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During fall of 1988 and 1989 we released a total of 32 bobcats throughout cumberland Island lamotrigine 50mg sale. All bobcats were captured from the coastal plain of Georgia and ftted with a radio-collar to monitor post-release movements order 200mg lamotrigine otc, survival discount lamotrigine 50mg on line, and reproduction. This translocation of bobcats to cumberland Island afforded the opportunity to conduct a reintroduction experiment for a mid-sized felid, in which failure would have no adverse effect on the global status of the species. In this paper we 1) identify key lessons we learned that could be useful for future felid reintroductions, 2) demonstrate the importance of post-reintroduction monitoring to learn more about the role of predators in ecosystem functioning and 3) summarize insights Fi g u r e 1. To the north is Little cumberland Island, which is separated from cumberland Island by <0. The interior of the island is dominated by live oak (Quercus virginianus) and pine (Pinus) forests with much of the understory dominated by stands of sawtooth palmetto (Serenoa repens). Freshwater wetlands follow natural depressions between former dune ridges in the interior of the islands. We captured bobcats using hunting dogs (canis familiaris), foot-hold traps, and cage traps from the coastal plain of Georgia in the hope that these bobcats would have gene complexes adapted to the environment on cumberland Island (Templeton, 1986). Only adult bobcats (1 year old) were reintroduced to cumberland Island and all reintroduced bobcats were vaccinated for feline panleukopenia, rhinotracheitis, and calicivirus. Also, we held bobcats in captivity until we had 4-6 individuals to release so we could evaluate the scent-station population monitoring technique with a controlled increase in population size (Diefenbach et al. Our goal was to release approximately 30 bobcats because this would result in a density similar to maximum densities on the mainland (1 bobcat/2. All releases of bobcats were hard releases in which bobcats2 were transported to the release site and freed. Release sites occurred throughout the island that were easily accessible by vehicle and likely were outside the home range of previously reintroduced bobcats. Po s t -R e l e a s e m o n I t o R I n g We began trapping on cumberland Island to recapture bobcats a few months after the frst bobcats were released on the island (Diefenbach et al. This recapture effort provided information on the physiological status of bobcats, allowed us to replace radio-collars before batteries failed, and capture bobcats born on the island to assess recruitment and survival of juveniles. We used only cage traps because they were less controversial than foot-hold traps even though they were ineffcient and less effective. We monitored survival and locations of bobcats via triangulation of radio signals from the ground or by locating bobcats with fxed-wing aircraft throughout the year and the 24-hour day (Diefenbach et al. We monitored reproduction by conducting intensive telemetry monitoring of females during the denning season (see Ragsdale [1993] for details) to located dens and document reproduction. To monitor food habits and prey selection we collected bobcat scats and measured prey abundance (Baker, 1991; Baker et al. From november 1988 through July 1990 we surveyed prey abundance during a three-week period in november, March and July. We defned four habitats for purposes of analysis: woodlands with understories of saw palmetto (oak-palmetto), woodlands with understories not dominated by saw palmetto (open woodland), interdune meadow and an area that burned in 1981 (scrub thicket). Whenever possible, we used distance sampling methods (trapping webs or line transect surveys, Buckland et al. We used spotlight transects to estimate island- wide abundance of white-tailed deer and raccoons (Procyon lotor). In november 1988 and March 1989 we walked each transect twice and alternated the starting point on consecutive days; four times thereafter. Each transect traversed multiple habitat types and pooled transect lengths in each habitat type were 11. If we obtained too few observations or could not meet the assumptions of distance sampling we calculated indices of abundance (captures per 100 trap nights or numbers seen per km). We collected bobcat scats by walking roads, trails, and dune/forest edges during a six week period encompassing each of the prey abundance surveys. We used prey abundance and bobcat diet data to examine differences in diet (prey use among species and spatial differences across the island) and changes in diet over time. Also, we tested predictions of functional relationships of bobcat diets, and if diets differed between males and females. Seasonal diets during 1997-98 were compared with the corresponding 1988-90 data (Baker et al. We aged deer via the tooth wear and replacement method (Severinghaus, 1949) except all deer estimated to be 4. Age distributions for harvested male and female deer were compared using chi-square tests for homogeneity. To test the effect of bobcat release period, the mean square error for the nested year effect was the divisor for the F test. We conducted deer spotlight surveys using protocols established for cInS by Ford (1987) and modifed by Baker (1991) to obtain estimates of deer density using distance sampling (Buckland et al. Deer density estimates were converted to abundance estimates assuming 6,110 ha of upland habitat. However, because deer population estimates based on distance sampling were available only for four years during 1980-98, other methods were used to obtain estimates to demonstrate population trends. We estimated annual deer abundance using hunt data with the DeLury technique (Roseberry and Woolf, 1991; Appendix I) using the number of hunters and deer kill from all hunts in each year. Seedlings and sprouts were counted in subplots but the total 16 m was treated as a single sample unit. We used Mcnemars test to test whether the number of plots with seedlings and sprouts changed between 1990 and 1997. We used the difference in mean sprout height at each plot to calculate the change in mean sprout heights between 1990 and 1997 at each plot. Some environmental organizations and individuals questioned whether herbivores should be controlled in national parks, whereas hunters voiced concern about bobcats preying on wild turkeys, a game species, and recommended that deer population control could be accomplished more cost-effectively using hunters. This approach to justifying the reintroduction was successful in reducing much of the controversy, and subsequent newspaper articles de-emphasized the controversial aspects and emphasized the broader ecological signifcance of the project (Warren et al. In hindsight, we underestimated public support for a reintroduction for its own sake, that of restoring a native predator. Details of the capture, handling, and transporting of bobcats was described in detail by Diefenbach et al. One bobcat died in captivity when it slipped its jaw through the radio-collar and suffocated; subsequently, bobcats were not ftted with a radio- collar until immediately prior to release. This resulted in additional handling of bobcats, but allowed us to assess bobcat condition immediately prior to release. Of those bobcats released in 1988, one female returned to the mainland in February 1989 and another died in January 1989, possibly due to injuries inficted by a feral hog. In fall 1989, we released 18 bobcats (12 males, 6 females); six on 5 October, six on 25 October and six on 4 December. One male released in the interdune area swam into the Atlantic Ocean and presumably drowned. Po s t -R e l e a s e m o n I t o R I n g The effort to recapture bobcats on the island resulted in recapturing eight of 12 bobcats from the frst years release and nine of 15 bobcats from the second years release. Thus, for the frst three years of the project we knew the fate of all but one female bobcat, due to transmitter failure. In 1989 we documented 10 kittens born in four litters, of which we monitored three from 4-10 months of age, captured and radio-collared three as adults in 1990, and recovered the carcass of one that died at two years of age. In 1990, we located one den with two kittens, and in 1991 we found no evidence that any females denned, although later in the year we observed two 3- to 4-month-old kittens. Recaptures of females for which we did not fnd dens with kittens indicated that they were not lactating and were unlikely to have produced young (Ragsdale, 1993). Bobcat prey abundance differed among regions and varied seasonally, but we detected no effect of season or year on diet composition during 1989-1990 (Baker et al. On an annual basis, marsh rabbits composed the largest proportion of the diet in three of four regions of the island in both years, whereas deer composed the largest proportion of the diet in the northwest region (Baker et al. Marsh rabbit, white-tailed deer and cotton rat were the only prey species identifed in bobcat diets during all surveys; thus, we considered these species the principal prey. This agrees with the predictions of a diet optimization model, in which increased use of alternate prey species (raccoons, feral hogs, and cotton mice) increases with decrease in abundance of a preferred prey species.

And that is exactly what we want: tests of clearly and logically formulated quantitative predictions discount 100mg lamotrigine with mastercard. Helper T cells pro- vide an important stimulus in the development of an antibody response generic 100mg lamotrigine visa. Thus order lamotrigine 100mg overnight delivery, an antigen must have two epitopes to stimulate a robust B cell response with anity maturation. Several factors likely aect the degree to which helper T cell epitopes modulate the immunodominance of B cellepitopes. In particular, ahelperTcellepitope near the hypervariable region of thehepatitis C virus envelope gene aids in generation of antibodies to the hypervariable region. As more parasite genomes are sequenced, it may be useful to look at which potential antigenic sites do in fact show signicant variation. Parasite Escape within Hosts 7 Specic immunity favors parasites that change their epitopes and escape recognition. In this chapter, I summarize examples of parasite escape and the consequences for antigenic diversity within hosts. Changing tissue tropisms over the course of an infection provide an additional force to drive the evolu- tion of parasite diversication within hosts. In some cases, parasite antigens may lack variation because the parasite repels immune attack by interfering with host im- munity rather than altering the specicity of its epitopes. The third sectionfocuseson parasites that escape host immunity by switching gene expression between variants stored within each genome. Each parasite lineage changes expression from one stored gene to another at a low rate. As host immunity builds against acommon variant, one or more newly expressed variants can rise. The host must then build another specic immune response against the new variants. Parasites that switch variants in this way may gain by extending the total time of infection. Additionally, switching may help to avoid the immunological memory of a previously infected host. The fourth section introduces processes that enhance or retard the coexistence of antigenic variants within hosts. Resource specialization allows dierent variants to coexist, for example, when each variant attacks a dierent cell type. Spatial vari- ation in the density of resources can allow dierent variants to dominate in dierent compartments of the hosts body. Natural selection favors variants that escape immune recognition, although escape is of- ten temporary. Selection may also favor diversication of the pathogens for the ability to attack dierent types of host cells. They compared the rate of nonsynonymous (dN) nucleotide replacements that cause an amino acid change versus the rate of synonymous (dS) nucleotide replacements that do not cause an amino acid change. A high dN/dS ratio suggests positive natural selection favoring amino acid change; a low dN/dS ratio suggests nega- tive natural selection opposing change in amino acids (Page and Holmes 1998; see chapter 15 below). The population of viruses accu- mulated diversity in the dominant epitopes over the course of infection within hosts. The early viruses infected macrophages, replicated slowly, and the viral particles were susceptible to antibody-mediated clearance. The late viruses with increased glycosylation were not recog- nized by antibodies that neutralized the early viruses. Viruses that es- cape antibody recognition gain signicant advantage during the course of infection(Chackerian et al. Addi- tional glycosylation apparently reduces the ability of antibodies to form against the viral surface. Presumably the glycosylation also hinders the ability of the virus to initiate infection; otherwise both early and late viruses would have enhanced glycosylation. They then compared the evolutionary pattern with the clinical outcome of infection, which follows one of three courses: clearance in about 15% of cases; chronic infection and either slowly or rapidly pro- gressive disease in about 85% of cases; and severe, fulminant hepatitis in rare cases. The sequence diversity within hosts identied two distinct regions of the envelope genes. The hypervariable region evolved quickly and appeared to be under positive selection from the host immune system, whereas other regions of the envelope genes had relatively little genetic variation and did not evolve rapidly under any circumstances. Those hosts that eventually cleared the virus had similar or higher rates of viral diversication before antibodies appeared than did those patients that developed chronic infection. By contrast, after antibod- ies appeared, chronic infection was correlated with signicantly higher viral diversity and rates of evolution than occurred when the infection was eventually cleared. It appears that hosts who cleared the infec- tion could contain viral diversity and eventually eliminate all variants, whereas those that progressed to chronic infection could not control viral diversication. Therareandhighly virulent fulminant pattern had low viral diversity and rates of evolution. This lack of diversity suggests either that the fulminant form may beassociatedwithasinglevirallin- eage that has a strong virulence determinant or that some hosts failed to mount an eective immune response. For every pair of sites, there will usually be at least one virus that carries mutations at both sites. Some within-host evolution very likely occurs, but it does not play a signicant role in the infection dynamics within hosts. But large population sizes, long infection times, and hy- permutation of epitopes could still lead tosignicantevolution within hosts. As more data accumulate, it will be interesting to compare the extent and the rate of within-host evolutionary change in various pathogens. I do not know of any evidence to support this idea, but it should be considered when studying candidate epitopes and their observed level of antigenic varia- tion. Some viruses alter expression of host cytokines or express their own copies of cytokines. Other viruses expressreceptors for cytokines or for the constant (Fc) portion of antibodies. These viral receptors reduce con- centrations of freely circulating host molecules or transmit signals that alter the regulation of host defense. Each individual parasite usually expresses only one of the alter- natives (Deitsch et al. Parasite lineages change expression from one stored gene to another at a low rate. In Trypano- soma brucei,theswitchrate is about 103 or 102 per cell division (Tur- ner 1997). For example, the blood-borne bacterial spirochete Bor- relia hermsii causes a sequence of relapsing fevers (Barbour 1987, 1993). The bacteria rise in abundance when new antigenic variants escape immune recognition and fall in abundance when the host generates a specic antibody response to clear the dominant variants. Many dierent kinds of parasites change their surface antigens by al- tering expression between variant genes in an archival library (Deitsch et al. This active switching raises interesting problems for the population dynamics and evolution of antigenic vari- ation within individual hosts. The numbers in the column headings and row labels are names for particular antigenic variants. Overall, it appears thateachtypecan potentially switch to several other types, with the probability of any transition typically on the order of 104 to 102. Trypanosoma brucei stores and uses many dierent antigenic variants, perhaps hundreds (Vickerman 1989; Barry 1997). But the sequence of variants that dominate sequential waves of para- sitemia tends to follow a repeatable order (Gray 1965; Barry 1986). Temporal separation in the rise of dierent antigenic variants allows trypanosomes to continue an infection for a longer period of time (Vick- erman 1989). If all variants rose in abundance early in the infection, they would all stimulate specic immune responses and be cleared, ending the infection. If the rise in dierent variants can be spread over time, then the infection can be prolonged.

Keywords Autoimmune bullous diseases pemphigus pemphigoid desmogleins Definition Pemphigus and bullous pemphigoid are autoimmune blis- suggest a wide geographic variability order 100 mg lamotrigine amex, with higher rates in tering diseases with an established immunological basis Jews of northern European origin (3) discount 200mg lamotrigine otc. Pemphigus is characterized by is the most common of the autoimmune blistering skin loss of cellcell adhesion (acantholysis) mediated by auto- diseases discount lamotrigine 200 mg without prescription. Bullous pemphigoid is characterized by sub- There is solid evidence that pemphigus autoantibodies are epidermal bullae and in vivo deposition of autoantibodies not just surrogate markers for the disease, but pathogenic and complement components and significant polymorpho- (5). The autoantibodies are invariably found in serum and nuclear cell infiltrates along the epidermal basement mem- bound in lesional epithelia; the severity of the disease brane zone (2). Transpla- cental transfer of pemphigus antibodies may induce a short-term blistering eruptioninneonates,andpassive Epidemiology transfer of human pemphigus antibodies to mice pro- duces acantholysis and intraepidermal detachment, Pemphigus vulgaris is the most common form of pemphi- reproducing the human disease with precision (5). Mean age of onset is desmosomal proteins have been identified as the target 5060 years, with an equal sex distribution. Its prevalence antigens in pemphigus: desmoglein 1 in pemphigus folia- in the general population is 110 per million. Although the ceus (molecular weight 165 kDa) and desmoglein 3 in disease affects members of all races, epidemiologic data pemphigus vulgaris (molecular weight 130 kDa). These antigens are key components of the Diagnostic Criteria epidermal hemidesmosomes, which are adhesion struc- tures that anchor the epidermal basal cells to the under- At present, there are no universally recognized diagnostic lying basement membrane. For a definitive diagnosis, we suggest positive findings on Clinical Manifestations direct immunofluorescence combined with two of the major criteria or one of the major and one of the minor The lesions of pemphigus vulgaris typically occur first in criteria identified in the table. The primary skin lesion consists of flaccid bullae that break to form a large painful erosion, which Prognosis usually fails to heal without specific intervention. Left untreated, it progresses steadily, and is The clinical manifestations of bullous pemphigoid associated with a very high risk of mortality within 2 differ from those of pemphigus vulgaris. The introduction of corticosteroids has rendered are rare, and the skin lesions are typically polymorphic the disease treatable, but not curable. Subsequently, tense flares, but symptoms frequently disappear after a few blisters arise, sometimes producing an extensive bullous months to a few years. Histologic study of pemphigus vulgaris lesions typically Criteria Pemphigus vulgaris Bullous pemphigoid reveals suprabasal acantholysis. Histologic skin sections Major from patients with bullous pemphigoid typically show Clinical picture Flaccid blisters and Polymorphic eruption with separation of the basal epidermis from the adjacent dermis erosions in mucosa, tense blisters and erosions (subepidermal plane) with eosinophils in the dermis. The immunoser- and C3 on along the basement epithelial cell membrane ologic hallmark of the disease is the presence of serum anti- surface desmogleins 1 and 3. Pemphigus variant associated with penicillin use: A case- cohort study of 363 patients from Israel. Arch Dermatol If pemphigus vulgaris is not treated definitively and 2007; 143: 7047. A comparison of oral ing (7, 8), which makes the disease more difficult to con- and topical corticosteroids in patients with bullous pemphi- trol. Int J Der- Bullous pemphigoid is more responsive to treatment matol 1988; 27: 5804. Epitope spreading: a mechanism for on corticosteroids (topical or systemic), alone or in con- progression of autoimmune disease. Arch Immunol Ther Exp junction with other immunosuppressive drugs, as well as (Warsz) 2000; 48: 34751. Theories concerning the pathogen- esis of vitiligo have concentrated on four different mechanisms: autoimmune, autocytotoxic, genetic, and neural. The autoimmune hypothesis focuses on the association of vitiligo with other autoimmune diseases. The autocytotoxic theory postulates that cytotoxic precursors to melanin synthesis accumulate occur in melanocytes causing cell death. The genetic hypothesis focuses on genetic data, and the neural hypothesis links segmental vitiligo with neurons that juxtapose melanocytes. For patients with generalized vitiligo, depigmentation of the remaining pigmented epidermis is sometimes the only alternative. Keywords Vitiligo melanocytes autoantibodies steroids phototherapy Vitiligo is an acquired, sometimes progressive disorder in one-third of patients with vitiligo have family members which some or all of the melanocytes in the interfollicular with the disease. Larger studies involving patients with viti- epidermis, and occasionally those in the hair follicles, are ligo and their families conclude that the disease is neither selectively destroyed. Vitiligo may be associated with other transmitted as an autosomal recessive nor as a dominant organ-specific autoimmune diseases, such as thyroid disease trait. Autoantibodies directed with the disease suggests a multifactorial genetic pattern. Epidemiology Pathogenesis The disease itself is not inherited, but the predisposition The concept of vitiligo as an autoimmune disease was for vitiligo is inherited. Vitiligo is relatively frequent, with introduced following reports of autoantibodies found in a rate of 12%. No sex-related difference in prevalence is serum from patients with active disease. Vitiligo may appear at any time from birth to has been studied in great detail, and antibodies directed senescence, though the onset is most commonly observed against melanocytes are clearly more prevalent in patients in childhood or young adulthood. These antibodies are generally reac- of those with vitiligo acquire the disease before the age of tive with intracellular antigens, but humoral immunity 20 years, and the incidence decreases with increasing age to pigment cells may constitute an epiphenomenon that (4). Epidemiologic studies have shown that one-fourth to occurs in response to cell damage. The demonstrating antibody-dependent cellular cytotoxicity same process, autoimmune destruction of melanocytes, is in vitro (7). Recently, it was found that there is an inflam- thought to be responsible for both melanoma-associated matory infiltrate surrounding expanding vitiligo lesions. They Infiltrates consist of macrophages, as well as dendritic cell appear identical histologically (9). The major difference is their distribution: vitiligo vitiligo with autoimmune diseases, together with studies usually begins centrally and spreads to the periphery demonstrating that vitiligo patients can have autoanti- whereas generalized vitiliginous lesions usually begin bodies and autoreactive T lymphocytes against pigmented distally. Vitiligo 355 findings in the denervated areas, (b) clinical evidence The disease is categorized according to the extent of of segmental, dermatomal vitiligo, (c) increased sweat- involvement and the distribution of depigmentation. Gen- ing and vasoconstriction in vitiliginous areas implying eralized vitiligo is the most common presentation with increased adrenergic activity, and (d) depigmentation in bilateral, symmetric depigmentation of the face (especially animal models with disconnected nerve fibers (10). Universal vitiligo stems from the belief that increased melanocyte activity implies loss of pigment over the entire body surface area. Electron micrograph examina- Most patients initially experience depigmentation in a sun- tions of vitiliginous interface and normal skin in patients exposed site. Depigmentation of body hair in vitiliginous with vitiligo demonstrated accumulation of extracellular macules may be present. Although the color of the irides granular material and basilar vacuolization of pigmented do not change in patients with even extensive vitiligo, skin in patients with rapidly progressing disease. This depigmented areas in the pigment epithelium and choroid theory has been supported by studies that have demon- occur in up to 40% of patients. Moreover, the incidence of strated an increased melanocyte susceptibility to precur- uveitis in patients with vitiligo is elevated, and the inci- sor molecules (such as dopachrome) with exposure to dence of vitiligo in patients with uveitis is also higher melanotropin (also known as melanocyte-stimulating than expected (2). Because vitiligo affects city may occur is through inhibition of thioredoxin all active melanocytes, auditory problems can result in reductase, a free-radical scavenger located on the mem- patients with vitiligo. This enzyme is inhibited by cal- who were younger than 40 years of age, 16% had cium, which has been shown to be membrane bound in higher concentrations on vitiliginous keratinocytes relative to controls. Higher extracellular calcium levels cause increased superoxide radicals that lead to inhibi- tion of tyrosinase by upsetting the equilibrium of oxi- dized and reduced thioredoxin in the epidermis, later causing vacuolization and eventually cell death (12). The premise that vitiligo, or a susceptibility to the disease, is inherited is based on the fact that familial aggregation is often seen. It is believed that Vitiligo is a polygenic trait and that a convergence theory, combining elements of different theories across a spectrum of expression, is the most accurate etiology. Schematic figure of the most common clinical Vitiligo appears as sharply circumscribed, cosmetically presentation of vitiligo. Typical clinical picture of vitiligo patient with depigmented lesions on dorsum of hand and around the lips. Although the pathogenic mechanisms of T cells have recently been well studied in vitiligo, the role of autoanti- Pathological Features bodies in the disease remains obscure.

A potential advantage conferred by Golgi stacking is improved efficiency of trafficking through the Golgi cheap lamotrigine 200mg free shipping, as there is little physical distance between cisternae 25mg lamotrigine otc. A mammalian cell contains multiple Golgi stacks that are connected laterally by membrane tubules to form a Golgi ribbon 25 mg lamotrigine otc. Tubules can also connect heterologous cisternae for example a cis-cisterna in one region and a trans-cisterna in the next region. Such connections could facilitate the movement of molecules forwards and/or backwards through the Golgi to a significant extent. In addition to stacks of cisternae, the Golgi is also composed of abundant vesicles, and of networks of branching tubules connected with the cis-most cisterna and the trans- most cisterna. Vesicles and tubules support transport of material within the Golgi, as well as transport to/from the Golgi. It is able to rapidly change its shape, and to even disassemble and reassemble under a variety of physiological and pathological conditions. These vesicles partition between the two daughter cells, and are able to reassemble to produce a functional Golgi apparatus at the end of mitosis. It houses the enzymes responsible for the processing of newly synthesized proteins and lipids, and serves as a site for the transport and sorting of these processed molecules to their final subcellular destinations. In contrast, O-linked glycosylation on serine or threonine residues is initiated in the Golgi. Not only proteins, but also lipids are substrates for N-linked and O-linked glycosylation and oligosaccharide-chain processing at the Golgi. The Golgi houses enzymes including glycosyltransferases and trimming enzymes which are able to respectively add and remove a variety of sugars at various stereospecific positions. Glycosyltransferases can be mannosidases, sialyltransferases, fucosyltransferases, galactosyltransferases or N- acetylglucosamine transferases. Apart from enzymes responsible for glycosylation, the Golgi contains enzymes required for other post-translational modifications of newly synthesized proteins and lipids (e. It also contains numerous pro-protein convertases (like furin) that cleave protein precursors into their mature forms. Golgi enzymes are compartmentalized, so that processing of cargo proteins and lipids occurs sequentially during passage through the Golgi. In general, enzymes acting early in glycan biosynthetic pathways are concentrated in cis and medial compartments, whereas enzymes acting later tend to reside within the trans-Golgi compartment. The Golgi apparatus can therefore be viewed as an assembly line for the production of correctly glycosylated proteins and lipids. Post-Golgi compartments are enriched in - 79 - processed compounds while pre-Golgi membranes are enriched in precursor and immature forms. Many pathways are possible for terminal glycosylation regarding the number of branches, and the number and identity of sugars added. Here, addition of terminal sialic acid, fucose and galactose residues are represented. In addition to the compartmentalization process, clusters of Golgi enzymes that direct the biosynthesis of specific glycan structures have been observed (de Graffenried and Bertozzi, 2004). Such associations have also been described in the case of enzymes involved in ganglioside biosynthesis (e. They are transported to the Golgi along microtubules, a process that requires microtubule motor proteins (primarily dynein, together with its cofactor dynactin) to drive motility (Scales et al. Cargo transport through the Golgi There are two models explaining cargo movement through the Golgi. The vesicle transport model proposes that the Golgi cisternae are stable pre-existing structures through which the cargo molecules pass. In this model, also called the stable - 81 - compartment model, resident Golgi proteins are retained in the cisterna representing their final destination. Transport of cargo molecules is mediated by vesicles that bud from one cisterna and then fuse with the next one. This model assumes that new Golgi cisternae form de novo at the cis face, progressively mature through the stack, and ultimately peel off from the trans face. Secretory cargo proteins are thought to be carried forward by this process of cisternal progression. Meanwhile, cisternae maturation implies that cisternal components are recycled by a return flow from older to younger cisternae. On the contrary, resident Golgi enzymes freely enter these vesicles (Pelham, 2001). More recently, a new model for intra-Golgi trafficking has been developed, called the rapid-partitioning model. The motivation for the development of this new model came from studies of the kinetics of cargo transport in living cells (Patterson et al. The classic cisternal maturation model predicts a lag before newly arrived cargo is exported from the Golgi. This prediction is based on the thesis that cargo molecules await arrival of enzymes for processing, which are delivered sequentially via retrograde trafficking, before they can exit from the Golgi. Recent studies of cargo kinetics demonstrated that, in contrast to the predictions of the cisternal maturation model, cargo molecules exited at an exponential rate proportional to their total Golgi abundance with no lag period (Patterson et al. Furthermore, upon arrival at the Golgi, cargo molecules quickly distributed throughout the system before differentially partitioning between two different membrane environments: processing domains enriched in processing enzymes and export domains from which transport intermediates bud from the Golgi. Given these - 83 - results, a new model of intra-Golgi transport was constructed, that involves partitioning of cargo and Golgi enzymes within a two-phase membrane system. The authors further included lipid trafficking pathways as an integral part of this model by showing that processing and export domains were characterized by specialized lipid environments that differentially retained resident and cargo proteins. It is well recognized that there is a cis-to-trans gradient of lipids through the Golgi, which mainly concerns glycerophospholipids and sphingolipids (Bretscher and Munro, 1993). This lipid gradient alone could explain the differential distribution of proteins within the stacks. Whereas domains enriched in glycerophospholipids preferentially retained Golgi processing enzymes, domains enriched in sphingolipids had a higher concentration of cargo molecules. A final key of this model relies on trafficking of cargo and processing enzymes in both directions through the Golgi. It has been proposed that rapid bidirectional trafficking throughout the Golgi system allows proteins to sample different lipid environments, and therefore promotes association with their optimal Golgi subdomain. For the first time, the rapid-partitioning model invokes lipid sorting as the driving force in intra-Golgi trafficking. Sorting from the Golgi Both the cis- and trans-faces of the Golgi apparatus are important sites for the sorting of proteins and lipids and delivery to specific subcellular destinations. Different machineries recognize these signals, driving their incorporation into different post-Golgi routes. Sorting signals are contained in the cytoplasmic tail of cargo molecules, and sometimes in specific receptors for these molecules. These signals have also been - 84 - Introduction identified in some basolateral-directed proteins. The presence of common signals for these two destinations is not surprising, since the indirect route to the endo-lysosomal system involves an intermediate step at the basolateral plasma membrane. Apical sorting signals are highlighted in blue, basolateral sorting signals in red, and endo-lysosomal sorting signals in green. Sorting signals meet different machineries (see circle) that mediate the incorporation of the cargo into different routes. Recycling of apical and basolateral membrane proteins internalized by endocytosis is also shown (routes 2a and 2b). These sorting signals can contribute to association with proteins driving transport to the apical plasma membrane, for example with microtubule motor proteins (Tai et al. N- linked and O-linked proteins and lipids can be recognized by lectin receptors such as galectin (Delacour et al. An unconventional mechanism for apical sorting is the association with lipid rafts. Many apical proteins have affinity for lipid microdomains assembled in the Golgi complex which are subsequently delivered to the apical membrane. Clustering of proteins associated with lipid rafts is the main mechanism for segregating apical raft-associated proteins from the basolateral proteins (Schuck and Simons, 2004). However, only the trans-most cisterna and the tubules originating from it show clathrin-coated buds. Therefore, they primarily represent the exit site of molecules destined to the endo- lysosomal pathway. In contrast, secretory molecules presumably exit the preceding trans-cisternae via non-coated vesicles.

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