Extreme hydrological events during the last 3500 years and their changes in the future

The Earth's climate has constantly varied over time due to the influence of internal processes and external factors. Together with the mean climate, spatial and temporal characteristics of extreme hydrological events, such as droughts and extreme precipitation, have also changed over time. For instance, droughts with multi-decadal duration, which have never been detected in the instrumental era, occurred during the Medieval climate anomaly (approximately 950-1200 CE) in North America and northern Europe. Devastating floods associated with heavy rainfall occurred more frequently during the Little Ice Age (about 1250-1850 CE) compared to other periods in the Common Era (the last 2k years) over Europe. These past extreme events significantly impacted the environment and ancient societies, sometimes influencing societal disruptions. Despite their impacts on the environment and society, until now, less attention has been paid to the variations of past extreme hydrological events and their drivers compared to the variations in mean precipitation. Among many factors that hinder the investigations of past extreme hydrological events, the main problem arises from the limited availability of observations and past reconstructions for this kind of sporadic events. Nowadays, complex climate models have become essential tools to examine the underlying dynamics of the Earth's climate. As these models can simulate the response of the climate to internal and external perturbations, they offer a possibility to address responsible drivers of climate variations and also extreme events on the global scale. In addition, simulations with climate models cover long time periods that can go far beyond the modern instrumental era. Hence, information from simulations can complement observations and reconstructions to illustrate better the characteristics of past droughts and extreme precipitation. This thesis uses a state-of-the-art earth system model, the Community Earth System Model (CESM), as the main investigation tool to understand the variability and dynamics of past extreme hydrological events, namely droughts and extreme precipitation, during the past three millennia. It also aims to address the effects of an external factor, i.e., volcanic eruptions, on the climate and the impacts of past change in the climate on ancient European society. The thesis mainly consists of three studies. The first study focuses on the dynamics of persistent Mediterranean droughts during 850-2099 CE. The Mediterranean region is one of the drought hot spots which is projected to experience an intensified drying by the end of the 21st century compared to the historical period. Hence, a more comprehensive understanding of the underlying mechanisms of past droughts over the region is necessary to better assess the changes of drought drivers in the historical and future period. In the study, temporal characteristics of Mediterranean droughts are assessed, and drivers of persistent long droughts are identified. In addition, the sensitivity of Mediterranean droughts to various drought metrics is tested. The second study deals with daily extreme precipitation during the last three millennia previous to the Industrial Era (1501 BCE-1849 CE). The study is based on the newly conducted 3500-year long CESM simulations, which include a new proxy record of reconstructed volcanic eruptions. Internal and externally generated processes that influence the long-term variability of extreme precipitation are identified across the globe using a statistical method based on the extreme value theory. Among the externally generated processes, the impacts of volcanic eruptions on extreme precipitation are analyzed in more detail. The third research topic concentrates on examining the impacts of the 43 BCE Okmok eruption in Alaska on the climate and early Mediterranean civilization. Abrupt large-scale changes of the Mediterranean climate after this large extratropical volcanic eruption are detected in various climate-related records, and the magnitudes of these changes are quantified with CESM. This change in climate is as a possible driver of the societal changes that occurred during the ancient Roman period. Lastly, an outlook and a general conclusion of the thesis are presented, also proposing some potential follow-up investigations

Histamine and Histamine H4 Receptor Promotes Osteoclastogenesis in Rheumatoid Arthritis.

Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP-positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA

Effect of modified fasting therapy on body weight, fat and muscle mass, and blood chemistry in patients with obesity

AbstractObjectiveThe aim of this study was to investigate the effects and safety of modified fasting therapy using fermented medicinal herbs and exercise on body weight, fat and muscle mass, and blood chemistry in obese subjects.MethodsTwenty-six patients participated in a 14-day fast, during which they ingested a supplement made from fermented medicinal herbs and carbohydrates (intake: 400-600 kcal/d). The schedule included 7 prefasting relief days and 14 days of stepwise reintroduction of food. The patients also took part in an exercise program that incorporated Qigong, weight training, and walking exercises. The efficacy of treatments was observed by assessing body fat mass and muscle mass, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and triglycerides in each study period. Specific symptoms or side effects were reported.ResultsBody weight and body fat mass both decreased significantly by (5.16 ± 0.95) and (3.89 ± 0.79) kg (both P < 0.05), while muscle mass decreased by an average of (0.26 ± 0.22) kg, without statistical significance. ALT levels were significantly decreased (P < 0.05), while AST levels decreased without statistical significance (P = 0.052). The levels of total cholesterol and triglycerides were also significantly decreased (both P < 0.05). There were few adverse events except for mild dizziness, which did not affect everyday living.ConclusionThese results suggest that modified fasting therapy using fermented medicinal herbs and exercise could be effective and safe on obese patients

Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor κB-dependent pathway in patients with rheumatoid arthritis

Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription–polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-α, IL-1β, IL-18 or transforming growth factor-β did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor κB (NF-κB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-κB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-κB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA

IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways

Recent studies of the pathogenesis of rheumatoid arthritis (RA) have revealed that both synovial fibroblasts and T cells participate in the perpetuation of joint inflammation as dynamic partners in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. In this study, we investigated the role of IL-17, a major Th1 cytokine produced by activated T cells, in the activation of RA synovial fibroblasts. Transcripts of IL-17R (IL-17 receptor) and IL-17RB (IL-17 receptor B) were present in fibroblast-like synoviocytes (FLS) of RA patients. IL-17R responded with increased expression upon in vitro stimulation with IL-17, while the level of IL-17RB did not change. IL-17 enhanced the production of IL-6 and IL-8 in FLS, as previously shown, but did not affect the synthesis of IL-15. IL-17 appears to be a stronger inducer of IL-6 and IL-8 than IL-15, and even exerted activation comparable to that of IL-1β in RA FLS. IL-17-mediated induction of IL-6 and IL-8 was transduced via activation of phosphatidylinositol 3-kinase/Akt and NF-κB, while CD40 ligation and p38 MAPK (mitogen-activated protein kinase) are not likely to partake in the process. Together these results suggest that IL-17 is capable of more than accessory roles in the activation of RA FLS and provide grounds for targeting IL-17-associated pathways in therapeutic modulation of arthritis inflammation

Genetic polymorphism of merozoite surface protein-1 and merozoite surface protein-2 in Plasmodium falciparum field isolates from Myanmar

<p>Abstract</p> <p>Background</p> <p>Merozoite surface protein-1 (MSP-1) and MSP-2 of <it>Plasmodium falciparum </it>are potential vaccine candidate antigens for malaria vaccine development. However, extensive genetic polymorphism of the antigens in field isolates of <it>P. falciparum </it>represents a major obstacle for the development of an effective vaccine. In this study, genetic polymorphism of MSP-1 and MSP-2 among <it>P. falciparum </it>field isolates from Myanmar was analysed.</p> <p>Methods</p> <p>A total of 63 <it>P. falciparum </it>infected blood samples, which were collected from patients attending a regional hospital in Mandalay Division, Myanmar, were used in this study. The regions flanking the highly polymorphic characters, block 2 for MSP-1 and block 3 for MSP-2, were genotyped by allele-specific nested-PCR to analyse the population diversity of the parasite. Sequence analysis of the polymorphic regions of MSP-1 and MSP-2 was also conducted to identify allelic diversity in the parasite population.</p> <p>Results</p> <p>Diverse allelic polymorphism of MSP-1 and MSP-2 was identified in <it>P. falciparum </it>isolates from Myanmar and most of the infections were determined to be mixed infections. Sequence analysis of MSP-1 block 2 revealed that 14 different alleles for MSP-1 (5 for K1 type and 9 for MAD20 type) were identified. For MSP-2 block 3, a total of 22 alleles (7 for FC27 type and 15 for 3D7 type) were identified.</p> <p>Conclusion</p> <p>Extensive genetic polymorphism with diverse allele types was identified in MSP-1 and MSP-2 in <it>P. falciparum </it>field isolates from Myanmar. A high level of mixed infections was also observed, as was a high degree of multiplicity of infection.</p