Therapy with regulatory T-cell infusion in autoimmune diseases and organ transplantation: A review of the strengths and limitations.

In the last decade, cell therapies have revolutionized the treatment of some diseases, earning the definition of being the "third pillar" of therapeutics. In particular, the infusion of regulatory T cells (Tregs) is explored for the prevention and control of autoimmune reactions and acute/chronic allograft rejection. Such an approach represents a promising new treatment for autoimmune diseases to recover an immunotolerance against autoantigens, and to prevent an immune response to alloantigens. The efficacy of the in vitro expanded polyclonal and antigen-specific Treg infusion in the treatment of a large number of autoimmune diseases has been extensively demonstrated in mouse models. Similarly, experimental work documented the efficacy of Treg infusions to prevent acute and chronic allograft rejections. The Treg therapy has shown encouraging results in the control of type 1 diabetes (T1D) as well as Crohn's disease, systemic lupus erythematosus, autoimmune hepatitis and delaying graft rejection in clinical trials. However, the best method for Treg expansion and the advantages and pitfalls with the different types of Tregs are not fully understood in terms of how these therapeutic treatments can be applied in the clinical setting. This review provides an up-to-date overview of Treg infusion-based treatments in autoimmune diseases and allograft transplantation, the current technical challenges, and the highlights and disadvantages of this therapeutic approaches."

Investigation of the Association Between ITPA Gene 94C>A Sequence Variant and Kidney Transplant Rejection in Iranian Kidney Transplant Recipients.

OBJECTIVES: Thiopurine prodrugs are commonly used in kidney transplant recipients. Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene. Alteration of ITPA gene is one of the pharmacogenetic sequence variants possibly involved in thiopurine metabolism. The ITPA 94C>A sequence variant (C-to-A substitution at nucleotide 94) is associated with an increased risk of adverse drug reactions in patients treated with the thiopurine drug. The aim of the present study was to investigate the effect of the ITPA 94C>A gene sequence variant in kidney transplant recipients. MATERIALS AND METHODS: The genotyping of the ITPA rs1127354 variant was performed by the polymerase chain reaction restriction fragment length polymorphism method in 140 kidney transplant recipients and in 100 control participants. Data were analyzed with SPSS statistical software. RESULTS: The results revealed a significant difference between control and nonrejection groups regarding the rs1127354 genotype and allele frequency. No significant difference was found between the rejection and nonrejection groups regarding the rs1127354 genotype and allele frequency. Also, a significant association was observed between the ageofthe control group and age of the rejection group. No significant differences between sex and underlying disease in patients with or without rejection were observed. CONCLUSIONS: We observed no significant differences between rejection and nonrejection transplant. Further studies are recommended, in a larger population and with different ethnicities.

Cohort Profile: Shiraz Pediatric Liver Cirrhosis Cohort (SPLCCS).

Liver diseases in children and adolescents are a significant and arising public health issue and should be surveyed from different dimensions (clinical and para-clinical, psychological, socio-economic) and in diverse populations. Shiraz Liver Transplant Center, Shiraz, Iran is the only center for pediatric liver transplantation and its pre-operative evaluations. This provides a unique and valuable situation for studying this vulnerable population. The Shiraz Pediatric Liver Cirrhosis Cohort Study (SPLCCS) was established to assess cirrhotic children, the course of their disease, and treatment over time. This cohort study aimed to prospectively evaluate the natural course and factors that contributed to complications and death of children with chronic liver disease in the region. SPLCCS was launched in September 2018 after obtaining ethical approval; until August 2022, 370 children with end-stage liver disease were enrolled and followed every six months. Here, the cohort's features, the included population's baseline characteristics, and primary outcomes are reported.

Altered Signatures of Plasma Inflammatory Proteins and Phonotypic Markers of NK Cells in Kidney Transplant Patients upon CMV Reactivation.

Cytomegalovirus (CMV) reactivation remains a common opportunistic infection with a prominent role in immune reconstitution in organ transplant recipients. CMVs as important drivers of natural killer (NK) cell differentiation has been indicated to prompt several phenotypic and functional alteration in these cells. We aimed to monitor the reconstitution of NK cells and change the signature of inflammatory proteins at the critical phase of CMV reactivation over six months after kidney transplantation. The present study indicated that CMV reactivation is associated with the development of IL-6, IL-10, and cytotoxic granules, including granzyme-B and granulysin, and the drop in the frequency of CD16 + NKG2A-CD57 + NK cell subset in kidney transplant recipients (KTRs) with reactivation versus non- reactivated ones. Our findings describe distinct immune signatures that emerged with CMV reactivation after kidney transplantation, which may be helpful in the timely management of CMV infection in KTRs.

An Update on Protective Effectiveness of Immune Responses After Recovery From COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits variable immunity responses among hosts based on symptom severity. Whether immunity in recovered individuals is effective for avoiding reinfection is poorly understood. Determination of immune memory status against SARS-CoV-2 helps identify reinfection risk and vaccine efficacy. Hence, after recovery from COVID-19, evaluation of protective effectiveness and durable immunity of prior disease could be significant. Recent reports described the dynamics of SARS-CoV-2 -specific humoral and cellular responses for more than six months in convalescent SARS-CoV-2 individuals. Given the current evidence, NK cell subpopulations, especially the memory-like NK cell subset, indicate a significant role in determining COVID-19 severity. Still, the information on the long-term NK cell immunity conferred by SARS-CoV-2 infection is scant. The evidence from vaccine clinical trials and observational studies indicates that hybrid natural/vaccine immunity to SARS-CoV-2 seems to be notably potent protection. We suggested the combination of plasma therapy from recovered donors and vaccination could be effective. This focused review aims to update the current information regarding immune correlates of COVID-19 recovery to understand better the probability of reinfection in COVID-19 infected cases that may serve as guides for ongoing vaccine strategy improvement.

The effects of metformin monotherapy and combination of metformin and glibenclamide therapy on the expression of RAGE, Sirt1, and Nrf2 genes in peripheral blood mononuclear cells of type 2 diabetic patients.

Purpose: Although metformin is the first-line treatment of type 2 diabetes mellitus (T2DM), a few studies have evaluated the benefits of monotherapies (metformin) versus combination therapy (metformin and glibenclamide) for treatment of T2DM patients. The present study aimed to evaluate the effect of monotherapy with metformin compared to combination therapy with metformin and glibenclamide on the expression of RAGE, Nrf 2, and Sirt1genes. Methods: EightyT2DM patients and 40 healthy individuals participated in this case-control study. The patients in the treatment group were divided into two groups who received either metformin alone (n = 40) or metformin in combination with glibenclamide (n = 40). FBS, HbA1c, and fructosamine were measured. The expression of RAGE, Nrf 2, and Sirt 1 genes in PBMC of all subjects were assessed using real-time PCR. Results: RAGE gene expression in both treatment groups was significantly lower than the control (P < 0.05). RAGE gene expression was significantly reduced in the combination of metformin and glibenclamide treated group compared to metformin group (P < 0.05). Additionally, the expression of Sirt 1 and Nrf 2 genes in both treatment groups was higher than that of the control group (P < 0.05). The expression of Sirt 1 and Nrf 2 genes in metformin and glibenclamide treated group were higher than the metformin group (P < 0.05). Conclusion: Combination therapy (metformin and glibenclamide) showed stronger effect on repression of the RAGE gene and activation of Nrf 2 and Sirt 1 genes compared to monotherapy (metformin); therefore, it can be concluded that combination therapy may have more protective effects on the T2DM patients. No significant correlation was observed between HbA1c and RAGE, Sirt 1, and Nrf 2 genes expression.

Loss of CCR7 Expression on CD57 + CD56/ CD16 + NK Cells Correlates with Viral Load in CMV Reactivated Kidney Transplant Recipients.

INTRODUCTION: Despite developing strategies for antiviral treatment, cytomegalovirus (CMV) infection remains one of the most common challenges in kidney transplant recipients (KTRs). The evaluation of CMV viral load is still the most practical main clinical approach for CMV assessment and guides decision-making in recipient antiviral treatment. However, there is not a specific viral load cut off for initiating treatment yet. On the other hand, the cellular immune system and the innate immune response prove their roles in diagnosing CMV reinfection and monitoring the therapeutic regime to control CMV. Interactions among the components of cellular immunity encounter CMV reactivation provide a strong treatment management plan for clinical decisions about antiviral therapy against CMV. Natural killer (NK) cells, as essential effector cells, present potentially antiviral activity through distinct subpopulations. CCR7expressing NK cells were identified by high cytotoxicity and functionality among NK cell subsets. Here, we explored the correlation between CCR7+ expressing NK cells with viral load in CMV reactivated-kidney transplant recipients. MATERIALS AND METHODS: A cross-sectional study was conducted among ten CMV reactivated KTRs. The CMV DNA copy number was evaluated utilizing real-time PCR.NK cell phenotypic profiling was done using flow cytometry. RESULTS: Increasing of CMV viral load in CMV reactivated KTRs had a negative correlation with CCR7+CD57+ CD56/CD16+ NK cell (P < .05 r = -0.7) after CMV reactivation. Significantly increased level of CCR7-CD57- CD56/CD16+ NK cell was associated with CMV viral load within CMV reactivated KTRs (P < .05, r = 0.68). CONCLUSION: CCR7 expression is associated with CMV reactivation, which offers a new aspect of CMV-associated immunity within the NK cell compartment.  DOI: 10.52547/ijkd.6721.

Effects of exercise training on immunological factors in kidney transplant recipients; a randomized controlled trial.

The purpose of this study was to investigate the effects of a 12 week exercise training on the immune system of kidney transplant recipients. 23 kidney transplant recipients were randomly divided into two groups including control (n = 10) and training (n =13) groups. The training groups participated in the training for 10 weeks (three days a week; each day 60-90 minutes). The control group performed no regular exercise during this time. The blood samples were taken before and after 12 weeks. ELISA and Real-time PCR were used to evaluate cytokine profiles, including TNF-a, IL-6, IL-4, IL-31 and IL-35 as well as T-bet, GATA-3, RORYt and FOXP3, respectively. Finally, the data were analyzed, using paired T-test. ELISA results showed decreased levels of TNF- α, increased levels of IL-6 and no significant differences in the IL-35, IL-31 and IL-4 levels in the training group in comparison to the control group. Gene expression profiles showed significantly increased expression of T-bet and no changes in the GATA-3, RORYt and FOXP3 levels. According to these results, a moderate exercise including aerobic and resistance training could inhibit inflammatory cytokines and have beneficial effects on the immune system, but this issue needs further research.

An Investigation of the Association Between Vascular Endothelial Growth Factor +405 G/C Polymorphism and Acute Liver Transplant Rejection in Iranian Liver Transplant Recipients.

OBJECTIVES: Vascular endothelial growth factor is an endothelial-specific growth factor that promotes endothelial cell proliferation, differentiation, and survival; mediates endothelium-dependent vasodilatation; induces microvascular hyperpermeability; and participates in interstitial matrix remodeling. The aim of the present study was to investigate the association between +405 G/C polymorphism of vascular endothelial growth factor and the risk of liver rejection in liver transplant recipients. MATERIALS AND METHODS: The present study included 124 patients with liver disease that led to liver transplant. There were 22 patients who experienced histologically proven acute liver rejection, and the other 102 patients showed no rejection. Both groups were matched for sex and age. The VEGF+405 G/C polymorphism was evaluated by the polymerase chain reaction-restriction fragment-length polymorphism method. RESULTS: Our analyses showed no significant relationships between genotypes and alleles of +405 G/C and risk of acute liver transplant rejection. CONCLUSIONS: Our report indicated that there was no association between the carrier states of +405 G/C gene polymorphism of vascular endothelial growth factor and acute rejection or nonrejection of liver transplant.

Effects of combined aerobic and anaerobic exercise training on cytokine profiles in patients with systemic lupus erythematosus (SLE); a randomized controlled trial.

BACKGROUND: Systemic lupus erythematosus (SLE) is an inflammatory rheumatic disease characterized by production of autoantibodies and organ damage. Elevated levels of cytokines have been reported in SLE patients. Physical activity could be considered one of the factors that affect the immune system status and function. The aim of the present study was to evaluate the effects of an 8-week supervised aerobic and anaerobic training program on the immune system of SLE patients through evaluation of serum cytokine levels. METHODS: This cross-sectional study included 24 SLE patients selected between September 2015 and March 2016. The patients were randomly divided into two groups, including exercise (n = 14) and control (n = 10) groups. The exercise group participated in an 8-week combined supervised exercise training program consisting of three times per week in 60-min exercise sessions. After collection of whole peripheral blood, peripheral blood mononuclear cells (PBMCs) were isolated from the blood samples. Following RNA extraction and cDNA synthesis, the expression levels of IFN-γ, TNF-α, IL-6, IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, and IL-22 were determined using in-house SYBER Green-based real-time polymerase chain reaction (PCR). Lastly, the data obtained were analyzed using t-test. RESULTS: The mean and standard deviation of age were 29.00 ± 3.19 and 21.50 ± 5.52 in the intervention and control groups, respectively. No significant differences were found among the mean serum levels of IFN-γ, IL6, IL-9, IL-17A, IL-17F and IL-21 among SLE patients in the intervention and control groups. The mean serum levels of TNF-α, IL2, IL-4, and IL-5 decreased significantly in the intervention as compared with the control group. The mean serum levels of IL-10, IL-13 and IL-22 significantly increased in the control group after eight weeks, as compared with the intervention group. CONCLUSIONS: Our findings indicated that the 8-week supervised aerobic and anaerobic training program could result in decreased inflammatory cytokines.

Investigation of the Association Between the ITPA Gene 94C>A Gene Sequence Variant and Liver Transplant Rejection in Iranian Liver Transplant Recipients.

OBJECTIVES: Inosine triphosphate pyrophosphatase is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of thiopurine nucleotides into DNA and RNA. Thiopurine drug metabolites such as azathioprine and 6-mercaptopurine have been included in the lists of inosine triphosphate pyrophosphatase substrates. Inosine triphosphatase gene alterations are other pharmacogenetic sequence variants possibly involved in thiopurine metabolism. This study aimed to evaluate the possible association between ITPA 94C>A gene sequence variant (C-to-A substitution at nucleotide 94) in liver transplant recipients. MATERIALS AND METHODS: The genotyping of ITPA 94C>A was evaluated by the polymerase chain reaction- restriction fragment length polymorphism method in 200 liver transplant recipients as well as 100 controls. Data were analyzed with SPSS statistical software. RESULTS: This study showed statistically significant associations between the CA genotype of the ITPA 94C>A sequence variant and liver transplant in the rejection and nonrejection groups. Moreover, the results reported in this study showed no significant differences between sex, age, and blood group in patients with liver transplant (with or without transplant rejection). CONCLUSIONS: Our results indicated that there were statistically significant associations of the CA genotype of ITPA 94C>A sequence variant with liver transplant in the rejection and nonrejection groups. Further studies are recommended.

The Direct Influence of Cytomegalovirus Lysate on the Natural Killer Cell Receptor Repertoire.

Natural killer (NK) cells are essential for controlling certain viral infections, including cytomegalovirus (CMV). In particular, the importance of NK cells in the context of CMV infection is underscored by the adaptive capabilities of these cells. Evidence suggests that some viruses can directly interfere with NK cell compartments and their activation and lead to shape-shifting the NK cell receptor repertoire. Still, it remains unknown whether the CMV can interact with NK cells without intermediaries. Here, we examined whether the direct effects of CMV lysate alter phenotypical properties of NK cells. To investigate this issue, NK cells were isolated from the blood of CMV seropositive healthy donors by negative magnetic separation. Isolated NK cells were cultured in the presence of CMV lysate and analyzed for the expression of NKG2A, NKG2C, and CD57 by FACS caliber. The results showed that NKG2C expression is significantly upregulated in the presence of CMV lysate compared to without stimulated group (mean increase, 6.65 %; 95% CI, 0.2582 to 13.02; p=0.043; R square: 0.38). Likewise, results have shown a significant decrease in the frequency of NKG2A+CD57- NK cell subsets (p=0.005; 95% CI, -13.49 to -3.151; R square: 0.5957) in the stimulated group compared to without stimulated ones. According to these results, CMV may drive a direct influence on NK cell receptor repertoire, including the expansion of NK cells expressing NKG2C receptor, which is needed for further studies.

Glutathione S-Transferase Omega-2 and Transforming Growth Factor-ß1 Polymorphisms in Iranian Glaucoma Patients.

BACKGROUND: To investigate the association of glutathione s-transferase omega 2 (GSTO2) (142N > D) and transforming growth factor-ß1 (TGF-ß1) (869T > C) gene polymorphisms on the pathogenesis of two common types of glaucoma (including primary open-angle glaucoma (POAG) and chronic angle-closure glaucoma (CACG)) in the Iranian population. METHODS: A total of 100 glaucoma patients (60% males and 40% females with an age mean ± SD of 34.66 ± 14.25 years; 56 cases of POAG and 44 cases of CACG) were enrolled in this study. GSTO2 (142N > D) and TGF-ß1 (869T > C) polymorphisms were evaluated by PCR-based methods in patients and controls. RESULTS: At locus GSTO2 (142N > D), the odds of ND genotype with respect to DD and NN genotypes were 1.55 and 2.08 times higher in POAG and CACG patients compared to those of patients in the control group (95% CI1: 0.80-2.98; 95% CI2: 1.00-4.33) which was statistically significant in CACG patients. However, the odds of DD and NN genotypes against the reference genotype in two patients group were not statistically significant as compared to those of patients in the control group. There was a significant association between the ND genotype and male patients (OR = 2.28, 95% CI: 1.06-4.92). The analysis of TGF-ß1 (869T > C) polymorphisms showed no significant difference between the genotypes of TGF-ß1 (869T > C) polymorphisms in patients and control groups; however, the CT genotype of TGF-ß1 significantly differed between female controls and patients (OR = 0.42, 95% CI: 0.18-0.96). CONCLUSION: The presented results revealed that there was a significant association between the ND genotype of GSTO2 and the pathogenesis of glaucoma. Furthermore, this genotype can be considered as a sex-dependent genetic risk factor for the development of glaucoma. In contrast, the CT genotype of TGF-ß1 is suggested to be a protective genetic factor against the pathogenesis of glaucoma.

Comparison of FOXP3 and Interleukin 35 Expression Profiles in Kidney Transplant Recipients With Excellent Long-Term Graft Function and Acute Rejection.

OBJECTIVES: Transplant tolerance is defined as graft acceptance without long-term use of immunosuppressive agents. Regulatory T cells are involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. In the present study, we compared the expression profiles of forkhead box protein P3 (FOXP3) and interleukin 35 in kidney transplant recipients who had excellent long-term graft function under immunosuppression versus recipients who had acute rejection. MATERIALS AND METHODS: The 40 kidney transplant recipients included in this study were divided into 2 groups: 27 recipients with excellent long-term graft function and 13 recipients with acute rejection. After collection of whole peripheral blood, peripheral blood mononuclear cells were isolated from the blood samples. After RNAextraction and cDNAsynthesis from each collected sample, expression levels of interleukin 35 and FOXP3 were determined using in-house SYBER green-based real-time polymerase chain reaction. We used t tests to analyze data. RESULTS: Mean ages of recipients with excellent longterm graft function and recipients with acute rejection were 42.1 and 45.5 years, respectively. We found that FOXP3 and interleukin 35 expression levels were significantly increased in recipients with excellentlongterm graftfunction comparedwith recipientswith acute rejection. FOXP3 expression levels were significantly higher in those with excellent long-term graft function with graft survivalrate of <10 years,whereas interleukin 35 expression levels were significantly higher in patients with graft survival rate >10 years (P < .05). Expression levels of FOXP3 and interleukin 35 were greater in those from 35 to 50 years old versus with those in the other age ranges. CONCLUSIONS: Expression patterns of FOXP3 and interleukin 35 may have the potential to be used as prognostic biomarkers for kidney transplant outcomes.

Circulating NKG2C + NK cell expressing CD107a/LAMP-1 subsets at the onset of CMV reactivation in seropositive kidney transplant recipients.

Cytomegalovirus (CMV) infection contributes to morbidity and mortality among kidney transplant recipients. Natural killer (NK) cells can battle against CMV in kidney transplant recipients (KTRs). This study aimed to analyze the association between CMV reactivation and the proportion of NK cell subsets and their activity. In a cross-sectional study, ten CMV reactivated KTRs, and ten non- CMV reactivated ones were recruited. Ten matched healthy controls were also included in this cohort. The presence of anti-CMV-IgG Ab in both KTR subgroups from seronegative donors and healthy controls was determined. The frequency of distinct subsets of memory-like NK cells was analyzed through NKG2C, NKG2A, and CD57 using flow cytometry. The activity of NK cells was evaluated after stimulation via coculture with K562 cell line and then assessment of the frequency of CD107a and granzyme B. The mRNA levels of transcription factors, including T-bet, EAT, and inflammatory proteins, including IFN-γ and perforin contributing to NK cell activation, were also evaluated. Results showed a significantly lower frequency of NKG2C + NKG2A-CD57+ NK cell population in CMV-reactivated KTRs compared to non-reactivated ones (P-value:0.003). NKG2C+ NK cells expressing CD107a/LAMP-1 significantly was increased in CMV-reactivated KTRs compared to non-reactivated ones (P-value: 0.0002). The mRNA level of IFN-γ had a significant increase in the CMV-reactivated KTRs vs. nonreactive ones (P-value: 0.004). Finally, evaluation of the NK cells' cytotoxicity and activity through assessment of CD107a/LAMP-1 expression and IFN-γ secretion may be helpful for the identification of the risk of CMV reactivation in KTRs.

The potential of the incorporated collagen microspheres in alginate hydrogel as an engineered three-dimensional microenvironment to attenuate apoptosis in human pancreatic islets.

BACKGROUND: Tissue engineering is considered as a promising tool for remodeling the native cells microenvironment. In the present study, the effect of alginate hydrogel and collagen microspheres integrated with extracellular matrix components were evaluated in the decrement of apoptosis in human pancreatic islets. MATERIALS/METHODS: For three-dimensional culture, the islets were encapsulated in collagen microspheres, containing laminin and collagen IV and embedded in alginate scaffold for one week. After that the islets were examined in terms of viability, apoptosis, genes and proteins expression including BAX, BCL2, active caspase-3, and insulin. Moreover, the islets function was evaluated through glucose-induced insulin and C-peptide secretion assay. In order to evaluate the structure of the scaffolds and the morphology of the pancreatic islets in three-dimensional microenvironments, we performed scanning electron microscopy. RESULTS: Our findings showed that the designed hydrogel scaffolds significantly improved the islets viability using the reduction of activated caspase-3 and TUNEL positive cells. CONCLUSIONS: The reconstruction of the destructed matrix with alginate hydrogels and collagen microspheres might be an effective step to promote the culture of the islets.

Alterations in MicroRNA gene expression profile in liver transplant patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) can lead to liver failure which renders to liver transplant. miRNAs might be detected as biomarkers in subclinical stage of several hepatobiliary disorders like HCC. Therefore, in the present study, alterations in miRNAs as biomarkers were detected in LT patients with HCC. METHODS: Fourteen tissue samples composed of 5 rejected and 9 non-rejected ones were used for studying the miRNAs expression pattern using LNA-array probe assay and the result was evaluated by in house SYBR Green Real-time PCR protocols on 30 other tissue samples composed of 10 rejected and 20 non-rejected ones for the selected miRNAs. All samples were collected from liver transplanted patients with HCC. RESULTS: The study results revealed that in rejected patients compared to non-rejected ones, hsa-miR-3158-5p, -4449, -4511, and -4633-5p were up-regulated and hsa-miR-122-3p, -194-5p, 548as-3p, and -4284 were down-regulated. ROC curve analysis also confirmed that miR194-5p and -548as-3p in up-regulated and also, miR-3158-5p, -4449 in down-regulated microRNAs are significantly important molecules in rejection. CONCLUSION: Finally, the tissue levels of specific miRNAs (especially hsa-miR-3158-5p, -4449, -194-5p and -548as-3p) significantly correlated with the development of HCC, which can be present as biomarkers after further completing studies.

TLR2 and TLR4 mRNA expression levels in liver transplant patients with acute rejection.

Toll-like receptors (TLRs) have important role in transplant outcomes by activating the innate immune system and production of pro-inflammatory cytokines, leading to graft rejection. We assessed the expression level of TL2 and TLR4 in acute rejection (AR) on the 1st and 7th-day post-transplantation. TLR2 and TLR4 expressions were evaluated by real-time PCR in both the AR group (n = 50) and non-AR (n = 50), compared with the control group. Also, the correlation of the expression levels of TLRs between both the 1st and 7th day was analyzed. ROC curve analysis was used to determine the cut-off value for TLRs expression. TLR4 mRNA expression was significantly up-regulated in AR patients vs. the controls on the 1st day (p ≤ 0.05) and it was down-regulated in non-AR vs. controls on the 1st day (p ≤ 0.05). Also, TLR4 expression had decreased in both AR and non-AR groups vs. control on the 7th day (p ≤ 0.05). Both TLR2 and TLR4 expression in comparison to non-AR had increased in the AR group on the 7th day (p ≤ 0.05). TLR2 expression positively correlated between 1st and 7th day in AR (r = 0.3, (p ≤ 0.05) and non-AR group (r = 0.2, p ≤ 0.05). ROC curve analysis showed a cut-off value of TLR2 up to 0.98 with sensitivity 71.05 (95%CI = 54.1-84.6) and specificity 63.27 (95%CI = 48.3-76.6) that could distinguish between AR and non-AR group (p ≤ 0.05). The data support that both TLR2 and TLR4 expression have an effective role in AR after liver transplantation and could be used as possible biomarkers for AR to choose better therapeutic strategies based on immunological aspects.

A Recurrent Temporal Model for Semantic Levels Categorization Based on Human Visual System.

Humans can categorize an object in different semantic levels. For example, a dog can be categorized as an animal (superordinate), a terrestrial animal (basic), or a dog (subordinate). Recent studies have shown that the duration of stimulus presentation can affect the mechanism of categorization in the brain. Rapid stimulus presentation will not allow top-down influences to be applied on the visual cortex, whereas in the nonrapid, top-down influences can be established and the final result will be different. In this paper, a spiking recurrent temporal model based on the human visual system for semantic levels of categorization is introduced. We showed that the categorization problem for up-right and inverted images can be solved without taking advantage of feedback, but for the occlusion and deletion problems, top-down feedback is necessary. The proposed computational model has three feedback paths that express the effects of expectation and the perceptual task, and it is described by the type of problem that the model seeks to solve and the level of categorization. Depending on the semantic level of the asked question, the model changes its neuronal structure and connections. Another application of recursive paths is solving the expectation effect problem, that is, compensating the reduce in firing rate by the top-down influences due to the available features in the object. In addition, in this paper, a psychophysical experiment is performed and top-down influences are investigated through this experiment. In this experiment, by top-down influences, the speed and accuracy of the categorization of the subjects increased for all three categorization levels. In both the presence and absence of top-down influences, the remarkable point is the superordinate advantage.

Expression Pattern of MicroRNA-21 during the Liver Ischemia/Reperfusion.

Ischemia/reperfusion (I/R) injury in cadaveric liver transplantation is not avoidable. Liver I/R injury is an important phenomenon in hepatic damage. MicroRNA-21 (miR-21) plays an important role in I/R injury. The present study aimed to determine the expression pattern of miR-21 in liver I/R injury/recovery and its correlation with the immunologic transmission signals pathways several days post-reperfusion. In an animal model for I/R in the liver, 40 male Balb/c mice were divided into 3 groups. The animals were monitored for 3 and 24 hours, and also for 4, 7, 14, and 28 days post-reperfusion. Liver tissue damage was assessed by histopathology. The plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total antioxidant capacity (TAC) levels were measured with enzymatic assays. MiR-21, programmed cell death 4 (PDCD4) mRNA, T-cell-restricted intracellular antigen 1 (TIA1) mRNA, and fas ligand (FASL) mRNA expression levels were measured; using reverse transcription-polymerase chain reaction (RT-PCR) at different times after the reperfusion in liver tissue and blood. Histopathology and plasma ALT, AST, ALP, and TAC levels confirmed liver damage induced by I/R injury. MiR-21 increased by twofold in the liver tissue and on the inflammatory phase after 24 hours of reperfusion; it then continued to decrease up to day 7 post-reperfusion. Afterward, it continued to rise slightly up to day 14 post-reperfusion. This trend was in parallel with the recovery of the liver damage. MiR-21 expression level in the liver and blood is a predictor of the extent of I/R injury.