proneural genes are transcribed in all the cells within a proneural cluster, as are

*Notch* and *Delta.* Achaete and other proneural bHLH proteins promote expression of *Delta.* When one cell at random begins to produce slightly more Achaete (*le... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
Several classes of cell-surface receptors discussed in Chapters 13 and 14 are linked to more than one intracellular signaltransduction pathway (see Table 14-1). Multiple intracellular signaling possibilities are most evident with G protein-coupled receptors, cytokine receptors, and receptor tyrosine kinases. This pheno... | {
"Header 1": "**A FIGURE 15-30 Processing of Hedgehog (Hh) precursor protein.** Removal of the N-terminal signal peptide from the initial translation product yields the 45-kDa Hh precursor consisting of residues 83–471 in the original protein. Nucleophilic attack by the thiol side chain of cysteine 258 (Cys-258) on ... |
Vertebrate limbs grow from small "buds" composed of an inner mass of mesoderm cells surrounded by a sheath of ectoderm. Secreted signals from both cell layers coordinate limb development and instruct cells about their proper fates within limbs. The first signal, fibroblast growth factor 10 (FGF10) is secreted from the ... | {
"Header 1": "**A FIGURE 15-40 Sequential action of critical signals in** *Drosophila* muscle development. Signal transduction through the RTK pathway is governed by Wnt and TGF $\\beta$ signals. Wingless (Wg) is produced in a stripe of cells running in a belt around part of each body segment of the embryo (purple).... |
Piccolo et al., 1997, *Cell* 91:407.]

(b) Release of inhibition by xolloid

animal cap produces BMP4, a member of the TGFβ family of signals, and will therefore not produce neural tissue. The effect of signals and other regulators on neural induction can... | {
"Header 1": "**A FIGURE 15-40 Sequential action of critical signals in** *Drosophila* muscle development. Signal transduction through the RTK pathway is governed by Wnt and TGF $\\beta$ signals. Wingless (Wg) is produced in a stripe of cells running in a belt around part of each body segment of the embryo (purple).... |
*dorsal* mutant embryos could be expected to yield information on all genes regulated by the Dorsal protein. Why? Other than new genes regulated by Dorsal, one would expect to see changes in regulation of previously identified genes. Which genes would be increased or decreased in expression in *dorsal* mutants?
- **7.*... | {
"Header 1": "**A FIGURE 15-40 Sequential action of critical signals in** *Drosophila* muscle development. Signal transduction through the RTK pathway is governed by Wnt and TGF $\\beta$ signals. Wingless (Wg) is produced in a stripe of cells running in a belt around part of each body segment of the embryo (purple).... |
#### Reciprocal Induction and Lateral Inhibition
Artavanis-Tsakonas, S., M. D. Rand, and R. J. Lake. 1999. Notch signaling: cell fate control and signal integration in development. *Science* **284**:770–776.
Cooke, J. E., and C. B. Moens. 2002. Boundary formation in the hindbrain: Eph only it were simple. *Trends... | {
"Header 1": "**A FIGURE 15-40 Sequential action of critical signals in** *Drosophila* muscle development. Signal transduction through the RTK pathway is governed by Wnt and TGF $\\beta$ signals. Wingless (Wg) is produced in a stripe of cells running in a belt around part of each body segment of the embryo (purple).... |

A live bovine endothelial cell stained to reveal different intracellular compartments. The lacelike membranes of the endoplasmic reticulum were stained with a green fluorescent dye, and the wormlike mitochondria were stained with an orange fluorescent dye. [Molecular Probes, Inc.]
typi... | {
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Pancreatic acinar cells, for instance, synthesize large quantities of several digestive enzymes that are secreted into ductules that lead to the intestine. Because such secretory cells contain the organelles of the secretory pathway (e.g., ER and Golgi) in great abundance, they have been widely used in studying this pa... | {
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The soluble SRP receptor fragment, however, retains its ability to interact with the SRP/nascent chain/ribosome complex, causing release of SRP and allowing chain elongation to proceed. Thus the SRP and SRP receptor not only help mediate interaction of a ▲ **FIGURE 16-5 Structure of the signal-recognition particle (SRP... | {
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When ribosomes were added, translocons (blue) reassembled in artificial phospholipid bilayers. The resulting particles were frozen, and electron micrographs of a large number of particles were generated, stored in a computer, and then averaged to produce a single image. A representation of the approximate size and posi... | {
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Topological classes I, II, and III comprise *single-pass* proteins, which have only one membranespanning -helical segment. Type I proteins have a cleaved N-terminal signal sequence and are anchored in the membrane with their hydrophilic N-terminal region on the luminal face (also known as the **exoplasmic face**) and t... | {
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The nascent chain becomes oriented in the translocon with its N-terminal portion toward the cytosol. This orientation is believed to be mediated by the positively charged residues shown N-terminal to the signal-anchor sequence. Step 2: As the chain is elongated and extruded into the lumen, the internal signal-anchor mo... | {
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Nat'l. Acad. Sci. USA* **89**:4982.] ▲
stop-transfer anchor sequence and transfers the remainder of the protein to a preformed GPI anchor in the membrane (Figure 16-14b).
Why change one type of membrane anchor for another? Attachment of the GPI anchor, which results in removal of the cytosol-facing hydrophilic doma... | {
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Membrane and soluble secretory proteins synthesized on the rough ER undergo four principal modifications before they reach their final destinations: (1) addition and processing of carbohydrates (glycosylation) in the ER and Golgi, (2) formation of disulfide bonds in the ER, (3) proper folding of polypeptide chains and ... | {
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"Header 2": "16.3 Protein Modifications, Folding, and Quality Control in the ER",
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Biosynthesis of all *N*-linked oligosaccharides begins in the rough ER with addition of a preformed oligosaccharide precursor containing 14 residues (Figure 16-16). The structure of this precursor is the same in plants, animals, and single-celled eukaryotes—a branched oligosaccharide, containing three glucose (Glc), ni... | {
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"Header 2": "A Preformed *N*-Linked Oligosaccharide Is Added to Many Proteins in the Rough ER",
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The oligosaccharides attached to glycoproteins serve various functions. For example, some proteins require N-linked oligosaccharides in order to fold properly in the ER. This function has been demonstrated in studies with the antibiotic tunicamycin, which blocks the first step in formation of the dolichol-linked precur... | {
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"Header 2": "Oligosaccharide Side Chains May Promote Folding and Stability of Glycoproteins",
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Dolichol phosphate is a strongly hydrophobic lipid, containing 75–95 carbon atoms, that is embedded in the ER membrane. Two *N*-acetylglucosamine (GlcNAc) and five mannose residues are added one at a time to a dolichol phosphate on the cytosolic face of the ER membrane (steps 11–12). The nucleotide-sugar donors in thes... | {
"Header 1": "MOVING PROTEINS INTO MEMBRANES AND ORGANELLES",
"Header 2": "▲ FIGURE 16-17 Biosynthesis of the dolichol pyrophosphoryl oligosaccharide precursor of *N*-linked oligosaccharides.",
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After it became clear that disulfide-bond formation occurs spontaneously only in the ER lumen, biotechnologists eventually developed expression vectors that can be used in animal cells (Chapter 9). Nowadays, such vectors and cultured animal cells are preferred for large-scale production of therapeutic proteins such as ... | {
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Other important protein-folding catalysts in the ER lumen are *peptidyl-prolyl isomerases*, a family of enzymes that accelerate the rotation about peptidyl-prolyl bonds in unfolded segments of a polypeptide:
$$\begin{array}{c} \text{O} \\ \text{C} \\ \text{C} \\ \text{C} \\ \text{N} \\ \text{C} \\ \text{H}_2 \\ \te... | {
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"Header 2": "▲ FIGURE 16-17 Biosynthesis of the dolichol pyrophosphoryl oligosaccharide precursor of *N*-linked oligosaccharides.",
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A total of seven *N*-linked oligosaccharide chains are added to the luminal portion of the nascent chain during cotranslational translocation, and PDI catalyzes the formation of six disulfide bonds per monomer. Completed HA0 monomers are anchored in the membrane by a **1a 1b**
single membrane-spanning helix with thei... | {
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#### **KEY CONCEPTS OF SECTION 16.3**
#### **Protein Modifications, Folding, and Quality Control in the ER**
- All *N*-linked oligosaccharides, which are bound to asparagine residues, contain a core of three mannose and two *N*-acetylglucosamine residues and usually have several branches (see Figure 16-16).
- *O*... | {
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polypeptide segment through the channel (steps 1, 2). Repetition of this cycle results in movement of the polypeptide through the channel in one direction. Current evidence indicates that the N-terminal signal sequence moves from the channel into the bilayer but at some point is cleaved by a signal peptidase, so that t... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Quite different mechanisms from the one shown in Figure 16-23 are used to translocate bacterial proteins from the cytosol across both the inner and outer bacterial membranes to the extracellular space. These secretion mechanisms are particularly important for pathogenic bacteria, which commonly use secreted extracellul... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Yersinia pestis is the bacterial species responsible for the bubonic plague, one of the deadliest diseases in human history. One reason Yersinia is such a virulent pathogen lies in its ability to disable host macrophage cells that might otherwise engulf and destroy the invading bacterial cells. The incapacitating effec... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
| Target Organelle | Location of Sequence<br>Within Protein | Removal of<br>Sequence | Nature of Sequence |
|----------------------------------|--------------------------... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
As discussed in Chapter 3, chaperonin proteins actively facilitate protein folding in a process that depends on ATP. For instance, yeast mutants defective in Hsc60, a chaperonin in the mitochondrial matrix, can import matrix proteins and cleave their uptake-targeting sequence normally, but the imported polypeptides fai... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Unlike targeting to the matrix, targeting of proteins to the intermembrane space, inner membrane, and outer membrane of mitochondria generally requires more than one targeting sequence and occurs via one of several pathways. Figure 16-28 summarizes the organization of targeting sequences in proteins sorted to different... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Proteins with different targeting sequences are directed to the inner membrane via different pathways. In all three pathways, proteins cross the outer membrane via the Tom40 general import pore. Proteins delivered by pathways A and B contain an N-terminal matrix-targeting sequence that is recognized by the Tom20/22 imp... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Import into the stroma depends on ATP hydrolysis catalyzed by a stromal Hsc70 chaperone whose function is similar to Hsc70 in the mitochondrial matrix and BiP in the ER lumen. Unlike mitochondria, chloroplasts cannot generate an electrochemical gradient (proton-motive force) across their inner membrane. Thus protein im... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
By testing various mutant catalase proteins in this system, researchers discovered that the sequence Ser-Lys-Leu (SKL in one-letter code) or a related sequence at the C-terminus was necessary for peroxisomal targeting. Further, addition of the SKL sequence to the C-terminus of a normally cytosolic protein leads to upta... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Neither targeting sequence is cleaved after import.
- All proteins destined for the peroxisomal matrix bind to a cytosolic receptor, which differs for PTS1- and PTS2-

#### ▲ **FIGURE 16-34 Model of peroxisomal biogenesis and**
**division.** The first stage in the de novo formation o... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
- **8.** Describe how you might use recombinant DNA to engineer a strain of *Yersinia* such that it would be capable of inserting a protein of interest into the cytosol of mammalian macrophage cells.
- **9.** Describe what would happen to the precursor of a mitochondrial matrix protein in the following types of mitoc... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Opin. Cell Biol.* **13**:349–355.
Plemper, R. K., and D. H. Wolf. 1999. Retrograde protein translocation: eradication of secretory proteins in health and disease. *Trends Biochem. Sci.* **24**:266–270.
Sevier, C. S., and C. A. Kaiser. 2002. Formation and transfer of disulphide bonds in living cells. *Nature Rev. Mo... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |

Electron micrograph of clathrin cages, like those that surround clathrin-coated transport vesicles, formed by the in vitro polymerization of clathrin heavy and light chains. [John Heuser, Washington University School of Medicine.]
n the previous chapter we explored how proteins are tar... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Because the radioactive amino acids were administered in a short pulse, only those proteins synthesized immediately after injection were labeled, forming a distinct group, or cohort, of labeled proteins whose transport could be followed. In addition, because pancreatic acinar cells are dedicated secretory cells, almost... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
The general organization of the secretory pathway and many of the molecular components required for vesicle trafficking are similar in all eukaryotic cells. Because of this conservation, genetic studies with yeast have been useful in confirming the sequence of steps in the secretory pathway and in identifying many of t... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
#### (a) Coated vesicle budding

#### (b) Uncoated vesicle fusion

▲ **FIGURE 17-7 Overview of vesicle budding and fusion with a target membrane.** (a) Budding is initiated by recruitment of a small GTP-binding protein to a patch of donor membrane. Com... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Drawing on the structural similarities of Sar1 and ARF to other small GTPase switch proteins, researchers have

▲ **FIGURE 17-9 Model for the role of Sar1 in the assembly and disassembly of COPII coats.** Step : Interaction of soluble GDP-bound Sar1 with the exchange factor Sec12, an ... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
After Rab-mediated docking of a vesicle on its target (destination) membrane, the interaction of cognate SNAREs brings the two membranes close enough together that they can fuse.
One of the best-understood examples of SNARE-mediated fusion occurs during exocytosis of secreted proteins (Figure 17-11, steps 2 and 3 ). ... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
(a) At pH ≈7, part of each HA1 subunit forms a globular domain (green) at the tip of the native spike. These domains bind to sialic acid residues on the host-cell plasma membrane, initiating viral entry. Each HA1 subunit is linked to one HA2 subunit by a disulfide bond at the base of the molecule near the viral envelop... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
4 6 1 3
vesicle transport serves to retrieve v-SNARE proteins and the membrane itself back to the ER to provide the necessary material for additional rounds of vesicle budding from the ER. COPI-mediated retrograde transport also retrieves missorted ER-resident proteins from the *cis*-Golgi to correct sorting mistakes... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Clearly, the partitioning of proteins between the ER and Golgi complex is a highly selective and regulated process ultimately controlled by the specificity of cargo loading into both COPII (anterograde) and COPI (retrograde) vesicles. The selective entry of proteins into membrane-bounded transport vesicles, the recyc... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Presley et al., 1997, *Nature* **389**:81.] 5 4 3 2 1
#### **Vesicles Coated with Clathrin and/or Adapter Proteins Mediate Several Transport Steps**
The best-characterized vesicles that bud from the *trans-*Golgi network (TGN) have a two-layered coat: an outer layer composed of the fibrous protein clathrin and an i... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Conformational changes that occur when ARF switches from the GTP-bound to GDP-bound state are thought to regulate the timing of clathrin coat depolymerization. How the action of Hsc70 might be coupled to ARF switching is not well understood.
#### **Mannose 6-Phosphate Residues Target Soluble Proteins to Lysosomes** ... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Specialized secretory cells also store other proteins in vesicles and secrete them only when triggered by a specific stimulus. One example of such *regulated secretion* occurs in pancreatic cells, which store newly made insulin in special secretory vesicles and secrete insulin in response to an elevation in blood gluco... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
#### **Several Pathways Sort Membrane Proteins to the Apical or Basolateral Region of Polarized Cells**
The plasma membrane of polarized epithelial cells is divided into two domains, **apical** and **basolateral;** tight junctions located between the two domains prevent the movement of plasma-membrane proteins betw... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
#### **Receptor-Mediated Endocytosis and the Sorting of Internalized Proteins 17.5**
In previous sections we have explored the main pathways whereby secretory and membrane proteins synthesized on the rough ER are delivered to the cell surface or other destinations. Cells also can internalize materials from their su... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
A mutation in any of the conserved residues of the NPXY signal will abolish the ability of the LDL receptor to be incorporated into coated pits.
A small number of individuals who exhibit the usual symptoms associated with familial hypercholesterolemia produce normal LDL receptors. In these individuals, the gene encod... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
At a pH below 6.0, the two bound Fe<sup>3+</sup> atoms dissociate from ferrotransferrin, are reduced to Fe<sup>2+</sup> by an unknown mechanism, and then are exported into the cytosol by an endosomal transporter specific for divalent metal ions. The receptor-apotransferrin complex remaining after dissociation of the ir... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
The major function of lysosomes is to degrade extracellular materials taken up by the cell and intracellular components under certain conditions. Materials to be degraded must be delivered to the lumen of the lysosome where the various degradative enzymes reside. As just discussed, endocytosed ligands (e.g., LDL partic... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Ubiquitinated Gag near a budding particle functions like Hrs. See text for discussion. [Adapted from O. Pornillos et al., 2002, *Trends Cell Biol.* **12**:569.] 4 6 3 2

shell, producing a structure that looks like a vesicle bud protruding outward from the plasma membrane. Mutational stu... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
The exocytosis of neurotransmitters from synaptic vesicles involves targeting and fusion events similar to those that lead to release of secreted proteins in the secretory pathway. However, several unique features permit the very rapid release of neurotransmitters in response to arrival of an action potential at the pr... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Fusion of synaptic vesicles with the plasma membrane of axon terminals depends on the same proteins that mediate membrane fusion of other regulated secretory vesicles. The principal v-SNARE in synaptic vesicles (VAMP) tightly binds syntaxin and SNAP-25, the principal t-SNAREs in the plasma membrane of axon terminals, t... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Synaptic vesicles are formed primarily by endocytic budding from the plasma membrane of axon terminals. Endocytosis usually involves clathrin-coated pits and is quite specific, in that several membrane proteins unique to the synaptic vesicles (e.g., neurotransmitter transporters) are specifically incorporated into the ... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
Propose an experiment to test whether the effect of EAGE microinjection is initially on anterograde or retrograde transport.
- **6.** Specificity in fusion between vesicles involves two discrete and sequential processes. Describe the first of the two processes and its regulation by GTPase switch proteins. What effect o... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |
#### Molecular Mechanisms of Vesicular Traffic
Jahn, R., et al. 2003. Membrane fusion. *Cell* **112**:519–533.
Kirchhausen, T. 2000. Three ways to make a vesicle. *Nature Rev. Mol. Cell Biol.* **1**:187–198.
McNew, J. A., et al. 2000. Compartmental specificity of cellular membrane fusion encoded in SNARE protei... | {
"Header 1": "▲ FIGURE 16-23 Post-translational translocation across inner membrane in gram-negative bacteria. The bacterial inner membrane contains a translocon channel composed of three subunits that are homologous to the components of the eukaryotic Sec61 complex. Translocation of polypeptides from the cytosol to... |

**Fluorescence micrograph of hamster intestinal epithelium after cellular uptake into lipid droplets of an orally administered fluorescent analog of cholesterol (fluoresterol, dissolved in corn oil) from the intestinal lumen (upper left, unstained).** [C. P. Sparrow et al., 1999, *J. Lip... | {
"Header 1": "**18**",
"Header 2": "**METABOLISM AND MOVEMENT OF LIPIDS**",
"token_count": 1206,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
A cell cannot divide or enlarge unless it makes sufficient amounts of additional membranes to accommodate the expanded area of its outer surface and internal organelles. Thus the generation of new cell membranes is as fundamentally important to the life of a cell as is protein synthesis or DNA replication. Although the... | {
"Header 1": "**18**",
"Header 2": "18.1 Phospholipids and Sphingolipids: Synthesis and Intracellular Movement",
"token_count": 339,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Fatty acids are key components of both phospholipids and sphingolipids; they also anchor some proteins to cellular membranes (see Figure 5-15). Thus the regulation of fatty acid synthesis plays a key role in the regulation of membrane synthesis as a whole. A fatty acid consists of a long hydrocarbon chain with a carbox... | {
"Header 1": "**18**",
"Header 2": "Fatty Acids Are Precursors for Phospholipids and Other Membrane Components",
"token_count": 1297,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Unesterified fatty acids within cells are commonly bound by *fatty acid-binding proteins* (FABPs), which belong to a group of small cytosolic proteins that facilitate the intracellular movement of many lipids. These proteins contain a hydrophobic pocket lined by $\beta$ sheets (Figure 18-3). A long-chain fatty acid c... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2027,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
These vesicles were obtained by introducing cDNA encoding mammalian ABCB4 into a temperature-sensitive
| TABLE 18-2 | Selected Human ABC Proteins | | |
|--------------|---------... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2037,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Mevalonate, the 6-carbon product formed by HMG-CoA reductase, is converted in several steps into the 5-carbon isoprenoid compound isopentenyl pyrophosphate (IPP) and its stereoisomer dimethylallyl pyrophosphate (DMPP). These reactions are catalyzed by cytosolic enzymes, as are the subsequent reactions in which six IP... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2007,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
In mechanism (c), transfer is
an N-terminal targeting sequence that directs the protein to the mitochondrial outer membrane (Chapter 16) and a C-terminal START (StAR-related transfer) domain that has a cholesterolbinding hydrophobic pocket. Similar START domains are found in several proteins implicated in intracellul... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2045,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Several integral membrane proteins have been shown to participate in fatty acid import in cell culture and whole-animal experiments. These proteins include various *fatty acid transport proteins (FATPs)* and the multifunctional cell-surface protein *CD36.* These transporters mediate the movement of substrates down thei... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2038,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
| Major Classes of Human Plasma Lipoproteins<br>TABLE 18-3 | | ... | {
"Header 1": "**18**",
"Header 2": "Unesterified Fatty Acids Move Within Cells Bound to Small Cytosolic Proteins",
"token_count": 2007,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
For maximum efficiency, the lipids within circulating lipoproteins should be taken up only by those cells that require them for membrane formation (e.g., dividing cells), steroid hormone synthesis (e.g., endocrine cells), energy production (e.g., muscle cells), or storage (adipose cells, endocrine cells). The targeting... | {
"Header 1": "**18**",
"Header 2": "Cells Use Several Protein-Mediated Mechanisms to Import Lipoprotein Lipids",
"token_count": 2029,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
1215.]
leading to its premature degradation (Chapter 16); still other mutations reduce the ability of the LDL receptor to bind LDL tightly. A particularly informative group of mutant receptors are expressed on the cell surface and bind LDL normally but cannot mediate the internalization of bound LDL. Analyses of such... | {
"Header 1": "**18**",
"Header 2": "Cells Use Several Protein-Mediated Mechanisms to Import Lipoprotein Lipids",
"token_count": 777,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Findings from studies of HDL metabolism led to the discovery of a second, distinct mechanism of receptor-facilitated uptake of lipoprotein lipids. In these studies, experimental animals were injected with purified HDL particles in which the apolipoproteins were labeled with 125 I and the core cholesteryl esters were la... | {
"Header 1": "**18**",
"Header 2": "Cholesteryl Esters in Lipoproteins Can Be Selectively Taken Up by the Receptor SR-BI",
"token_count": 2035,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
SREBP has three distinct domains: an N-terminal cytosolic domain that includes a basic helix-loop-helix (bHLH) DNA-binding motif (see Figure 11-22b) and functions as a transcription factor, a central membrane-anchoring domain containing two transmembrane helices, and a C-terminal cytosolic regulatory domain. SCAP has e... | {
"Header 1": "**18**",
"Header 2": "Cholesteryl Esters in Lipoproteins Can Be Selectively Taken Up by the Receptor SR-BI",
"token_count": 2033,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
This domain senses high levels of cholesterol, some cholesterol derivatives, and certain nonsteroidal precursors of cholesterol, triggering the rapid, ubiquitin-dependent proteasomal degradation of the enzyme. As a consequence, HMG-CoA reductase activity drops, causing reduced cholesterol synthesis. Like SCAP, HMG-CoA ... | {
"Header 1": "**18**",
"Header 2": "Cholesteryl Esters in Lipoproteins Can Be Selectively Taken Up by the Receptor SR-BI",
"token_count": 1888,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
For instance, macrophages and other leukocytes release proteins and small molecules
#### (a) Normal artery wall (b) Fatty streak stage


(c) Atheroslerotic plaque stage (d) Rupture of endothelium and occlusive blood clot formation
 by Site-1/2 proteases... | {
"Header 1": "**18**",
"Header 2": "Two Treatments for Atherosclerosis Are Based on SREBP-Regulated Cellular Cholesterol Metabolism",
"token_count": 2041,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Hajri, T., and N. A. Abumrad. 2002. Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. *Ann. Rev. Nutr.* **22**:383–415.
Havel, R. J., and J. P. Kane. 2001. Introduction: Structure and Metabolism of Plasma Lipoproteins. In C. R. Scriver et al., eds., *The Metabolic and Molecular ... | {
"Header 1": "**18**",
"Header 2": "Two Treatments for Atherosclerosis Are Based on SREBP-Regulated Cellular Cholesterol Metabolism",
"token_count": 1767,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |

The macrophage cytoskeleton. Prominent structures include a network of intermediate filaments (red) and the punctate distributions of cell adhesions (yellow) containing both actin and vimentin. [Courtesy of J. Evans.]
he ability of cells to migrate is one of the crowning achievements o... | {
"Header 1": "**18**",
"Header 2": "MICROFILAMENTS AND INTERMEDIATE FILAMENTS",
"token_count": 2013,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Although these differences among isoforms seem minor, the isoforms have different functions: $\alpha$ -actin is associated with contractile structures; $\gamma$ actin accounts for filaments in stress fibers; and β-actin is at the front, or leading edge, of moving cells where actin filaments polymerize (Figure 19-2). ... | {
"Header 1": "**18**",
"Header 2": "MICROFILAMENTS AND INTERMEDIATE FILAMENTS",
"token_count": 2025,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
Each of these CH-domain proteins has a pair of actin-binding domains whose sequence is homologous to that of calponin, a muscle protein. The actin-binding domains are separated by repeats of helical coiled-coil or -sheet immunoglobulin motifs. The organization of the actin-binding sites in these proteins determines whe... | {
"Header 1": "**18**",
"Header 2": "MICROFILAMENTS AND INTERMEDIATE FILAMENTS",
"token_count": 2038,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
In this third *steady-state phase*, G-actin monomers exchange with subunits at the filament ends, but there is no net change in the total mass of filaments. The kinetic curves presented in Figure 19-6b show that the lag period can be eliminated by the addition of a small number of F-actin nuclei to the solution of G-ac... | {
"Header 1": "**18**",
"Header 2": "MICROFILAMENTS AND INTERMEDIATE FILAMENTS",
"token_count": 358,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
We saw earlier that myosin decoration experiments reveal an inherent structural polarity of F-actin (see Figure 19-4). This polarity is also manifested by the different rates at which ATP-G-actin adds to the two ends. One end of the filament, the (+) end, elongates 5–10 times as fast as does the opposite, or (-), end. ... | {
"Header 1": "**18**",
"Header 2": "Actin Filaments Grow Faster at (+) End Than at (-) End",
"token_count": 1329,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
In the artificial world of a test tube, experimenters can start the polymerization process by adding salts to G-actin or can depolymerize F-actin by simply diluting the filaments. Cells, however, must maintain a nearly constant cytosolic ionic concentration and thus employ a different mechanism for controlling actin po... | {
"Header 1": "**18**",
"Header 2": "Actin Polymerization Is Regulated by Proteins That Bind G-Actin",
"token_count": 2038,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
The capping and severing proteins are regulated by several signaling pathways. For example, both cofilin and gelsolin bind $PIP_2$ in a way that inhibits their binding to actin filaments and thus their severing activity. Hydrolysis of $PIP_2$ by phospholipase C releases these proteins and induces rapid severing o... | {
"Header 1": "**18**",
"Header 2": "Actin Polymerization Is Regulated by Proteins That Bind G-Actin",
"token_count": 2041,
"source_pdf": "datasets/websources/biochem/s-molecularcellbiology.pdf"
} |
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