Signal specificity amongst STAT1- and STAT3- inducing cytokines in the context of Th17 differentiation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.Includes bibliographical references.The adaptive immune response is very important for our survival in that it gives us the capability of detecting a wide variety of foreign material, allows for the elimination of pathogens, and provides memory to protect against future attacks by the same pathogen. Key mediators of the adaptive immune response are CD4+ T cells, which depending on the cytokine milieu, and the activating conditions during antigen recognition, can differentiate into different effector T cells. One particular type of effector T cell, Th 17, is highly inflammatory and has been implicated in various autoimmune diseases, such as Multiple Sclerosis. Three chapters within this thesis investigate the conditions which lead to Th17 differentiation and the mechanisms involved in their regulation. Th 17 cells can be obtained in vitro by culturing naive CD4+ T cells with IL-6 and TGF-p under activating conditions. IL-6 was thought to primarily activate the transcription factor STAT3, which has been shown to be necessary for ThI7 differentiation. Numerous cytokines activate STAT3, but IL-6 is the most potent inducer of TH17 cells, so we sought to find out what is special about IL-6's induction of STAT3. In the first of these three chapters, we propose a simple genetic network which is capable of translating IL-6's high amplitude, transient STAT3 signal into a pro-inflammatory response and IL-10's low amplitude, sustained STAT3 signal into an antiinflammatory response. This network is able to predict that IL-6 and IL-10 would induce an indistinguishable anti-inflammatory response in SOCS3-/- cells where IL-6's STAT3 signal is sustained. In the second of these chapters, we continue our research into the origin of signal specificity in cytokine signaling by systematically characterizing the activation of STAT1 and STAT3 by IL-6, IL-10, IL-21, IL- 27, and different combinations of cytokines in CD4+ T cells. In this analysis we find that the ratio of STAT3 to STAT1 activated is the important quantity in determining whether or not a cytokine will be an inducer of TH17 differentiation (IL-6, IL-21) or an inhibitor (IL-27). We show that in the absence of STAT1, that IL-6 and IL-27 are both potent inducers of TH17 differentiation since they have similar STAT3 activation profiles. In the third of these chapters, we develop a simple algorithm for clustering gene activation profiles for intermediate numbers of genes measured (10-50) and use it to analyze a 96- hour time course of gene activation during Th 17 differentiation for a number of genes of interest. In order for T cells to differentiate into effector cells, they must first recognize antigen which is presented on the surface of an antigen presenting cell by a membrane-bound extracellular complex called MHC. The MHC have a groove which peptide fragments (antigen) are bound in. Without peptide loaded in the pocket, the MHC are quite unstable so they are synthesized with a generic peptide fragment loaded. A protein, DM, is responsible for stabilizing the MHC while the generic peptide is ejected and the peptide fragment of interested is loaded. Two chapters within this thesis investigate the role of DM in peptide loading / unloading and attempt to characterize the interaction of DM with MHC.by Kevin D. Fowler.Ph.D

Comment on “Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice” and “Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps”

Peer reviewedPublisher PD

Leveraging existing data sets to generate new insights into Alzheimer’s disease biology in specific patient subsets

To generate new insights into the biology of Alzheimer’s Disease (AD), we developed methods to combine and reuse a wide variety of existing data sets in new ways. We first identified genes consistently associated with AD in each of four separate expression studies, and confirmed this result using a fifth study. We next developed algorithms to search hundreds of thousands of Gene Expression Omnibus (GEO) data sets, identifying a link between an AD-associated gene (NEUROD6) and gender. We therefore stratified patients by gender along with APOE4 status, and analyzed multiple SNP data sets to identify variants associated with AD. SNPs in either the region of NEUROD6 or SNAP25 were significantly associated with AD, in APOE4+ females and APOE4+ males, respectively. We developed algorithms to search Connectivity Map (CMAP) data for medicines that modulate AD-associated genes, identifying hypotheses that warrant further investigation for treating specific AD patient subsets. In contrast to other methods, this approach focused on integrating multiple gene expression datasets across platforms in order to achieve a robust intersection of disease-affected genes, and then leveraging these results in combination with genetic studies in order to prioritize potential genes for targeted therapy

The KRESCENT Program (2005-2015) : an evaluation of the state of Kidney Research Training in Canada

Background: The Kidney Research Scientist Core Education and National Training (KRESCENT) Program was launched in 2005 to enhance kidney research capacity in Canada and foster knowledge translation across the 4 themes of health research. Objective: To evaluate the impact of KRESCENT on its major objectives and on the careers of trainees after its first 10 years. Methods: An online survey of trainees (n = 53) who had completed or were enrolled in KRESCENT was conducted in 2015. Information was also obtained from curriculum vitae (CVs). A bibliometric analysis assessed scientific productivity, collaboration, and impact in comparison with unsuccessful applicants to KRESCENT over the same period. The analysis included a comparison of Canadian with international kidney research metrics from 2000 to 2014. Results: Thirty-nine KRESCENT trainees completed the survey (74%), and 44 trainees (83%) submitted CVs. KRESCENT trainees had a high success rate at obtaining grant funding from the Canadian Institutes of Health Research (CIHR; 79%), and 76% of Post-Doctoral Fellows received academic appointments at the Assistant Professor level within 8 months of completing training. The majority of trainees reported that KRESCENT had contributed significantly to their success in securing CIHR funding (90%), and to the creation of knowledge (93%) and development of new methodologies (50%). Bibliometric analysis revealed a small but steady decline in total international kidney research output from 2000 to 2014, as a percentage of all health research, although overall impact of kidney research in Canada increased from 2000-2005 to 2009- 2014 compared with other countries. KRESCENT trainees demonstrated increased productivity, multiauthored papers, impact, and international collaborations after their training, compared with nonfunded applicants. Conclusions: The KRESCENT Program has fostered kidney research career development and contributed to increased capacity, productivity, and collaboration. To further enhance knowledge creation and translation in kidney research in Canada, programs such as KRESCENT should be sustained via long-term funding partnerships.Mise en contexte: Le programme KRESCENT (Kidney Research Scientist Core Education and National Training) a été lancé en 2005 pour augmenter la capacité de la recherche sur les maladies du rein à travers le Canada, et pour encourager la transmission des connaissances au sein des quatre axes de recherche en santé. Objectifs de l’étude: Cette étude avait pour but d’évaluer les répercussions du programme KRESCENT sur ses principaux objectifs ainsi que des retombées sur la carrière des stagiaires participants, dix ans après sa création. Méthodologie: Un sondage en ligne a été mené en 2015 auprès des stagiaires (n = 53) ayant été admis ou ayant complété le programme KRESCENT. Des renseignements ont également été obtenus par la consultation de curriculum vitae (CV). Une analyse bibliométrique a évalué la productivité scientifique et la collaboration des participants ainsi que les répercussions de leur participation à KRESCENT sur leur carrière. Les données de cette analyse ont été comparées à celles des candidats n’ayant pas été retenus au cours de la même période. L’analyse comprenait également une comparaison des données canadiennes avec celles obtenues en recherche sur les maladies du rein ailleurs dans le monde

The Atacama Cosmology Telescope: Temperature and Gravitational Lensing Power Spectrum Measurements from Three Seasons of Data

We present the temperature power spectra of the cosmic microwave background (CMB) derived from the three seasons of data from the Atacama Cosmology Telescope (ACT) at 148 GHz and 218 GHz, as well as the cross-frequency spectrum between the two channels. We detect and correct for contamination due to the Galactic cirrus in our equatorial maps. We present the results of a number of tests for possible systematic error and conclude that any effects are not significant compared to the statistical errors we quote. Where they overlap, we cross-correlate the ACT and the South Pole Telescope (SPT) maps and show they are consistent. The measurements of higher-order peaks in the CMB power spectrum provide an additional test of the Lambda CDM cosmological model, and help constrain extensions beyond the standard model. The small angular scale power spectrum also provides constraining power on the Sunyaev-Zel'dovich effects and extragalactic foregrounds. We also present a measurement of the CMB gravitational lensing convergence power spectrum at 4.6-sigma detection significance.Comment: 21 pages; 20 figures, Submitted to JCAP, some typos correcte

The Atacama Cosmology Telescope: A Measurement of the Thermal Sunyaev-Zel'dovich Effect Using the Skewness of the CMB Temperature Distribution

We present a detection of the unnormalized skewness induced by the thermal Sunyaev-Zel'dovich (tSZ) effect in filtered Atacama Cosmology Telescope (ACT) 148 GHz cosmic microwave background temperature maps. Contamination due to infrared and radio sources is minimized by template subtraction of resolved sources and by constructing a mask using outlying values in the 218 GHz (tSZ-null) ACT maps. We measure = -31 +- 6 \mu K^3 (measurement error only) or +- 14 \mu K^3 (including cosmic variance error) in the filtered ACT data, a 5-sigma detection. We show that the skewness is a sensitive probe of sigma_8, and use analytic calculations and tSZ simulations to obtain cosmological constraints from this measurement. From this signal alone we infer a value of sigma_8= 0.79 +0.03 -0.03 (68 % C.L.) +0.06 -0.06 (95 % C.L.). Our results demonstrate that measurements of non-Gaussianity can be a useful method for characterizing the tSZ effect and extracting the underlying cosmological information.Comment: 9 pages, 5 figures. Replaced with version accepted by Phys. Rev. D, with improvements to the likelihood function and the IR source treatment; only minor changes in the result

Total knee replacement after high tibial osteotomy: Time-to-event analysis and predictors

© 2021 Joule Inc. or its licensors. BACKGROUND: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it. METHODS: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery. RESULTS: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m2, 95% CI 1.12–1.53). INTERPRETATION: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO

Detection of the Power Spectrum of Cosmic Microwave Background Lensing by the Atacama Cosmology Telescope

We report the first detection of the gravitational lensing of the cosmic microwave background through a measurement of the four-point correlation function in the temperature maps made by the Atacama Cosmology Telescope. We verify our detection by calculating the levels of potential contaminants and performing a number of null tests. The resulting convergence power spectrum at 2-degree angular scales measures the amplitude of matter density fluctuations on comoving length scales of around 100 Mpc at redshifts around 0.5 to 3. The measured amplitude of the signal agrees with Lambda Cold Dark Matter cosmology predictions. Since the amplitude of the convergence power spectrum scales as the square of the amplitude of the density fluctuations, the 4-sigma detection of the lensing signal measures the amplitude of density fluctuations to 12%.Comment: 4 pages, 4 figures, replaced title and author list with version accepted by Physical Review Letters. Likelihood code can be downloaded from http://bccp.lbl.gov/~sudeep/ACTLensLike.htm