Derivatív pénzügyi termékek árdinamikája és az új típusú kamatlábmodellek (Interest rate models and the price processes of financial derivatives)

Ennek a cikknek az a célja, hogy áttekintést adjon annak a folyamatnak néhány főbb állomásáról, amit Black, Scholes és Merton opcióárazásról írt cikkei indítottak el a 70-es évek elején, és ami egyszerre forradalmasította a fejlett nyugati pénzügyi piacokat és a pénzügyi elméletet. / === / This review article compares the development of financial theory within and outside Hungary in the last three decades starting with the Black-Scholes revolution. Problems like the term structure of interest rate volatilities which is in the focus of many research internationally has not received the proper attention among the Hungarian economists. The article gives an overview of no-arbitrage pricing, the partial differential equation approach and the related numerical techniques, like the lattice methods in pricing financial derivatives. The relevant concepts of the martingal approach are overviewed. There is a special focus on the HJM framework of the interest rate development. The idea that the volatility and the correlation can be traded is a new horizon to the Hungarian capital market.

Nemlineáris dinamika klasszikus növekedési modellekben (Nonlinear dynamics in classical economic growth models)

Ebben a tanulmányban a klasszikus Harrod növekedési modellt nemlineáris kiterjesztéssel, keynesi és schumpeteri tradíciók bevezetésével reprezentatív ügynök modellbe alakítjuk. A híres Lucas kritika igazolásaként megmutatjuk, hogy az intrinsic gazdasági növekedési ütemek trajektóriái vagy egy turbulens káoszba szóródnak szét, vagy egy nagyméretű rendhez vezetnek, ami elsődlegesen a megfelelő fogyasztási függvény típusától függ, s bizonyos paraméterek piaci értékei, pedig csak másodlagos szerepet játszanak. A másik meglepő eredmény empirikus, ami szerint külkereskedelmi többlet, a hazai valuta bizonyos devizapiaci értékei mellett, különös attraktorokat generálhat. _____ In this paper the classical Harrodian growth model is transformed into a representative agent model by its nonlinear extensions and the Keynesian and Schumpeterian traditions. For the proof of the celebrated Lucas critique it is shown that the trajectories of intrinsic economic growth rates either are scattered into a turbulent chaos or lead to a large scale order. It depends on the type of the appropriate consumption function, and the market values of some parameters are playing only secondary role.Another surprising result is empirical: the international trade su±cit may generate strange attractors under some exchange rate values.

Using extreme value theory to value stock market returns

Extreme stock price movements are of great concern to both investors and the entire economy. For investors, a single negative return, or a combination of several smaller returns, can possible wipe out so much capital that the firm or portfolio becomes illiquid or insolvent. If enough investors experience this loss, it could shock the entire economy. An example of such a case is the stock market crash of 1987. Furthermore, there has been a lot of recent interest regarding the increasing volatility of stock prices. ^ This study presents an analysis of extreme stock price movements. The data utilized was the daily returns for the Standard and Poor's 500 index from January 3, 1978 to May 31, 2001. Research questions were analyzed using the statistical models provided by extreme value theory. One of the difficulties in examining stock price data is that there is no consensus regarding the correct shape of the distribution function generating the data. An advantage with extreme value theory is that no detailed knowledge of this distribution function is required to apply the asymptotic theory. We focus on the tail of the distribution. ^ Extreme value theory allows us to estimate a tail index, which we use to derive bounds on the returns for very low probabilities on an excess. Such information is useful in evaluating the volatility of stock prices. There are three possible limit laws for the maximum: Gumbel (thick-tailed), Fréchet (thin-tailed) or Weibull (no tail). Results indicated that extreme returns during the time period studied follow a Fréchet distribution. Thus, this study finds that extreme value analysis is a valuable tool for examining stock price movements and can be more efficient than the usual variance in measuring risk. ^

Measurement of single spin asymmetry and fifth structure function for the p( e&ar; ,e'K +)Λ reaction with CEBAF Large Acceptance Spectrometer (CLAS)

The single spin asymmetry, ALT ′, and the polarized structure function, σ LT′, for the p( e&ar; , e′K +)Λ reaction in the resonance region have been measured and extracted using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. Data were taken at an electron beam energy of 2.567 GeV. The large acceptance of CLAS allows for full azimuthal angle coverage over a large range of center-of-mass scattering angles. Results were obtained that span a range in Q 2 from 0.5 to 1.3 GeV2 and W from threshold up to 2.1 GeV and were compared to existing theoretical calculations. The polarized structure function is sensitive to the interferences between various resonant amplitudes, as well as to resonant and non-resonant amplitudes. This measurement is essential for understanding the structure of nucleons and searching for previously undetected nucleon excited states (resonances) predicted by quark models. The W dependence of the σ LT′ in the kinematic regions dominated by s and u channel exchange (cos qcmk = −0.50, −0.167, 0.167) indicated possible resonance structures not predicted by theoretical calculations. The σLT ′ behavior around W = 1.875 GeV could be the signature of a resonance predicted by the quark models and possibly seen in photoproduction. In the very forward angles where the reaction is dominated by the t-channel, the average σLT ′ was zero. There was no indication of the interference between resonances or resonant and non-resonant amplitudes. This might be indicating the dominance of a single t-channel exchange. Study of the sensitivity of the fifth structure function data to the resonance around 1900 MeV showed that these data were highly sensitive to the various assumptions of the models for the quantum number of this resonance. This project was part of a larger CLAS program to measure cross sections and polarization observables for kaon electroproduction in the nucleon resonance region. ^

Three essays on asset pricing

In this dissertation, I investigate three related topics on asset pricing: the consumption-based asset pricing under long-run risks and fat tails, the pricing of VIX (CBOE Volatility Index) options and the market price of risk embedded in stock returns and stock options. These three topics are fully explored in Chapter II through IV. Chapter V summarizes the main conclusions. In Chapter II, I explore the effects of fat tails on the equilibrium implications of the long run risks model of asset pricing by introducing innovations with dampened power law to consumption and dividends growth processes. I estimate the structural parameters of the proposed model by maximum likelihood. I find that the stochastic volatility model with fat tails can, without resorting to high risk aversion, generate implied risk premium, expected risk free rate and their volatilities comparable to the magnitudes observed in data. In Chapter III, I examine the pricing performance of VIX option models. The contention that simpler-is-better is supported by the empirical evidence using actual VIX option market data. I find that no model has small pricing errors over the entire range of strike prices and times to expiration. In general, Whaley’s Black-like option model produces the best overall results, supporting the simpler-is-better contention. However, the Whaley model does under/overprice out-of-the-money call/put VIX options, which is contrary to the behavior of stock index option pricing models. In Chapter IV, I explore risk pricing through a model of time-changed Lvy processes based on the joint evidence from individual stock options and underlying stocks. I specify a pricing kernel that prices idiosyncratic and systematic risks. This approach to examining risk premia on stocks deviates from existing studies. The empirical results show that the market pays positive premia for idiosyncratic and market jump-diffusion risk, and idiosyncratic volatility risk. However, there is no consensus on the premium for market volatility risk. It can be positive or negative. The positive premium on idiosyncratic risk runs contrary to the implications of traditional capital asset pricing theory.

Developing performance measures of mangrove wetlands using simulation models of hydrology, nutrient biogeochemistry, and community dynamics

The goal of mangrove restoration projects should be to improve community structure and ecosystem function of degraded coastal landscapes. This requires the ability to forecast how mangrove structure and function will respond to prescribed changes in site conditions including hydrology, topography, and geophysical energies. There are global, regional, and local factors that can explain gradients of regulators (e.g., salinity, sulfides), resources (nutrients, light, water), and hydroperiod (frequency, duration of flooding) that collectively account for stressors that result in diverse patterns of mangrove properties across a variety of environmental settings. Simulation models of hydrology, nutrient biogeochemistry, and vegetation dynamics have been developed to forecast patterns in mangroves in the Florida Coastal Everglades. These models provide insight to mangrove response to specific restoration alternatives, testing causal mechanisms of system degradation. We propose that these models can also assist in selecting performance measures for monitoring programs that evaluate project effectiveness. This selection process in turn improves model development and calibration for forecasting mangrove response to restoration alternatives. Hydrologic performance measures include soil regulators, particularly soil salinity, surface topography of mangrove landscape, and hydroperiod, including both the frequency and duration of flooding. Estuarine performance measures should include salinity of the bay, tidal amplitude, and conditions of fresh water discharge (included in the salinity value). The most important performance measures from the mangrove biogeochemistry model should include soil resources (bulk density, total nitrogen, and phosphorus) and soil accretion. Mangrove ecology performance measures should include forest dimension analysis (transects and/or plots), sapling recruitment, leaf area index, and faunal relationships. Estuarine ecology performance measures should include the habitat function of mangroves, which can be evaluated with growth rate of key species, habitat suitability analysis, isotope abundance of indicator species, and bird census. The list of performance measures can be modified according to the model output that is used to define the scientific goals during the restoration planning process that reflect specific goals of the project.

A Critical Review of the Implied Cost of Equity: A New Way to Estimate the Expected Return

For the last three decades, the Capital Asset Pricing Model (CAPM) has been a dominant model to calculate expected return. In early 1990% Fama and French (1992) developed the Fama and French Three Factor model by adding two additional factors to the CAPM. However even with these present models, it has been found that estimates of the expected return are not accurate (Elton, 1999; Fama &French, 1997). Botosan (1997) introduced a new approach to estimate the expected return. This approach employs an equity valuation model to calculate the internal rate of return (IRR) which is often called, 'implied cost of equity capital" as a proxy of the expected return. This approach has been gaining in popularity among researchers. A critical review of the literature will help inform hospitality researchers regarding the issue and encourage them to implement the new approach into their own studies.

Diatom-based Models for Inferring Hydrology and Periphyton Abundance in a Subtropical Karstic Wetland: Implications for Ecosystem-Scale Bioassessment

We developed diatom-based prediction models of hydrology and periphyton abundance to inform assessment tools for a hydrologically managed wetland. Because hydrology is an important driver of ecosystem change, hydrologic alterations by restoration efforts could modify biological responses, such as periphyton characteristics. In karstic wetlands, diatoms are particularly important components of mat-forming calcareous periphyton assemblages that both respond and contribute to the structural organization and function of the periphyton matrix. We examined the distribution of diatoms across the Florida Everglades landscape and found hydroperiod and periphyton biovolume were strongly correlated with assemblage composition. We present species optima and tolerances for hydroperiod and periphyton biovolume, for use in interpreting the directionality of change in these important variables. Predictions of these variables were mapped to visualize landscape-scale spatial patterns in a dominant driver of change in this ecosystem (hydroperiod) and an ecosystem-level response metric of hydrologic change (periphyton biovolume). Specific diatom assemblages inhabiting periphyton mats of differing abundance can be used to infer past conditions and inform management decisions based on how assemblages are changing. This study captures diatom responses to wide gradients of hydrology and periphyton characteristics to inform ecosystem-scale bioassessment efforts in a large wetland.

The association of depression and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes

Background: Diabetes and diabetes-related complications are major causes of morbidity and mortality in the United States. Depressive symptoms and perceived stress have been identified as possible risk factors for beta cell dysfunction and diabetes. The purpose of this study was to assess associations between depression symptoms and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes. Participants and Methods: Informed consent and data were available for 462 participants (231 African Americans and 231 Haitian Americans) for this cross-sectional study. A demographic questionnaire developed by the Primary Investigator was used to collect information regarding age, gender, smoking, and ethnicity. Diabetes status was determined by self-report and confirmed by fasting blood glucose. Anthropometrics (weight, and height and waist circumference) and vital signs (blood pressure) were taken. Blood samples were drawn after 8 10 hours over-night fasting to measure lipid panel, fasting plasma glucose and serum insulin concentrations. The homeostatic model assessment, version 2 (HOMA2) computer model was used to calculate beta cell function. Depression was assessed using the Beck Depression Inventory-II (BDI-II) and stress levels were assessed using the Perceived Stress Scale (PSS). Results: Moderate to severe depressive symptoms were more likely for persons with diabetes (p = 0.030). There were no differences in perceived stress between ethnicity and diabetes status (p = 0.283). General linear models for participants with and without type 2 diabetes using beta cell function as the dependent variable showed no association with depressive symptoms and perceived stress; however, Haitian Americans had significantly lower beta cell function than African Americans both with and without diabetes and adjusting for age, gender, waist circumference and smoking. Further research is needed to compare these risk factors in other race/ethnic groups.

Three Essays on Asset Pricing

In this dissertation, I investigate three related topics on asset pricing: the consumption-based asset pricing under long-run risks and fat tails, the pricing of VIX (CBOE Volatility Index) options and the market price of risk embedded in stock returns and stock options. These three topics are fully explored in Chapter II through IV. Chapter V summarizes the main conclusions. In Chapter II, I explore the effects of fat tails on the equilibrium implications of the long run risks model of asset pricing by introducing innovations with dampened power law to consumption and dividends growth processes. I estimate the structural parameters of the proposed model by maximum likelihood. I find that the stochastic volatility model with fat tails can, without resorting to high risk aversion, generate implied risk premium, expected risk free rate and their volatilities comparable to the magnitudes observed in data. In Chapter III, I examine the pricing performance of VIX option models. The contention that simpler-is-better is supported by the empirical evidence using actual VIX option market data. I find that no model has small pricing errors over the entire range of strike prices and times to expiration. In general, Whaley’s Black-like option model produces the best overall results, supporting the simpler-is-better contention. However, the Whaley model does under/overprice out-of-the-money call/put VIX options, which is contrary to the behavior of stock index option pricing models. In Chapter IV, I explore risk pricing through a model of time-changed Lévy processes based on the joint evidence from individual stock options and underlying stocks. I specify a pricing kernel that prices idiosyncratic and systematic risks. This approach to examining risk premia on stocks deviates from existing studies. The empirical results show that the market pays positive premia for idiosyncratic and market jump-diffusion risk, and idiosyncratic volatility risk. However, there is no consensus on the premium for market volatility risk. It can be positive or negative. The positive premium on idiosyncratic risk runs contrary to the implications of traditional capital asset pricing theory.

Advanced thermal analysis of microelectronics using spreading resistance models

Thermal analysis of electronic devices is one of the most important steps for designing of modern devices. Precise thermal analysis is essential for designing an effective thermal management system of modern electronic devices such as batteries, LEDs, microelectronics, ICs, circuit boards, semiconductors and heat spreaders. For having a precise thermal analysis, the temperature profile and thermal spreading resistance of the device should be calculated by considering the geometry, property and boundary conditions. Thermal spreading resistance occurs when heat enters through a portion of a surface and flows by conduction. It is the primary source of thermal resistance when heat flows from a tiny heat source to a thin and wide heat spreader. In this thesis, analytical models for modeling the temperature behavior and thermal resistance in some common geometries of microelectronic devices such as heat channels and heat tubes are investigated. Different boundary conditions for the system are considered. Along the source plane, a combination of discretely specified heat flux, specified temperatures and adiabatic condition are studied. Along the walls of the system, adiabatic or convective cooling boundary conditions are assumed. Along the sink plane, convective cooling with constant or variable heat transfer coefficient are considered. Also, the effect of orthotropic properties is discussed. This thesis contains nine chapters. Chapter one is the introduction and shows the concepts of thermal spreading resistance besides the originality and importance of the work. Chapter two reviews the literatures on the thermal spreading resistance in the past fifty years with a focus on the recent advances. In chapters three and four, thermal resistance of a twodimensional flux channel with non-uniform convection coefficient in the heat sink plane is studied. The non-uniform convection is modeled by using two functions than can simulate a wide variety of different heat sink configurations. In chapter five, a non-symmetrical flux channel with different heat transfer coefficient along the right and left edges and sink plane is analytically modeled. Due to the edge cooling and non-symmetry, the eigenvalues of the system are defined using the heat transfer coefficient on both edges and for satisfying the orthogonality condition, a normalized function is calculated. In chapter six, thermal behavior of two-dimensional rectangular flux channel with arbitrary boundary conditions on the source plane is presented. The boundary condition along the source plane can be a combination of the first kind boundary condition (Dirichlet or prescribed temperature) and the second kind boundary condition (Neumann or prescribed heat flux). The proposed solution can be used for modeling the flux channels with numerous different source plane boundary conditions without any limitations in the number and position of heat sources. In chapter seven, temperature profile of a circular flux tube with discretely specified boundary conditions along the source plane is presented. Also, the effect of orthotropic properties are discussed. In chapter 8, a three-dimensional rectangular flux channel with a non-uniform heat convection along the heat sink plane is analytically modeled. In chapter nine, a summary of the achievements is presented and some systems are proposed for the future studies. It is worth mentioning that all the models and case studies in the thesis are compared with the Finite Element Method (FEM).

Surface velocity fields, digital elevation models, ice front positions and grounding line derived from remote sensing data at Dinsmoor-Bombardier-Edgeworth glacier system, Antarctic Peninsula (1992-2014)

The northern Antarctic Peninsula is one of the fastest changing regions on Earth. The disintegration of the Larsen-A Ice Shelf in 1995 caused tributary glaciers to adjust by speeding up, surface lowering, and overall increased ice-mass discharge. In this study, we investigate the temporal variation of these changes at the Dinsmoor-Bombardier-Edgeworth glacier system by analyzing dense time series from various spaceborne and airborne Earth observation missions. Precollapse ice shelf conditions and subsequent adjustments through 2014 were covered. Our results show a response of the glacier system some months after the breakup, reaching maximum surface velocities at the glacier front of up to 8.8 m/d in 1999 and a subsequent decrease to ~1.5 m/d in 2014. Using a dense time series of interferometrically derived TanDEM-X digital elevation models and photogrammetric data, an exponential function was fitted for the decrease in surface elevation. Elevation changes in areas below 1000 m a.s.l. amounted to at least 130±15 m130±15 m between 1995 and 2014, with change rates of ~3.15 m/a between 2003 and 2008. Current change rates (2010-2014) are in the range of 1.7 m/a. Mass imbalances were computed with different scenarios of boundary conditions. The most plausible results amount to -40.7±3.9 Gt-40.7±3.9 Gt. The contribution to sea level rise was estimated to be 18.8±1.8 Gt18.8±1.8 Gt, corresponding to a 0.052±0.005 mm0.052±0.005 mm sea level equivalent, for the period 1995-2014. Our analysis and scenario considerations revealed that major uncertainties still exist due to insufficiently accurate ice-thickness information. The second largest uncertainty in the computations was the glacier surface mass balance, which is still poorly known. Our time series analysis facilitates an improved comparison with GRACE data and as input to modeling of glacio-isostatic uplift in this region. The study contributed to a better understanding of how glacier systems adjust to ice shelf disintegration.

Interpreting Human Genetic Variation through Genomics and In Vivo Models

Improvements in genomic technology, both in the increased speed and reduced cost of sequencing, have expanded the appreciation of the abundance of human genetic variation. However the sheer amount of variation, as well as the varying type and genomic content of variation, poses a challenge in understanding the clinical consequence of a single mutation. This work uses several methodologies to interpret the observed variation in the human genome, and presents novel strategies for the prediction of allele pathogenicity.

Using the zebrafish model system as an in vivo assay of allele function, we identified a novel driver of Bardet-Biedl Syndrome (BBS) in CEP76. A combination of targeted sequencing of 785 cilia-associated genes in a cohort of BBS patients and subsequent in vivo functional assays recapitulating the human phenotype gave strong evidence for the role of CEP76 mutations in the pathology of an affected family. This portion of the work demonstrated the necessity of functional testing in validating disease-associated mutations, and added to the catalogue of known BBS disease genes.

Further study into the role of copy-number variations (CNVs) in a cohort of BBS patients showed the significant contribution of CNVs to disease pathology. Using high-density array comparative genomic hybridization (aCGH) we were able to identify pathogenic CNVs as small as several hundred bp. Dissection of constituent gene and in vivo experiments investigating epistatic interactions between affected genes allowed for an appreciation of several paradigms by which CNVs can contribute to disease. This study revealed that the contribution of CNVs to disease in BBS patients is much higher than previously expected, and demonstrated the necessity of consideration of CNV contribution in future (and retrospective) investigations of human genetic disease.

Finally, we used a combination of comparative genomics and in vivo complementation assays to identify second-site compensatory modification of pathogenic alleles. These pathogenic alleles, which are found compensated in other species (termed compensated pathogenic deviations [CPDs]), represent a significant fraction (from 3 – 10%) of human disease-associated alleles. In silico pathogenicity prediction algorithms, a valuable method of allele prioritization, often misrepresent these alleles as benign, leading to omission of possibly informative variants in studies of human genetic disease. We created a mathematical model that was able to predict CPDs and putative compensatory sites, and functionally showed in vivo that second-site mutation can mitigate the pathogenicity of disease alleles. Additionally, we made publically available an in silico module for the prediction of CPDs and modifier sites.

These studies have advanced the ability to interpret the pathogenicity of multiple types of human variation, as well as made available tools for others to do so as well.

Elucidating the Space-Time Structure of Low Level Warm Season Precipitation Processes in the Southern Appalachian Mountains Using Models and Observations

Light rainfall is the baseline input to the annual water budget in mountainous landscapes through the tropics and at mid-latitudes. In the Southern Appalachians, the contribution from light rainfall ranges from 50-60% during wet years to 80-90% during dry years, with convective activity and tropical cyclone input providing most of the interannual variability. The Southern Appalachians is a region characterized by rich biodiversity that is vulnerable to land use/land cover changes due to its proximity to a rapidly growing population. Persistent near surface moisture and associated microclimates observed in this region has been well documented since the colonization of the area in terms of species health, fire frequency, and overall biodiversity. The overarching objective of this research is to elucidate the microphysics of light rainfall and the dynamics of low level moisture in the inner region of the Southern Appalachians during the warm season, with a focus on orographically mediated processes. The overarching research hypothesis is that physical processes leading to and governing the life cycle of orographic fog, low level clouds, and precipitation, and their interactions, are strongly tied to landform, land cover, and the diurnal cycles of flow patterns, radiative forcing, and surface fluxes at the ridge-valley scale. The following science questions will be addressed specifically: 1) How do orographic clouds and fog affect the hydrometeorological regime from event to annual scale and as a function of terrain characteristics and land cover?; 2) What are the source areas, governing processes, and relevant time-scales of near surface moisture convergence patterns in the region?; and 3) What are the four dimensional microphysical and dynamical characteristics, including variability and controlling factors and processes, of fog and light rainfall? The research was conducted with two major components: 1) ground-based high-quality observations using multi-sensor platforms and 2) interpretive numerical modeling guided by the analysis of the in situ data collection. Findings illuminate a high level of spatial – down to the ridge scale - and temporal – from event to annual scale - heterogeneity in observations, and a significant impact on the hydrological regime as a result of seeder-feeder interactions among fog, low level clouds, and stratiform rainfall that enhance coalescence efficiency and lead to significantly higher rainfall rates at the land surface. Specifically, results show that enhancement of an event up to one order of magnitude in short-term accumulation can occur as a result of concurrent fog presence. Results also show that events are modulated strongly by terrain characteristics including elevation, slope, geometry, and land cover. These factors produce interactions between highly localized flows and gradients of temperature and moisture with larger scale circulations. Resulting observations of DSD and rainfall patterns are stratified by region and altitude and exhibit clear diurnal and seasonal cycles.

Molecular Insights of CD4+ T Cell Differentiation, Effector Formation and Helper Function

CD4+ T cells play a crucial in the adaptive immune system. They function as the central hub to orchestrate the rest of immunity: CD4+ T cells are essential governing machinery in antibacterial and antiviral responses by facilitating B cell affinity maturation and coordinating the innate and adaptive immune systems to boost the overall immune outcome; on the contrary, hyperactivation of the inflammatory lineages of CD4+ T cells, as well as the impairments of suppressive CD4+ regulatory T cells, are the etiology of various autoimmunity and inflammatory diseases. The broad role of CD4+ T cells in both physiological and pathological contexts prompted me to explore the modulation of CD4+ T cells on the molecular level.

microRNAs (miRNAs) are small RNA molecules capable of regulating gene expression post-transcriptionally. miRNAs have been shown to exert substantial regulatory effects on CD4+ T cell activation, differentiation and helper function. Specifically, my lab has previously established the function of the miR-17-92 cluster in Th1 differentiation and anti-tumor responses. Here, I further analyzed the role of this miRNA cluster in Th17 differentiation, specifically, in the context of autoimmune diseases. Using both gain- and loss-of-function approaches, I demonstrated that miRNAs in miR-17-92, specifically, miR-17 and miR-19b in this cluster, is a crucial promoter of Th17 differentiation. Consequently, loss of miR-17-92 expression in T cells mitigated the progression of experimental autoimmune encephalomyelitis and T cell-induced colitis. In combination with my previous data, the molecular dissection of this cluster establishes that miR-19b and miR-17 play a comprehensive role in promoting multiple aspects of inflammatory T cell responses, which underscore them as potential targets for oligonucleotide-based therapy in treating autoimmune diseases.

To systematically study miRNA regulation in effector CD4+ T cells, I devised a large-scale miRNAome profiling to track in vivo miRNA changes in antigen-specific CD4+ T cells activated by Listeria challenge. From this screening, I identified that miR-23a expression tightly correlates with CD4+ effector expansion. Ectopic expression and genetic deletion strategies validated that miR-23a was required for antigen-stimulated effector CD4+ T cell survival in vitro and in vivo. I further determined that miR-23a targets Ppif, a gatekeeper of mitochondrial reactive oxygen species (ROS) release that protects CD4+ T cells from necrosis. Necrosis is a type of cell death that provokes inflammation, and it is prominently triggered by ROS release and its consequent oxidative stress. My finding that miR-23a curbs ROS-mediated necrosis highlights the essential role of this miRNA in maintaining immune homeostasis.

A key feature of miRNAs is their ability to modulate different biological aspects in different cell populations. Previously, my lab found that miR-23a potently suppresses CD8+ T cell cytotoxicity by restricting BLIMP1 expression. Since BLIMP1 has been found to inhibit T follicular helper (Tfh) differentiation by antagonizing the master transcription factor BCL6, I investigated whether miR-23a is also involved in Tfh differentiation. However, I found that miR-23a does not target BLIMP1 in CD4+ T cells and loss of miR-23a even fostered Tfh differentiation. This data indicate that miR-23a may target other pathways in CD4+ T cells regarding the Tfh differentiation pathway.

Although the lineage identity and regulatory networks for Tfh cells have been defined, the differentiation path of Tfh cells remains elusive. Two models have been proposed to explain the differentiation process of Tfh cells: in the parallel differentiation model, the Tfh lineage is segregated from other effector lineages at the early stage of antigen activation; alternatively, the sequential differentiation model suggests that naïve CD4+ T cells first differentiate into various effector lineages, then further program into Tfh cells. To address this question, I developed a novel in vitro co-culture system that employed antigen-specific CD4+ T cells, naïve B cells presenting cognate T cell antigen and BAFF-producing feeder cells to mimic germinal center. Using this system, I were able to robustly generate GC-like B cells. Notably, well-differentiated Th1 or Th2 effector cells also quickly acquired Tfh phenotype and function during in vitro co-culture, which suggested a sequential differentiation path for Tfh cells. To examine this path in vivo, under conditions of classical Th1- or Th2-type immunizations, I employed a TCRβ repertoire sequencing technique to track the clonotype origin of Tfh cells. Under both Th1- and Th2- immunization conditions, I observed profound repertoire overlaps between the Teff and Tfh populations, which strongly supports the proposed sequential differentiation model. Therefore, my studies establish a new platform to conveniently study Tfh-GC B cell interactions and provide insights into Tfh differentiation processes.