Effects of SARS-CoV-2 vaccine (Vero cells) on disease activity in patients with inflammatory bowel disease in China: a multicenter study.

AIMS: To evaluate the impact of SARS-CoV-2 vaccine on IBD activity. METHODS: Adult IBD patients from five large IBD centers in China were enrolled and followed up for 6 months. Patients were divided into vaccinated and unvaccinated groups according to vaccination status. Demographic and clinical data were collected. RESULTS: A total of 280 individuals (213 UC and 67 CD patients) were enrolled in the study. The unvaccinated and vaccinated groups of UC patients were comparable for basic characteristics, including age (t = - 0.8, p = 0.425), sex (χ2 = 0.980, p = 0.322), course of disease (z = - 0.513, p = 0.608), surgical conditions (χ2 = 1.042, p = 0.838), disease extent (χ2 = 4.853, p = 0.088), or baseline drug therapy (χ2 = 7.784, p = 0.064). In the subgroup of UC patients, there was no association between vaccination and disease activities, according to the medium disease activity scores for two groups: unvaccinated patients having scores (IQR) 1(2.75), 1(2), 1(2), and 1(2) at baseline, 1, 3, and 6 months, respectively, whereas vaccinated patients having scores (IQR) 1(2), 1(2), 1(2), and 1(2). Similar conclusions were also derived in the subgroup of CD patients. There were also no statistically significant differences in age (t = - 1.48, p = 0.144), sex (χ2 = 0.003, p = 0.957), course of disease (z = - 0.074, p = 0.941), surgical conditions (χ2 = 0.613, p = 0.594), localization (χ2 = 6.261, p = 0.199), or baseline drug therapy (χ2 = 5.881, p = 0.114) between 2 groups of CD patients. The medium disease activity scores (IQR) of the unvaccinated group at baseline, 1, 3, and 6 months were 1(4), 1(3), 1(3), and 1(3), respectively, whereas those of vaccinated group were 2.5(3.75), 2.5(3.75), 3(2), and 2(2), respectively. Overall, very few participants in this study described worsening IBD disease activity requiring a change or addition of medication. CONCLUSIONS: SARS-CoV-2 vaccine has no adverse effect on disease activity in IBD population. IBD patients should be recommended to receive SARS-CoV-2 vaccine in time.

ETV1 inhibition depressed M2 polarization of tumor-associated macrophage and cell process in gastrointestinal stromal tumor via down-regulating PDE3A.

M2-type polarization of tumor associated-macrophage (TAM) is involved in the malignancy of gastrointestinal stromal tumor (GIST) progression. ETS variant 1 (ETV1) has been previously validated to regulate GIST pathogenesis. Our study intended to explore the role and mechanism of ETV1 in mediating the M2-polarization of TAM in GIST progression. First, we analyzed the correlation between ETV1 expression and M2-polarization in GIST tissues. IL-4 was used to treat THP-1-derived TAM cells and IL-4-stimulated TAM were co-cultured with GIST-T1 cells to mimic the GIST microenvironment. A loss-of-function assay was performed to explore the role of ETV1. Results showed that ETV1 elevation was positively correlated with M2-polarization. IL-4-induced TAM promoted ETV1 expression, silencing ETV1 inhibited proliferation, invasion and KIT activation in IL-4-treated GIST cells, while cell apoptosis was enhanced. Besides, co-culture of ETV1-silenced GIST cells significantly depressed M2-polarization in TAM, presented as decreased levels of CD206, Agr-1 and cytokines, as well as the proportion of CD206-positive TAM. PDE3A was positively correlated with ETV1 and M2-polarization. Overexpressing PDE3A reversed the inhibitory effects of ETV1 silencing. Generally, ETV1 inhibition depressed M2-polarization of TAM in GIST and its promotion on pathological aggravation via down-regulating PDE3A. This evidence may provide a new target for GIST regulation.

Genome-wide analysis of long noncoding RNA and mRNA profiles in PRRSV-infected porcine alveolar macrophages.

Porcine reproductive and respiratory syndrome (PRRS), which is caused by PRRS virus (PRRSV), is one of the most globally devastating swine diseases. It is essential to develop new strategy to control PRRS via an understanding of mechanisms that PRRSV utilizes to interfere with the host's innate immunity. In this study, we deeply sequenced and analyzed long noncoding RNA (lncRNA) and mRNA expression profiles of the porcine alveolar macrophages (PAMs) after PRRSV infection. 126 lncRNAs and 753 mRNAs were differentially expressed between PRRSV-infected and control PAMs. The co-expressed genes of down-regulated lncRNAs were significantly enriched within NF-kappa B and toll-like receptor signaling pathways. Co-expression network analysis indicated that part of the dysregulated lncRNAs associated with the interferon-induced genes. These dysregulated lncRNAs may play an important role in the host's innate immune responses to PRRSV infection. However, further research is required to characterize the function of these lncRNAs.

PGC-1α/SNAI1 axis regulates tumor growth and metastasis by targeting miR-128b in gastric cancer.

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that has been characterized as master regulators of mitochondrial biogenesis. It has been reported that aberrant regulation of PGC-1α is involved in a variety of human cancers. However, whether PGC-1α is involved in the regulation of tumor growth and metastasis in gastric cancer (GC) remains unknown. In the present study, we found that the expression of PGC-1α was upregulated in GC tissues and GC cell lines. Inhibition of PGC-1α inhibited cell viability, migration, and invasion, and promoted cell apoptosis of GC cells. Furthermore, inhibition of PGC-1α downregulated the SNAI1 expression, whereas upregulated microRNA (miR)-128b expression. The expression of SNAI1 was upregulated and the expression of miR-128b was downregulated in GC tissues. We further found that there was a positive correlation between PGC-1α and SNAI1 expression, and a negative correlation between PGC-1α and miR-128b expression or between SNAI1 and miR-128b expression in GC tissues. Moreover, PGC-1α inhibition-induced increased miR-128b expression, and PGC-1α overexpression-induced decreased miR-128b expression were both markedly suppressed by SNAI1 overexpression. In addition, SNAI1 overexpression or miR-128b inhibition partly reversed the effects of PGC-1α inhibition in GC cells. Furthermore, inhibition of PGC-1α suppressed the tumor growth in a nude mouse model, which may be related with the dysregulation of SNAI1 and miR-128b. In conclusion, these data indicate that the PGC-1α/SNAI1/miR-128b axis plays a vital role in GC via regulating cell viability, migration, invasion, and apoptosis.

An eight-long noncoding RNA expression signature for colorectal cancer patients' prognosis.

Long noncoding RNAs (lncRNAs) have recently emerged as important biomarkers of cancer progression. Here, we proposed to develop a lncRNA-based signature with a prognostic value for colorectal cancer (CRC) overall survival (OS). Through mining microarray datasets, we analyzed the lncRNA expression profiles of 122 patients with CRC from Gene Expression Omnibus. Associations between lncRNA and CRC OS were firstly evaluated through univariate Cox regression analysis. A random survival forest method was applied for further screening of the lncRNA signature, which resulted in eight lncRNAs, including PEG3-AS1, LOC100505715, MINCR, DBH-AS1, LINC00664, FAM224A, LOC642852, and LINC00662. Combination of the eight lncRNAs weighted by their multivariate Cox regression coefficients formed a prognostic signature, through which, we could divide the 122 patients with CRC into two subgroups with significantly different OS. Good robustness of the lncRNA signature's prognostic value was verified through an independent data set consisting of 55 patients with CRC. In addition, gene set enrichment analysis indicated the potential association between high prognostic value and oxygen metabolism-related processes. This result should indicate that lncRNAs could be a useful signature for CRC prognosis.

Neural differentiation of bone marrow mesenchymal stem cells with human brain-derived neurotrophic factor gene-modified in functionalized self-assembling peptide hydrogel in vitro.

OBJECTIVE: To investigate the biocompatibility and differentiation of human brain-derived neurotrophic factor (hBDNF) gene-modified bone marrow mesenchymal stem cells (hBDNF-rMSCs) in a functionalized self-assembling peptide hydrogel. METHODS: hBDNF was engineered in rMSCs using adenovirus vector and the enhanced green fluorescence protein (eGFP) was used as a reporter gene. Mesenchymal stem cell-specific surface markers (CD90, CD29, and CD45) were used for identifying rat-derived MSCs. Fluorescence microscope was used to detect the transfection of rMSCs. hBDNF-rMSCs and control cells (eGFP-rMSCs) were seeded in a functional self-assembling peptide hydrogel (RADA16-PRG hydrogel) and a control hydrogel (RADA16 hydrogel). Cells were divided into three groups (hBDNF-rMSCs + RADA16 hydrogel, hBDNF-rMSCs + RADA16-PRG hydrogel, and eGFP-rMSCs + RADA16-PRG hydrogel) and a control group (eGFP-rMSCs + RADA16 hydrogel). Cell growth, cell proliferation, expression of hBDNF-mRNA, the level of hBDNF, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) protein were analyzed for each group. RESULTS: rMSCs were positive for CD90 and CD29 and negative for CD45, green fluorescence was strongly visible at 72 hours after transfection. Compared with control group, the expression of hBDNF-mRNA and levels of hBDNF protein in both hBDNF group were significantly increased (P < 0.01), the cell growth, cell proliferation, and levels of NSE and GFAP protein were significantly increased in three groups ( P < 0.01). Cell growth, cell proliferation, expression of hBDNF-mRNA, and levels of hBDNF, NSE, and GFAP protein in hBDNF-rMSCs + RADA16-PRG hydrogel group were significantly higher than that of hBDNF-rMSCs + RADA16 hydrogel group ( P < 0.01). CONCLUSION: Bone marrow MSCs can be induced into neural cells by the human brain-derived neurotrophic factor gene in a RADA16-PRG functionalized self-assembling peptide hydrogel.

MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer.

MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future.

MiR-506 inhibits PRRSV replication in MARC-145 cells via CD151.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important diseases of swine, which is caused by PRRS virus (PRRSV). CD151, one of PRRSV entry mediators, determines the cell susceptibility for PRRSV. Emerging evidence indicates that the host microRNAs (miRNAs) play key roles in modulating virus infection and viral pathogenesis. In the present study, targeting porcine CD151 miRNAs were identified, and their function during PRRSV infection in MARC-145 cells was further verified. We found that miR-506 could directly target porcine CD151 3'-UTR mRNA by luciferase reporter assay. Overexpression of miR-506 significantly decreased CD151 expression at both mRNA and protein levels. Furthermore, overexpression of miR-506 reduced cellular PRRSV replication and virus release in MARC-145 cells. Our results suggested that miR-506 could inhibit PRRSV replication by directly targeting PRRSV receptor of CD151 in MARC-145 cells. However, the molecular mechanisms of miR-506 and its function in vivo need further investigation.

Multiple cystic echinococcosis in abdominal and pelvic cavity treated by surgery with a 4-year follow-up: a case report.

We report a case of a male patient who presented with multiple abdominal and pelvic echinococcosis. The patient had been diagnosed with hepatic echinococcosis for 7 years and developed intermittent distension and discomfort in the upper abdomen after an accidental fall. In recent years, the patient's abdominal distention increased gradually. Computed tomography revealed multiple hydatid cysts in the liver, spleen, abdominal cavity, and pelvic cavity. Abdominal organs were severely compressed, such that he could not eat normally except for a liquid diet. The patient underwent radical surgical resection based on the multi-disciplinary treatment (MDT) and the operation lasted 10 h, nearly 100 hydatid cysts were excised, about 18 liters of cyst fluid and cyst contents were removed, and the patient lost 20 kg of weight after surgery. The operation was successful, but there were still some postoperative complications such as hypovolemic shock, postoperative ascites, postoperative bile leakage. Treatment measures for the patient were anti-infection, antishock, clamping the abdominal drainage tube, and negative pressure abdominal puncture drainage. At follow up the patient's quality of life had been significantly improved with 15 kg weight gain compared to before.

Multi-Objective Optimization Design and Performance Comparison of Magnetorheological Torsional Vibration Absorbers of Different Configurations.

The purpose of this study is to provide a convenient optimization design method for magnetorheological torsional vibration absorbers (MR-TVA) suitable for automotive engines, which is a damper matching design method that takes into account the needs of the engine operating conditions. In this study, three kinds of MR-TVA with certain characteristics and applicability are proposed: axial single-coil configuration, axial multi-coil configuration and circumferential configuration. The magnetic circuit model, damping torque model and response time model of MR-TVA are established. Then, under the constraints of weight, size and inertia ratio, according to different torsional vibration conditions, the MR-TVA mass, damping torque and response time are multi-objective optimized in two directions. The optimal configurations of the three configurations are obtained from the intersection of the two optimal solutions, and the performance of the optimized MR-TVA is compared and analyzed. The results show that the axial multi-coil structure has large damping torque and the shortest response time (140 ms), which is suitable for complex working conditions. The damping torque of the axial single coil structure is generally large (207.05 N.m), which is suitable for heavy load conditions. The circumferential structure has a minimum mass (11.03 kg) and is suitable for light load conditions.

Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway.

Introduction: Tientsin albino 2 (TA2) mice can develop spontaneous breast cancer (SBC), which is associated with multiple pregnancies and infection with the mouse mammary tumor virus (MMTV). In this study, we sought to elucidate the molecular mechanisms underlying the development of SBC in TA2 mice induced by MMTV. Methods: The integration site of MMTV in TA2 SBC was identified using whole-genome sequencing. The expression of fibroblast growth factor 3 (FGF3) in SBCs and normal breast tissues was compared. The primary cell line, TA-1106, derived from SBC, was cultured. The proliferation, cell cycle, migration, invasion, and tumorigenicity abilities, as well as the expression of epithelial-mesenchymal transition-related proteins, phosphorylated STAT3, and phosphorylated Akt, were assessed in MA-891cell line from TA2 and TA-1106 cells after FGF3 knockdown. The binding of FGF3 to FGF receptor 1 (FGFR1) was determined by co-immunoprecipitation. Additionally, the relationship between STAT3 and Akt phosphorylation was investigated using a small molecule inhibitor and STAT3 knockdown. Results: MMTV integrated upstream of the FGF3 gene, and the FGF3 protein was highly expressed in TA2 SBCs. FGF3 knockdown in MA-891 and TA-1106 decreased their proliferation, migration, and invasion abilities, affected the cell cycle and expression of epithelial-mesenchymal transition-related proteins, and inhibited the growth of animal xenografts. FGF3 binds to FGFR1, and either FGF3 or FGFR1 knockdown decreases STAT3 and Akt phosphorylation levels. Inhibition of phosphorylation or expression of STAT3 resulted in decreased Akt phosphorylation levels. Inhibition of Akt phosphorylation also resulted in decreased STAT3 phosphorylation levels. Furthermore, treatment of MA-891 and TA-1106 cells with Wortmannin or Stattic caused FGFR1 upregulation in addition to inhibiting Akt or STAT3 phosphorylation. Conclusion: The results of this study demonstrate that FGF3 plays a significant role in the development of SBC through the FGF3/FGFR1/STAT3 signaling pathway. There is a reciprocal activation between STAT3 and Akt. Inhibition of STAT3 or Akt phosphorylation promoted the expression of FGFR1. Validating the conclusions obtained in this study in human breast cancer (HBC) may contribute to targeted therapy and it is worth exploring whether the homologous sequences of MMTV in HBC have a similar oncogenic effect.

KAT7 promoted gastric cancer progression through promoting YAP1 activation.

Lysine acetyltransferase 7 (KAT7) was upregulated in gastric cancer (GC) patient tissues, and associated with poor prognosis and metastasis. However, its specific role in GC remains unclear. This study aimed to annotate the role of KAT7 in GC cells. The results showed that the overexpression of KAT7 promoted cell growth, migration, and invasion, while KAT7 inhibition has the opposite effect. Besides, KAT7 participated in cell cycle phase distribution and epithelial-mesenchymal transition (EMT) process of GC cells. In addition, KAT7 promoted the transcription and nuclear translocation of Yes-associated protein 1 (YAP1) in MKN45 cells. Silence of YAP1 partly reversed the promoting effect of KAT7 on GC cells progression. In summary, this study indicates that KAT7 promoted GC cells progression through promoting YAP1 activation, contributes to understand the specific role of KAT7 in GC.

Association of IFNA16 and TNFRSF19 Polymorphisms with Intramuscular Fat Content and Fatty Acid Composition in Pigs.

Interferon-alpha-16 (IFNA16) and tumor necrosis factor receptor superfamily member 19 (TNFRSF19) are cytokines that may play a role in adipogenesis and fatness. Single nucleotide polymorphisms (SNPs) of the porcine IFNA16 and TNFRSF19 genes were verified and their association with intramuscular fat (IMF) content and fatty acid (FA) composition were evaluated in commercial crossbred pigs. Two non-synonymous SNPs of the porcine IFNA16 c.413G > A and TNFRSF19 c.860G > C loci were detected in commercial crossbred pigs. The porcine IFNA16 c.413G >A polymorphism was significantly associated with stearic acid, total saturated FAs (SFAs), and the ratio of monounsaturated FAs (MUFAs) to SFAs (p < 0.05). Furthermore, the porcine TNFRSF19 c.860G > C polymorphism was found to be significantly associated with IMF content and arachidic acid levels (p < 0.05). The results revealed that porcine IFNA16 and TNFRSF19 polymorphisms are related to IMF content and/or FA composition and affirmed the importance of these cytokine genes as potential candidate genes for lipid deposition and FA composition in the muscle tissue of pigs.

Correction: An integrated surgical training program for hepatic cystic echinococcosis in Xinjiang of China.

[This corrects the article DOI: 10.1371/journal.pntd.0008023.].

Intestinal Immune System and Amplification of Mouse Mammary Tumor Virus.

Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer's patches (PPs) in mouse intestine are the first and specific target organ. MMTV can be transported into PPs by microfold cells and then activate antigen-presenting cells (APCs) by directly binding with Toll-like receptors (TLRs) whereas infect them through mouse transferrin receptor 1 (mTfR1). After being endocytosed, MMTV is reversely transcribed and the cDNA inserts into the host genome. Superantigen (SAg) expressed by provirus is presented by APCs to cognate CD4+ T cells via MHCII molecules to induce SAg response, which leads to substantial proliferation and recruitment of related immune cells. Both APCs and T cells can be infected by MMTV and these extensively proliferated lymphocytes and recruited dendritic cells act as hotbeds for viral replication and amplification. In this case, intestinal lymphatic tissues can actually become the source of infection for the transmission of MMTV in vivo, which results in mammary gland infection by MMTV and eventually lead to the occurrence of breast cancer.

Association of adipocytokine IL-1A and IL-6 genes with intramuscular fat content and fatty acid composition in pigs.

Several adipocytokines are involved in inflammatory and immune responses as well as regulated fat deposition and lipid metabolism in mammals. This study aimed to verify the polymorphisms of the porcine interleukin 1A (IL-1A) and interleukin 6 (IL-6) genes and to assess their association with intramuscular fat (IMF) content and fatty acid (FA) composition in commercial crossbred pigs. Two single nucleotide polymorphisms (SNPs) of the porcine IL-1A g.43722547A>G and IL-6 g.91508173C>T loci were found to be segregating in these crossbred pigs. Furthermore, the porcine IL-1A g.43722547A>G polymorphism was found to be significantly associated with myristic, palmitic, palmitoleic, and eicosadienoic acid levels. Moreover, the porcine IL-6 g.91508173C>T polymorphism was significantly associated with IMF content and homolinolenic acid levels. These results suggest that the polymorphisms of the porcine IL-1A and IL-6 genes correlated with lipid content and FA composition and confirmed the importance of the adipocytokine IL-1A and IL-6 genes as candidate genes for fatty acid composition in the muscles of pigs.

Association of IL-4 and IL-4R Polymorphisms with Litter Size Traits in Pigs.

The interleukin-4 (IL-4) and interleukin-4 receptor (IL-4R) are cytokines that are involved in the immune and reproductive systems. This study aimed to verify the polymorphisms in the porcine IL-4 and IL-4R genes and to assess their effects on litter size traits in commercial pigs. Single nucleotide polymorphisms (SNPs) in the porcine IL-4 and IL-4R genes were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A non-coding SNP of IL-4 g.134993898T > C and a non-synonymous SNP of IL-4R c.1577A > T (amino acid change at position 526, Q526L) were found to be segregating in Landrace sows. The IL-4 g.134993898T > C polymorphism was significantly associated with the number of piglets weaned alive (NWA) trait. The IL-4R c.1577A > T polymorphism was significantly associated with the number born alive (NBA) and NWA traits. Moreover, the accumulation of favorable alleles of these two SNP markers revealed significant associations with the NBA, NWA, and mean weight of piglets at weaning (MWW) traits. These findings indicate that the porcine IL-4 and IL-4R genes may contribute to the reproductive traits of pigs and could be used as candidate genes to improve litter size traits in the pig breeding industry.

An integrated surgical training program for hepatic cystic echinococcosis in Xinjiang of China.

BACKGROUND: Human cystic echinococcosis (CE) is one of the commonest zoonoses, and it is endemic in many parts of the world including China. Complications and recurrences after the surgical treatment of hepatic CE (HCE) incur a large personal, healthcare, and societal burden. There has been some progress in HCE prevention, diagnosis, and treatment, but there is no "one size fits all" approach, and surgery still remains the cornerstone of treatment for some cyst stages and locations or in areas with little knowledge or access to other treatment modalities. In 2009 we designed and implemented a program to improve surgical outcomes from HCE in Xinjiang province, China. METHODOLOGY/PRINCIPAL FINDINGS: A multimodal HCE training program was implemented in eleven primary hospitals in Xinjiang province, China, which provided education and training on HCE clinical knowledge and practice, the application of diagnostic and treatment options, and optimal surgery. The management of HCE cases was analyzed before and after program implementation. Contrast enhanced CT use, application of scoloicidal agents, removal of necrotic cyst wall remnants, appropriate perioperative drug use, and the use of optimal surgical approach increased after program implementation. Further, postoperative recurrences and residual cavity complications creased from 7.4% to 1.3% and 15.2% to 9.0% after program implementation, respectively. CONCLUSIONS/SIGNIFICANCE: Tis integrated surgical training program is useful for improving outcomes of patients with HCE and can be used in institutions in other endemic areas.

Transcription elements AREB6 and miR-34a affect apoptosis of PAMs by regulating the expression of SS2-related gene PPP1R11.

In our previous work, gene PPP1R11 (protein phosphatase 1 regulatory subunit 11) was significantly expressed in pigs after Streptococcus suis 2 (SS2) challenged. This study firstly confirmed that SS2 induced significant expression of PPP1R11 gene in porcine alveolar macrophage (PAM) cells, and apoptosis of PAM cells were observed. After that, the core promoter of porcine PPP1R11 was identified and its transcription factor AREB6 which significantly regulated PPP1R11. We also characterized that the PPP1R11 gene is a target of miR-34a. Further, we found that PPP1R11 helped to inhibit apoptosis of PAM cells under SS2 infecting, through transcription factor AREB6 was negatively correlated with apoptosis whereas miR-34a was positively correlated. Those findings provide a functional connection among the transcription factor AREB6, miR-34a, PPP1R11 gene and apoptosis of PAM cells in the pathogenesis of the SS2 infection.