Moreover, the amount of inclusion carrying cells decreases from 4

Moreover, the amount of inclusion carrying cells decreases from 48 hpi to 72 hpi when a small initial infec tious dose was used. However, further investigations need either to be done to Inhibitors,Modulators,Libraries prove an actual release mechanism. The question remains open what the molecular factors are that lead to release of bacteria and cell death. Signals leading to cell death could be Inhibitors,Modulators,Libraries the contact of Chlamydia with pro teins in the cytoplasm. Although metabolically active Chlamydia are released from inclusions, current data do not allow to determine whether it is the contact of RBs or and EBs with the cytoplasm. Another possibility could be that chlamydial proteins that are released along with the pathogens during inclusion rupture induce cell death. A membrane lysing substance targeting preferentially eukaryotic membranes could induce permeabilization in major membranous structures.

The nature of such pro teins putatively involved in cell death induction remains to be elucidated. Moreover, treatment of Chlamydia infected cells with chlo ramphenicol completely Inhibitors,Modulators,Libraries abolished cell death induction. This indicates that the initial bacterial burden can be excluded as an initiator Inhibitors,Modulators,Libraries of aponecrosis. Although chlamydial induction of apoptosis was described in some studies strikingly low numbers of single TUNEL positive cells were observed throughout the infection cycle in our experiments, a reflection of sponta neous apoptosis of residual uninfected cells within the infected population. It is evident that Chlamydia can influ ence cell death in order to successfully end the replication cycle.

However, it is also evident that the nature of induced cell death is more intricate than a sole activation of the apoptotic pathway. Depending on different cell types, chlamydial strains and experimental apoptotic pro cedures, a combination between apoptosis and necrosis in a cell population and aponecrosis Inhibitors,Modulators,Libraries at the single cell level have been described. In this study, infected dead HAEC displayed apoptotic features such as condensation of the chromatin together with necrotic fea tures, including early damage to organelles and disruption of the cell membrane. This morphology was previously observed also in other cells and was termed aponecrosis. Additionally, we show that cell death mor phology does not differ between Ganetespib solubility cells infected with high infection doses for a short period of time and cells sub jected to low infection doses for longer time. We never observed dead HAEC containing inclusions, which is in accordance with previous studies showing that Chlamydia possesses both pro and anti apoptotic capabil ities. Chlamydia inhibits apoptosis by blocking the release of cytochrome c through the interaction with pro apoptotic agents such as BH3 only proteins and Bax Bak.

Several transcription factors have been identified that mediate d

Several transcription factors have been identified that mediate drought response pathways independent from the ABF3 pathway. thoroughly Members of the DREB family of transcription factors function in abiotic stress signalling and members of the DREB2 subfamily are known to function in ABA independent drought stress signalling. DREB2A and DREB2B, as expected, were upregulated Inhibitors,Modulators,Libraries in Inhibitors,Modulators,Libraries response to drought in both plant lines at both time points. Inhibitors,Modulators,Libraries In addi tion, DREB1B CBF1 and DREB1C CBF2 were also upregulated in both lines at both time points and DDF1 was upregulated at 24 h. While the DREB1 subfamily is primarily associated with cold stress signalling, there is some evidence that members also function in dehydration stress. Three NAC transcription factors also function in a drought signalling pathway that is independent from ABF3.

ANAC19, ANAC055 ATNAC3, Inhibitors,Modulators,Libraries and ANAC072 RD26 are all expressed at both time points in both plant lines. Another six members of the NAC family of tran scription factors are also com monly regulated in both 35S ABF3 and control plant lines. Also in this category are Inhibitors,Modulators,Libraries many genes that are known to be regulated in response to drought stress. This includes genes involved in the biosynthesis of osmo lytes, late embryogenesis abundant proteins, kinases, phosphatases, and transcription factors, as well as several different types of transporters. This further suggests that some drought signalling pathways are unaffected by ABF3 overexpression Genes with an enhanced response in 35S ABF3 plants There are 407 genes that demonstrated an enhanced response in 35S ABF3 plants.

Of these, 332 are uniquely regulated in 35S ABF3 plants with 9 differentially expressed at both time points, 87 differentially expressed only at 2 h and 236 differentially expressed at 24 h. In addition, 47 genes are differentially expressed in the control line at only selleck inhibitor 24 h and 27 genes are differentially expressed in the control line at only 2 h while in the 35S ABF3 line they are differentially expressed at both time points. Finally, there is a transposable element gene that is differentially expressed in 35S ABF3 plants at 2 h but is only differentially expressed in control plants at 24 h. A number of genes in this category could contribute to the enhanced drought tolerance of 35S ABF3 plants. Several genes involved in the biosynthesis of the osmolyte trehalose show enhanced upregulation while two genes involved in osmolyte catabolism show enhanced downregulation. Two genes involved in detox ification show enhanced upregulation in 35S ABF3 as do three LEA proteins. A number of transporters also show enhanced regulation in 35S ABF3 lines.

others have functions in protein

others have functions in protein selleck kinase inhibitor turnover, organization of the cytoskeleton and DNA repair. To further examine the link between Tra1 and cellular stress response we tested the sensitivity of the tra1SRR3413 strain to rapamy cin and to staurosporine. As shown in Figure 4, the tra1SRR3413 strain was partially sensitive to rapamycin, and to a lesser extent staurosporine. As staurosporine results in cell wall instability through its action on Protein Kinase C, we also examined the tra1SRR3413 strain for sensi tivity to the combination Inhibitors,Modulators,Libraries of calcofluor white and stau rosporine. The tra1SRR3413 Inhibitors,Modulators,Libraries strain was extremely sensitive to calcofluor white in the presence of staurosporine, consist ent with a role for Tra1 in events required for cell wall integrity.

Relationship of tra1SRR3413 to other mutations in SAGA SLIK and NuA4 components Bruno et al. have shown that deletion of the Ada2 homologue in C. albicans results in sensitivity to cell wall destabilizing agents. In addition, both SAGA SLIK and NuA4 have been suggested to be involved in stress response based upon the transcription profiles of deletion strains. Inhibitors,Modulators,Libraries As some of the genetic interactions and phenotypes of the tra1SRR3413 strain may result from a SAGA SLIK or NuA4 dependent inability to induce stress response genes, we analyzed staurosporine, calcofluor white, calcofluor white plus staurosporine and rapamycin sensitivity in strains deleted for additional components of these complexes. The effect of tra1SRR3413 under each of these conditions is similar to, though slightly less severe than, that seen upon deletion of the ada genes of the SAGA SLIK com plexes.

Interestingly, despite the fact that deletion of spt7 results in disruption of the complexes, spt7 0 results in less of an effect on rapamycin and calcofluor white than dele tion of the ada genes, suggesting a potential role for an independent Ada complex. This similarity between the ada genes and tra1SRR3413 is also consistent with our previous Inhibitors,Modulators,Libraries finding that the expression profile in the tra1SRR3413 strain most closely resembled deletion of ada2. Less similarity was seen in the phenotypes with NuA4 components though deletion of yaf9 and eaf7 did lead to reduced growth in calcofluor white plus staurosporine containing media and deletion of yaf9 resulted in a slight reduction of growth in media containing rapamycin.

GFP tagged Tra1 localizes to nucleus The requirement for an intact C terminal FATC domain has meant that Tra1 localization has not been tested in genome wide screens. Localization of Tra1 Inhibitors,Modulators,Libraries to sites outside the nucleus potentially could account for the broad range of genetic interactions seen for the molecule. To examine selleck chemicals MEK162 cellular localization, we engineered an N terminally GFP tagged allele of TRA1 that is functional as determined by plasmid shuffling assays.

Additional controls on each array in cluded 6 positive controls c

Additional controls on each array in cluded 6 positive controls consisting of Cy 3 labeled anti bodies, 6 negative controls containing bovine serum albumin, and empty spots containing no antibody, with the 6 replicates scattered throughout selleck screening library the array. The antibody microarray was performed according to the manufacturers protocol and slides were scanned using Full Moon Biosystems Scanning Array Service. Array data analysis Each spot throughout the array was scanned to provide its signal intensity values, including positive and negative controls. For background correc tion, the median value of the negative control signal was subtracted from the values of each antibody and phospho Inhibitors,Modulators,Libraries antibody. The background corrected signal was log2 trans formed and normalized by the mean value of beta actin signal.

For each phosphorylated antibody, Inhibitors,Modulators,Libraries the background corrected signal was normalized by the mean value of the corresponding total antibody. The fold changes between treatment groups were derived from ratios of geometric mean signal intensities. Treatment groups included con trol non infected monocytes co cultured with HBMEC, HIV infected monocytes co cultured with HBMEC, and HIV infected monocytes treated with CCR5 blockers and co cultured with HBMEC. ANOVA with heterogeneous variance was used for statistical analyses of protein expression between groups, and the Tukey Kramer method used for multiple compar isons. The Benjamini Hochberg method was then used to control the false discovery rate. Proteins with BH adjusted p value less than 0. 05 were considered to be dif ferentially expressed.

Ingenuity pathway analysis Differentially expressed and phosphorylated proteins identi fied in HIV 1 infected monocytes co cultured with HBMEC, compared Inhibitors,Modulators,Libraries to non infected monocytes co cultured with HBMEC, or infected monocytes treated with CCR5 blockers and co cultured with HBMEC, were analyzed using the In genuity Pathways Analysis 3. 0. The networks obtained through IPA software describe func tional relationships between proteins products based on known interactions, biological functions and canonical path ways. Using a false discovery rate of 0. 05, only phospho proteins upregulated or downregulated by at least 1. 5 fold were considered. Inhibitors,Modulators,Libraries and for non phosphorylated proteins, only those upregulated or downregulated by at Inhibitors,Modulators,Libraries least 2 fold were considered. Monocyte adhesion to an in vitro BBB model For adhesion assays, HBMEC were plated on 96 well collagen coated black bottom plates and cultured to con fluence. Infected monocytes treated or non treated with CCR5 blockers or CCR5 antibodies were labeled with 5 carboxyfluorescein diacetate, acetoxymethyl ester, 10 uM1106 for 1 hour, and co cultured with HBMEC for 15 min.

We suspect this may be due to the differing procedures adopted in

We suspect this may be due to the differing procedures adopted in brain injury and reduced area and density in the corpus callosum after TBI. In addition to these interesting Lapatinib mechanism results observed in the Nogo AB deficient mice, the NgR defi cient mice also display impaired cognitive outcomes in the Morris water maze task after TBI. It has also been reported that Nogo A plays a critical role in stabilizing and maintaining the architecture of hippocampal pyramidal neurons. These results suggest that the role of Nogo A in TBI induced neuronal damage is very complex and may also be age dependent. Brain edema is one of the characteristic features observed in patients suffering from severe traumatic brain injury, and induction. In our model, the TBI induced diffused dam age may not be restricted to neuronal injury.

It might also cause vessel ruptures and severe damage to the blood brain barrier. Consequently, TBI could have accelerated the recruitment of microglia and macro phages, and in turn promptly Inhibitors,Modulators,Libraries stimulated earlier Nogo A expression. The other possible explanation for the varia tions in Nogo A expression profiles may be the specific brain area that was subject to investigation in this study. Based on the results from our previous studies showing that the hippocampus exhibits rather severe neuronal Inhibitors,Modulators,Libraries loss due to TBI, it follows that a more rapid TBI re sponse, including Nogo A upregulation, should be more clearly observed in the hippocampus. The role of Nogo A is controversial.

Using monoclonal antibodies to neutralize Nogo A or using soluble fragments of NgR to block the Nogo A NgR interaction has been found to increase axonal outgrowth and sprouting significantly, which correlates with an im provement of functional outcome Inhibitors,Modulators,Libraries after cerebral ischemia or stroke. Neutralization of Nogo A by mAbs has also been shown to improve cognitive recovery after TBI. These studies suggest that Nogo A elicits the axonal inhibitory effects after injury and provide a po tential treatment strategy for TBI. However, contrary to the pharmacological results, the genetic deletion of Nogo A did not improve functional and histological out comes after TBI in aging animals. Compared with wild littermates, the Nogo AB deficient mice showed diminished recovery from neurological motor deficits it can be classified into vasogenic edema and cytotoxic edema.

Vasogenic edema, a secondary response to BBB compromise following TBI, can lead Inhibitors,Modulators,Libraries to a swelling process and a subsequent rise in intracranial pressure. Cytotoxic edema causes intracellular fluid accumulation Inhibitors,Modulators,Libraries and occurs during water intoxication and under anoxia generating conditions, such as trauma and stroke. Earlier studies have demonstrated that some neuroprotective agents, such as tamoxifen, could protect animals from spinal cord injury induced edema and neuronal damage via the attenu ation of Nogo A.

For graphical rendering, the output was read into a user written

For graphical rendering, the output was read into a user written POV Ray program. A POV Ray movie was then produced from a series of these programs. Sensitivity Analysis Sensitivity analysis was performed for key parameters. Cell displacement rates, migration rates, random Lapatinib weighting, branching probability and timesteps were adjusted over a wide range of values, while other factors were held constant. Sample graphs from the sensitivity analysis are provided in figures, where details of the parameters are relevant to the results and discussion. An exhaustive systematic sensitivity analysis can be per formed when the model is restricted to a specific tissue type. Inhibitors,Modulators,Libraries Timestep The timestep currently is defined as a constant. As experimental details of events become available, it could be made variable.

There is no inherent limit on the number of timesteps. Results The model results show cellular activation, proliferation, and movement during the initial steps in angiogenesis. Four main applications Inhibitors,Modulators,Libraries of the model were explored in silico knockout experiments, characterization of persis tence effects on vessel formation, differentiation of tip cell and stalk cell branching, and the effect of Dll4 haploinsufficiency on sprouting. First, to give a basis of how the models representation of cell activation Inhibitors,Modulators,Libraries and chemotaxis correlates with experi ments that can serve as validation of the model, cumulative sprout length was compared with and without VEGF at different concentrations. In developing the model, rules for determining the experimental relationship between VEGF concentration and cell migration and cell proliferation were estimated from experiments on endothelial cells.

Cell proliferation experiments were 2D in vitro cell culture assays, and cell migration experiments used VEGF as a stimulus for movement of cells in a Boyden chamber assay. In vitro experiments provide an estimate in the computational model for the maximum in vivo changes in response to an activated cell sensing a specified local concentration Inhibitors,Modulators,Libraries of VEGF. The effect of VEGF concentration on sprout formation was then predicted by the simula tion in three dimensions. The model output was qualitatively compared to independent data from experiments on sprout length changes as a function of VEGF in three dimensional HUVEC spheroid experi ments. Without VEGF or with local VEGF levels less than 0.

6 ng ml, the cells in the model do not become activated, and there are no cumulative sprout Inhibitors,Modulators,Libraries length selleck Regorafenib changes. Migration, Proliferation and Elongation Once the premise of cell activation by a threshold VEGF and migration in response to a VEGF gradient was established, varied combinations of the migration and proliferation rules were explored. One highlight of the described modeling approach is that methods were designed with modularity. The effects of allowing or prohibiting processes that would not be feasible to manipulate independently in vivo, can be predicted for specific cell types.

Taken together, a schematic hypothesis of the role of CTGF in the

Taken together, a schematic hypothesis of the role of CTGF in the RA pathogenesis is presented in Figure 7. It has been reported that CTGF adenovirus vector transfection into knee joints of mice induces linier overexpression of CTGF in the synovium and results in cartilage damages with increas ing of mRNA cording for degradative enzymes such as MMP Inhibitors,Modulators,Libraries 3. Manns and co workers also reported that CTGF is up regulated in an experimental animal model of RA, and they have shown that treatment with thrombospondin 1 derived peptide is associated with down regulation of CTGF concomitant Inhibitors,Modulators,Libraries with the disease amelioration. Furthermore, the null knock down of the CTGF gene dramatically inhibits osteoclast like formation in mice. Their reports indicate that CTGF has a significant role for RA pathogenesis and our present data can support these previous reports.

The synovial tissue in the inflamed joints of RA can invade bones and this is supported by the invasive nature of the syn ovial fibroblasts gaining the capacity to move and penetrate into cartilages and bones. Osteoclasts are the sole bone absorbing cells and the functions of osteoclasts Inhibitors,Modulators,Libraries are increased in RA patients as well as in patients with osteoporosis. Osteo clasts are commonly found within the erosive pit at the interfer ence of synovial inflammatory tissue and subchondral bone. RANKL is a membrane residing protein on osteoblasts and recognizes its receptor expressed on marrow macrophages, promoting them to differentiate into the osteo clast phenotype in the presence of M CSF.

These molecules are expressed locally in Inhibitors,Modulators,Libraries the synovial tissues of RA patients and TNF is an inducer of RANKL expression as well Inhibitors,Modulators,Libraries as IL 1 and IL 6. Therefore, aberrant osteoclastogen esis play an important role in the development of RA and this process is further positively regulated by proinflammatory cytokines like TNF under pathogenic conditions. As shown in Figure 2, strong CTGF expression appeared to be observed at inflamed synovial fibroblasts derived from surgical samples of RA patients. Furthermore, CTGF was upregulated by TNF in human synovial fibroblasts cell line, MH7A, as shown in Figure 3A. The present data indicate that excessive CTGF pro duction from synovial fibroblasts with RA patients induced by TNF can promote aberrant activation of osteoclasts in com bination with RANKL M CSF, resulting in bone destruction. In addition, we found a CTGF receptor, integrin V 3, on the osteoclasts. Integrins are heterodimec adhesion receptors that mediate mostly cell matrix interaction.

In this context, the several fold change differences measured in

In this context, the several fold change differences measured in the micro RNA cluster covering hsa miR selleckchem 371 373 is of interest. Based on our findings, hsa miR 371 373 expression in NTERA 2 R increased 4. 0 4. 7 fold relative to the paternal cisplatin sensitive NTERA 2 line, and even more in NCCIT R, relative to the cisplatin sensi tive paternal NCCIT cells, showing an 12. 0 16. 3 fold upregulation, table 1. Noteworthy, this micro RNA clus ter has been discussed in the context of the presence of wild type p53 in germ cell Inhibitors,Modulators,Libraries tumors, counteracting tumorigenesis by induction of senescence. By up regulation, the cluster prevents p53 driven cellular senescence via a plethora of target genes, e. g. NEO1 or LATS2, therefore leading to cell proliferation even in the presence of wild type p53.

Furthermore, this cluster has been described in cells exhibiting stem cell properties. Noteworthy, this cluster has recently been identified by other authors to be the most signifi cant differentially expressed Inhibitors,Modulators,Libraries microRNA in human germ cell tumors. Therefore, it appears a promising tar get for further analysis in germ cell tumors, e. g. by posttranscriptional silencing with siRNA, to examine the functional role of the cluster in altering gene expression and thereby elucidate its contribution to the development of cisplatin resistance. As already mentioned, there are other gene changes Inhibitors,Modulators,Libraries which have been discussed in the context of cisplatin resistance. The tumor suppressor Inhibitors,Modulators,Libraries p21, regulating transition through the cell cycle and acting downstream of p53, has already been associated with hsa miR520 belonging to the miR 106 302 family.

An increased Inhibitors,Modulators,Libraries expression of miR 106 302 family members inhibits the tumor suppressor p21 and rescues human mammary epithelial cells from Ras induced senescence. In our analysis, hsa miR520c as well as hsa miR520h were up regulated in NTERA 2 R NTERA 2 and NCCIT R NCCIT cell line pairs, which could point towards another mechanism counteracting senescence. In an in vitro model of cisplatin resistance of a squa mous cell carcinoma cell line, has miR 21 was found to be down regulated in cisplatin resistant cells. In our cell line pairs, significant down regulation of has miR 21 was observed in NCCIT R compared to sensitive NCCIT cells. Furthermore, hsa miR 146a, a microRNA targeting BRCA1, was the most highly up regulated microRNA in another in vitro model of cisplatin resis tance of the breast cancer cell line MCF7.

Similarly, both NTERA 2 R NTERA 2 and NCCIT R NCCIT showed up regulation in our analysis, yet to a lesser extent. However, has miR 221, which was also Trichostatin A TSA highly up regulated in cisplatin resistant MCF7 cells, was down regulated in NCCIT R and unaltered in the other two cell lines in our experiments, indicating that cispla tin resistance seems to be cell line or tumor type speci fic.

Causal proportional hazards estimator Loeys and Goethebeur presen

Causal proportional hazards estimator Loeys and Goethebeur present a method for calcu lating the true treatment efficacy in situations where all patients take their allocated treatment in one arm and compliance is all or nothing in the other arm. This means that if a patient in this arm switches, the switch is assumed to have sellckchem happened at time zero, and the patient is assumed to have only received the treatment they switched onto and none of their allocated treat ment. The method and its implementation in the Stata package are described further by Kim and White. The authors consider a clinical trial in which patients are randomised to receive either a control treatment or an experimental treatment. The method works on the assumption that all patients in the control arm comply fully, and patients in the experimental arm may either comply fully or not at all.

Patients in the control arm are also classed Inhibitors,Modulators,Libraries as either being a complier or non complier depending on how they would Inhibitors,Modulators,Libraries have behaved if they had been randomised to the experimental arm. The proportion of non compliers is assumed to be the same in both arms due to randomisation. The method then makes use of Kaplan Meier survival estimates and the assumed relationship between control and experimental compliers to find an estimate of the hazard ratio. Loeys and Goetghebeur give full details of the methodology used. The method was applied in this investigation using the Stata program stcomply as described by Kim and White.

The all or nothing compliance assumption is a very important limitation of this method Inhibitors,Modulators,Libraries as this type of compli ance is only likely Inhibitors,Modulators,Libraries to occur in very specific scenarios, such as a trial to investigate a new screening program where alternative treatment. Consider a randomised trial with two arms, a control arm receiving no treatment, and an experimental arm. Each patient i has an observed time to event or censoring Ti. Ri A or B is the patients randomised treatment arm. Each patient also has a counterfactual event time Ui which is the event time which would have been observed if no treatment had been received. Patients in the control arm who do not switch treatment will have Ti Ui, so their counterfactual event time will be observed. Ui is unobserved for all other patients. The assumption is made that Ui is independent of Ri due to randomisation balance.

Consider the observed event time Inhibitors,Modulators,Libraries Ti as being made up of a patients time on the control treatment TAi and their time on the experimental treatment TBi, so Ti TAi TBi. For patients who did not switch treatments, either TAi or TBi will be equal to zero. Ti is related to the counterfactual event time Ui by the following causal model patients may be allocated to attend screening but may not attend. As mentioned previously any other enquiries the method also makes the important exclusion restriction assumption, which although untestable, we feel is likely to hold in most set tings.

Lack of Bim

Lack of Bim selleck inhibitor leads to enhanced osteoclast survival and the pro survival factor M CSF decreases Bim levels in osteoclasts and osteoclast precursors, probably by increasing ubiquitin Inhibitors,Modulators,Libraries dependent degradation of Bim via upreg ulation of Inhibitors,Modulators,Libraries cCbl. The role of Bim in BP induced osteoclast apoptosis is not known, although a recent study showed that apoptosis of MCF 7 breast cancer cells induced by the BP risedronate involved increased levels of Bim. Upregula tion of Mcl 1 by RANKL is therefore a likely mechanism by which RANKL prevents BP induced apoptosis of osteoclasts. Conclusions We have shown that RANKL protects osteoclasts from the pro apoptotic and hence anti resorptive effects of the BPs CLO and ALN in vitro. This protective effect of RANKL is likely to be mediated at least in part by an increase in the level of the anti apoptotic protein Mcl 1.

The ability of RANKL, together with Inhibitors,Modulators,Libraries other factors such as TNF, to rescue osteoclasts from the pro apoptotic effects of BPs may account for the apparent lack of effectiveness of BPs in preventing local, inflam mation induced bone loss in RA. The salivary gland system, comprised of the parotid, sub mandibular, sublingual, and minor salivary glands, secretes flu ids rich in proteins that are critical for the maintenance of oral health. Saliva functions to buffer the acidification produced by bacteria residing within the oral cavity, replace ions, moisten food, and lubricate the oral cavity and esophagus. Saliva also contains diges tive enzymes like amylase, anti microbial substances like secretory immunoglobulins, histatins, and splunc, and growth factors like epidermal growth factor.

While there are multiple underlying causes for decreased secretions of saliva, one Inhibitors,Modulators,Libraries of the more severe causes of xerostomia sicca, or dry mouth disease, results from an autoimmune disease, referred to as Sj?grens syndrome, in which the immune system targets initially the salivary and or lacrimal glands. Despite expanding efforts to define the genetic, environmen tal, and immunological bases of SjS, the underlying etiology of this disease remains ill defined. Over the past 20 years, a vari ety of mouse strains have been developed to study the immuno pathophysiological nature of SjS. Based on results of studies using non obese diabetic mice and various sin gle gene knockout congenic partner strains of NOD, we have postulated that the development Inhibitors,Modulators,Libraries and onset of autoimmune exocrinopathy can be divided into at least three distinct tem poral, yet consecutive and overlapping, phases.

In phase 1, aberrant genetic, physiological, and biochemical activities, resulting presumably from retarded salivary gland develop ment and increased acinar cell apoptosis, occur between 6 and 10 weeks of age. In phase 2, occurring around 10 to 18 weeks of age, exocrine gland injury is observed in conjunction with the appearance of leukocytic infiltrates and formation of lymphocytic foci twice consisting mostly of T and B cell aggregates.