Immunometabolic network interactions of the kynurenine pathway in cutaneous malignant melanoma

Cancer is the second leading cause of mortality worldwide, and melanoma represents the most aggressive and deadliest form of skin cancer. Despite the various therapeutic approaches, metastatic melanoma is a disease with a poor prognosis. Recently, the evolution of immune checkpoint inhibitors (ICIs) led to a substantial improvement of the overall survival of patients. However, the long-term effectiveness of such treatments is restricted by the sometimes rapidly emerging resistance to treatment. Several molecular mechanisms underlying this resistant phenotype have begun to be elucidated. The Kynurenine pathway activity via indoleamine 2, 3-dioxygenase 1 (IDO1), is one such mediator of immunosuppression and resistance to ICIs. Studies included in this thesis, therefore, aim to clarify the role of the kynurenine pathway (KP) in metastatic cutaneous melanoma. To this end, we established an in vitro co-culture model consisting of CD4 +T cells in culture with different melanoma cell lines (MCLs) to investigate the implication of KP modifications on CD4 + T-cell function. We found that in addition to IDO1, other KP enzymatic activities such as KMO may regulate CD4 + T-cell immunity (Study I). Following this finding, we evaluated the immune-metabolic network interactions of KP in CMM patients to explore the link between KP metabolites (KPMs) and regulation of the anti-tumour immune response. Our data showed a significant association between MAPKIs treatments and alterations of 3-HK and 3HAA concentrations. These results suggest that KP is clinically relevant in CMM patients (Study II). We further aimed to identify possible KP-related predictive biomarkers of response to ICIs treatment (Study III, IV). Our findings demonstrate the elevated S100A9+ monocytes among PBMCs of the CMM patients who are not responding to the PD-1 inhibition (Study III). Subsequently, by using the PBMCs and plasma of CMM patients on ICI therapy, we observed that kynurinase (KYNU) and LGALS3 (Galectin-3) expression in protein and RNA levels are negatively linked to clinical outcomes. Moreover, we found that the KYNU-LGALS3 network in monocytes is connected to the CD74-MYC network in CD4+ T-cells. These results suggest that LGALS3, MYC, CD74, and KYNU are biologically connected, and perturbing their interaction will possibly modulate ICI efficacy in CMM patients (Study IV). In summary, this thesis provides insights into the induction of n immune-suppressive phenotype by KP activation in CD4+ T-cells and demonstrates the therapeutic potential of targeting KP in the treatment of malignant melanoma

Investigating of drying kinetics and mathematical modeling of turnip

The drying process of turnip and drying rate curves were investigated at different temperatures (55, 70 and 85°C) with air flow rate of 1.5 m/s.  Also effective diffusion coefficient and activation energy were calculated by using Arrhenius equation and Fick’s second law for infinite slab.  The effective diffusivity varied between 5.471×10-10 and 8.966×10-10 in the range of (55°C to 85°C).  The value of activation energy was found to be 16.013 kJ/mol.  The mathematical models (Newton, Page, Modified Page, Henderson and Pabis, Logarithmic, Two term, Two term exponential, Wang and Singh, Simplified Fick’s diffusion, Modified Page –II, Verma, Midilli–Kucuk, Hii, Law and Cloke, Approximation of diffusion, Modified Henderson and Pabis) were fitted to the experimental data.  Sigmaplot v10.0 software was used to find the best model for evaluating the rate of moisture change.  Decency of fit by these models was based on comparing the coefficient of determination (R2), reduced chi-square (χ2), mean bias error (MBE) and root mean square error (RMSE) between the observed and predicted variables.  Among 15 evaluated models, Modified Henderson and Pabis in 85°C and Hii, Law and Cloke in 55°C and 70°C with highest R2 and lowest MBE, χ2 and RMSE were selected to better estimate the drying curves.Keywords: Turnip, hot air convective drying, modeling, drying rate, effective diffusivity, activation energ

Applicability of CAAT box-derived polymorphism (CBDP) markers for analysis of genetic diversity in durum wheat

Progress in plant molecular tools has been resulted in the development of gene-targeted and functional marker systems. CAAT box region is a different pattern of nucleotides with a consensus sequence, GGCCAATCT, which situated upstream of the start codon of eukaryote genes and plays an important role during transcription. In the present study, several CAAT box-derived polymorphism (CBDP) primers were used for fingerprinting in mini-core collection of durum wheat (including internationally developed breeding lines and Iranian landraces). Twelve selected primers amplified 98 loci, of which all were polymorphic. The average values of the polymorphism information content (PIC) and resolving power (Rp) were 0.31 and 9.16, respectively, indicating a high level of variability among studied genotypes. Analysis of molecular variance (AMOVA) indicated that 92% of the total variation resided among populations. The values of the percentage polymorphic bands (PPL), the observed (Na) and effective (Ne) number of alleles, Nei’s gene diversity (He) and Shannon’s information index (I) for Iranian landraces were higher than the breeding lines. The Fandendrogram obtained by cluster analysis grouped all individuals into three main clusters. Our results showed a remarkable level of genetic diversity among studied durum wheat, especially among Iranian landraces, which can be interest for future breeding programs. More importantly, the present study also revealed that CBDP technique was efficient and powerful tool to assess genetic diversity in wheat germplasm. Hence, this technique could be employed individually or in combination with other molecular markers to evaluate genetic diversity and relations among different species

Frequency of a very rare 35delG mutation in two ethnic groups of Iranian populations

The 35delG mutation in the Connexin 26 gene (Cx26), at the DNFB1 locus is the most common mutation in the patients with autosomal recessive non-syndromic hearing loss (ARNSHL). We have studied a total of 224 deaf cases from 189 families in two populations of Iran (Sistan va Bluchestan and Hormozgan provinces) by prescreening nested PCR, polyacrylamide gel electrophoresis and consequent direct sequencing method for all cases. The aim of the present work was to find prevalence of GJB2 mutations in the populations studied. Four different GJB2 mutations including 35delG, W24X, R127H and (V27I + E114 G) were identified in 11 of 189 families (5.8). Two polymorphisms (V27I and V153I) also were detected in 14 families. A polymorphism S86T was determined in all cases. Homozygote 35delG mutation was found only in 1 of 189 families (0.5).The rate of Cx26 mutations found in this study was lower than other Iranian populations. So the cause of deafness in the populations studied remains to be detected in other loci or genes. © 2014, Iranian Journal of Public Health. All rights reserved

High carrier frequency of the GJB2 mutation (35delG) in the north of Iran

Objective: Mutations in the GJB2 gene are a major cause of autosomal recessive and sporadic non-syndromic hearing loss in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of mutations in Caucasians with a carrier frequency of 2-4% in Europe. This study aims to determine the rate of 35delG carrier frequency in Iran. Methods: Genomic DNA was extracted from a total of 550 unaffected unrelated subjects from 4 provinces of Iran following the standard phenol chloroform procedure. The one base pair deletion (35delG) was analysed using a nested PCR procedure; 35delG mutation carriers were subsequently confirmed by sequence analysis. Moreover, using the Binomial probability distribution, we compared the 35delG carrier frequency of Iranian population with the various Middle Eastern and overall European populations. Results: Of the four populations studied, we found a high carrier frequency of 2.8% in Gilan province in the north of Iran. The overall 35delG carrier frequency was found to be 1.25% in the populations studied (our present and previous data) which is similar to the overall 35delG carrier frequency detected in Middle Eastern populations, but Significantly tower than that identified in European populations. (c) 2007 Elsevier Ireland Ltd. All rights reserved

Comparison of the Effects of Public and Private Health Expenditures on the Health Status: A Panel Data Analysis in Eastern Mediterranean Countries

Background: Health expenditures are divided in two parts of public and private health expenditures. Public health expenditures contain social security spending, taxing to private and public sectors, and foreign resources like loans and subventions. On the other hand, private health expenditures contain out of pocket expenditures and private insurances. Each of these has different effects on the health status. The present study aims to compare the effects of these expenditures on health in Eastern Mediterranean Region (EMR). Methods: In this study, infant mortality rate was considered as an indicator of health status. We estimated the model using the panel data of EMR countries between 1995 and 2010. First, we used Pesaran CD test followed by Pesaran’s CADF unit root test. After the confirmation of having unit root, we used Westerlund panel cointegration test and found that the model was cointegrated and then after using Hausman and Breusch-Pagan tests, we estimated the model using the random effects. Results: The results showed that the public health expenditures had a strong negative relationship with infant mortality rate. However, a positive relationship was found between the private health expenditures and infant mortality rate (IMR). The relationship for public health expenditures was significant, but for private health expenditures was not. Conclusion: The study findings showed that the public health expenditures in the EMR countries improved health outcome, while the private health expenditures did not have any significant relationship with health status, so often increasing the public health expenditures leads to reduce IMR. But this relationship was not significant because of contradictory effects for poor and wealthy peoples

Autosomal recessive and sporadic non syndromic hearing loss and the incidence of Cx26 mutations in a province of Iran

Despite the enormous heterogeneity of genetic hearing loss, mutations in the GJB2 (connexin 26) gene located on "DFNB1" locus (13q12) account for up to 50 of cases of autosomal recessive non-syndromic hearing loss (ARNSHL) in some populations. This study describes the analysis of 100 autosomal recessive and sporadic nonsyndromic hearing loss individuals from 79 families each having at least one deaf child in Chehar Mahal va Bakhtiari province in west of Iran. We have investigated the prevalence of the connexin 26 gene mutations using nested PCR strategy to screen the predominant 35delG mutation and subsequent direct sequencing to detect other Cx26 mutations. Seven different genetic variants were detected from which one novel variant was including 363delC. The 35delG was the most common mutation found in 5 of 79 families (6.3). Cx26 related deafness mutations (35delG,V27I; E114G) and R127H) were found in 12 of 158 chromosomes studied (7.8%). We conclude that the association of Cx26 mutations with deafness in Chehar Mahal va Bakhtiari province is low and looks like most other populations of Iran

Early Jurassic (latest Toarcian) brachiopods from the northeastern margin of the Western Tethys (Central Iran) and their paleobiogeographical significance

Brachiopod fauna from central Iran, recorded in the upper part of the Shemshak Group and attributed to the upper Toarcian (Pseudoradiosa-Aalensis zones), are reported for the first time in Iran. The assemblage recognized includes six different taxa: Homoeorhynchia sepahanensis nov. sp., formally described in this paper, Globirhynchia subobsoleta, Pseudogibbirhynchia sp., Tetrarhynchiidae sp. indet., Monsardithyris? aff. haresfieldensis, and Zeilleria cf. leckenbyi. Analysis of faunal affinities with other paleobiogeographical regions shows a free connection the central Iranian brachiopod fauna with wide areas of the northern shelf margin of the Tethys Ocean. This is due to an apparent disruption of bioprovinciality inferred for the late Toarcian-earliest Aalenian, congruent with a connection through the northern seaway across the peri-Laurasian epicontinental platforms.The present research is partially supported by Research Group VIGROB-167 (University of Alicante)

Influence of food attractants (methionine, lysine and alanine) on sturgeon larvae and fingerlings nutrition

The objective of this study was to determine the influence of food attractants (methionine, lysine and alanine) on growth performance and survival rates of Acipenser percicus larvae and fingerlings during the acclimation period to the formulated diets. A total of 3300 Acipenser percicus larvae and 1500 Acipenser percicus fingerlings with the initial mean weights of 0.4±0.09 (mean±SD) and 1.8±0.3 (mean±SD) g, respectively were randomly distributed into 30 aerated plastic tanks of 30 L capacity for larval stage and 50 L capacity for fingerling stage provided with a water flow rate of 0.2 litre per second. This study was conducted at the International Sturgeon Research Institute for two periods of 62 and 70 days over two years. Nine iso-caloric diets were formulated to contain 0, 1 and 3 % of three amino acids methionine, lysine and alanine. In addition, a diet containing 50 % of plant protein supplemented with 3 % of methionine, lysine and alanine was also formulated to compare the effects of plant-protein-based diet with the experimental diets so as to prepare a cost-effective practical diet for this species. Fish were fed each of the ten experimental diets and a completely randomized design in a 3×3 factorial arrangement was used for the experiment. At the end of the feeding trial, final weight (7.5 ± 0.3 g) in Persian sturgeon larvae fed M3L1A3 diet (3% methionine and alanine and 1% lysine) was significantly higher than those of fish fed the other experimental diets (p≤0.05) and then M1L1A3 diet (1% methionine and lysine and 3% alanine) was significantly better (p≤0.05) than other experimental diets. There were no significant differences (p≥0.05) in final weights among M1L1A1, M3L1A1, M3L3A1, M1L3A3 and M3L3A3 diets, while theses diets showed significant differences in final weight with fish fed plant-protein-based diet (3.2±1 g) and without amino acids supplemented diet (M0L0A0) (3.6± 0.4 g). Based on final weigh obtained from Persian sturgeon fingerlings, there were significant differences (p≤0.05) between M3L3A3 (3% methionine, 3% lysine and 3% alanine) (11.1±3.6g) and M3L1A3 (3% methionine, 1% lysine and 3% alanine) (10.4±3.1g) diets with M1L1A1, M1L3A1, M1L1A3, M0L0A0 and plant-protein-based diets. Results of final weigh in fingerling stage also indicated that there were no significant differences (p≥0.05) among M1L1A1 (7±1.2 g), M3L1A1 (8.6±1.6 g), M1L3A1 (7±0.5 g) and M1L1A3 diets (6.6±1.0 g) with M0L0A0 (5.8±1.8 g) and plant-protein-based diets. Analysis of total length in Persian sturgeon fingerlings indicated that there were no significant differences (p≥0.05) among treatments. The highest total length (12±1.6 cm) was recorded in fish fed M3L1A3 diet. Results obtained from this study revealed that young growing Persian sturgeon has greater requirements for methionine in diet, while lysine and alanine at the levels of 1 and 3% for Persian sturgeon fingerlings and at the level of 3% for larvae stage show the same effects on growth performance. Hence, it may be concluded that the dietary alanine and lysine requirements for sturgeon larvae during the acclimation period to formulated diet is estimated to be more than 1 %. No significant differences were observed in survival rates in sturgeon larvae and fingerlings among treatments

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions