A METAGENOMIC STUDY OF THE TICK MIDGUT

A Metagenomic Study of the Tick Midgut Daniel Yuan, B.S. Supervisory Professor : Steven J. Norris, Ph.D. Southern tick–associated rash illness (STARI) or Master’s disease is a Lyme-like illness that occurs following bites by Amblyomma americanum, the lone-star tick. Clinical symptoms include a bull’s eye rash similar to the erythema migrans lesions of Lyme disease, as well as fever and joint pains. Lyme disease is caused by Borrelia burgdorferi and related spirochetes. However, B. burgdorferi has not been detected in STARI patients, or in ticks in the South Central U.S. The causative agent of STARI has not been identified, although it was once thought to be caused by another Borrelia species, Borrelia lonestari. Furthermore, while adult A. americanum have up to a 5.6% Borrelia lonestari infection rate, the prevalence of all Borrelia species in Texas ticks as a whole is not known. Previous studies indicate that 6%-30% of Northern Ixodes scapularis ticks are infected by Borrelia burgdorferi while only 10% of Northern A. americanum and I. scapularis ticks are infected by Borrelia species. The first specific aim of this project was to determine the bacterial community that inhabits the midgut of Texas and Northeastern ticks by using high throughput metagenomic sequencing to sequence bacterial 16S rDNA. Through the use of massively parallel 454 sequencing, we were able to individually sequence hundreds of thousands of 16S rDNA regions of the bacterial flora from 133 ticks from the New York, Missouri and Texas. The presence of previously confirmed endosymbionts, specifically the Rickettsia spp. and Coxiella spp., that are commonly found in ticks were confirmed, as well as some highly prevalent genera that were previously undocumented. Furthermore, multiple pathogenic genera sequences were often found in the same tick, suggesting the possibility of co-infection of multiple pathogenic species. The second specific aim was to use Borrelia specific primers to screen 344 individual ticks from Missouri, Texas and the Northeast to determine the prevalence of Borrelia species in ticks. To screen for Borrelia species, two housekeeping genes, uvrA and recG, were selected as well as the 16S-23S rDNA intergenic spacer. Ticks from Missouri, Texas and New York were screened. None of the Missouri or Texas ticks tested positive for Borrelia spp. The rate of I. scapularis infection by B.burgdorferi is dependent on tick feeding activity as well as reservoir availability. B. burgdorferi is endemic in the Northeast, sometimes reported as highly present in over 50% of all I. scapularis ticks. 11.6% of all New York ticks were positive for a species of Borrelia, however only 6.9% of all New York ticks were positive for B. burgdorferi. Despite being significantly lower than 50%, the results still fall in line with previous reports of about the prevalence of B. burgdorferi. 1.5% of all Texas ticks were positive for a Borrelia species, specifically B. lonestari. While this study was unable to identify the causative agent for STARI, 454 sequencing was able to provide a tremendous insight into the bacterial flora and possible pathogenic species of both the I. scapularis and the A. americanum tick.

Dynamic Remodeling of the Stressed Heart: Role of Protein Degradation Pathways

The heart is a remarkable organ. In order to maintain its function, it remodels in response to a variety of environmental stresses, including pressure overload, volume overload, mechanical or pharmacological unloading and hormonal or metabolic disturbances. All these responses are linked to the inherent capacity of the heart to rebuild itself. Particularly, cardiac pressure overload activates signaling pathways of both protein synthesis and degradation. While much is known about regulators of protein synthesis, little is known about regulators of protein degradation in hypertrophy. The ubiquitin-proteasome system (UPS) selectively degrades unused and abnormal intracellular proteins. I speculated that the UPS may play an important role in both qualitative and quantitative changes in the composition of heart muscle during hypertrophic remodeling. My study hypothesized that cardiac remodeling in response to hypertrophic stimuli is a dynamic process that requires activation of highly regulated mechanisms of protein degradation as much as it requires protein synthesis. My first aim was to adopt a model of left ventricular hypertrophy and determine its gene expression and structural changes. Male Sprague-Dawley rats were submitted to ascending aortic banding and sacrificed at 7 and 14 days after surgery. Sham operated animals served as controls. Effective aortic banding was confirmed by hemodynamic assessment by Doppler flow measurements in vivo. Banded rats showed a four-fold increase in peak stenotic jet velocities. Histomorphometric analysis revealed a significant increase in myocyte size as well as fibrosis in the banded animals. Transcript analysis showed that banded animals had reverted to the fetal gene program. My second aim was to assess if the UPS is increased and transcriptionally regulated in hypertrophic left ventricular remodeling. Protein extracts from the left ventricles of the banded and control animals were used to perform an in vitro peptidase assay to assess the overall catalytic activity of the UPS. The results showed no difference between hypertrophied and control animals. Transcript analysis revealed decreases in transcript levels of candidate UPS genes in the hypertrophied hearts at 7 days post-banding but not at 14 days. However, protein expression analysis showed no difference at either time point compared to controls. These findings indicate that elements of the UPS are downregulated in the early phase of hypertrophic remodeling and normalizes in a later phase. The results provide evidence in support of a dynamic transcriptional regulation of a major pathway of intracellular protein degradation in the heart. The discrepancy between transcript levels on the one hand and protein levels on the other hand supports post-transcriptional regulation of the UPS pathway in the hypertrophied heart. The exact mechanisms and the functional consequences remain to be elucidated.

ELUCIDATING FUNCTIONAL ROLES FOR MYOGENIN IN ADULT SKELETAL MUSCLE METABOLISM, EXERCISE CAPACITY, AND REGENERATION

The four basic helix-loop-helix myogenic transcription factors, myogenin, Myf5, MRF4, and MyoD are critical for embryonic skeletal muscle development. Myogenin is necessary for the terminal differentiation of myoblasts into myofibers during embryogenesis, but little is known about the roles played by myogenin in adult skeletal muscle function and metabolism. Furthermore, while metabolism is a well-studied physiological process, how it is regulated at the transcriptional level remains poorly understood. In this study, my aim was to determine the function of myogenin in adult skeletal muscle metabolism, exercise capacity, and regeneration. To investigate this, I utilized a mouse strain harboring the Myogflox allele and a Cre recombinase transgene, enabling the efficient deletion of myogenin in the adult mouse. Myogflox/flox mice were stressed physically through involuntary treadmill running and by breeding them with a strain harboring the Duchenne’s muscular dystrophy (DMDmdx) allele. Surprisingly, Myog-deleted animals exhibited an enhanced capacity for exercise, running farther and faster than their wild-type counterparts. Increased lactate production and utilization of glucose as a fuel source indicated that Myog-deleted animals exhibited an increased glycolytic flux. Hypoglycemic Myog-deleted mice no longer possessed the ability to outrun their wild-type counterparts, implying the ability of these animals to further deplete their glucose reserves confers their enhanced exercise capacity. Moreover, Myog-deleted mice exhibited an enhanced response to long-term exercise training. The mice developed a greater proportion of type 1 oxidative muscle fibers, and displayed increased levels of succinate dehydrogenase activity, indicative of increased oxidative metabolism. Mdx:Myog-deleted mice exhibited a similar phenotype, outperforming their mdx counterparts, although lagging behind wild-type animals. The morphology of muscle tissue from mdx:Myog-deleted mice appears to mimic that of mdx animals, indicating that myogenin is dispensable for adult skeletal muscle regeneration. Through global gene expression profiling and quantitative (q)RT-PCR, I identified a unique set of putative myogenin-dependent genes involved in regulating metabolic processes. These data suggest myogenin’s functions during adulthood are distinctly different than those during embryogenesis, and myogenin acts as a high-level transcription factor regulating metabolic activity in adult skeletal muscle.

DEFINING THE ROLE OF EGFR ACETYLATION IN CELLULAR PROCESSES: CLINICAL IMPLICATIONS

Epidermal growth factor receptor (EGFR) is a cell membrane tyrosine kinase receptor and plays a pivotal role in regulating cell growth, differentiation, cell cycle, and tumorigenesis. Deregulation of EGFR causes many diseases including cancers. Intensive investigation of EGFR alteration in human cancers has led to profound progress in developing drugs to target EGFR-mediated cancers. While exploring possible synergistic enhancement of therapeutic efficacy by combining EGFR tyrosine kinase inhibitors (TKI) with other anti-cancer agents, we observed that suberoylanilide hydroxamic acid (SAHA, a deacetylase inhibitor) enhanced TKI-induced cancer cell death, which further led us to question whether SAHA-mediated sensitization to TKI was associated with EGFR acetylation. What we know so far is that SAHA can inhibit class I and II histone deacetylases (HDACs), which could possibly preserve acetylation of underlying HDAC-targeted proteins including both histone and non-histone proteins. In addition, it has been reported that an HDAC inhibitor, TSA, enhanced EGFR phosphorylation in ovarian cancer cells. EGFR acetylation has also been reported to play a role in the regulation of EGFR endocytosis recently. These observations indicate that there might be an intrinsic correlation between acetylation and phosphorylation of EGFR. In other words, the interplay between EGFR acetylation and phosphorylation may contribute to HDAC inhibitors (HDACi)-augmented EGFR phosphorylation. In this investigation, we showed that CBP acetyltransferase acetylated EGFR in vivo. In response to EGF stimulation, CBP rapidly translocated from the nucleus to the cytoplasm. We also demonstrated protein-protein interaction between CBP and EGFR as well as the enhancement of EGFR acetylation by CBP. Moreover, EGFR acetylation enhanced EGFR tyrosine phosphorylation and augmented its association with Src kinase. Acetylation-deficient EGFR mutant (EGFR-K3R) significantly reduced the function and activity of EGFR. Furthermore, ectopic expression of EGFR-K3R mutant abrogated its ability to respond to EGF-induced cell proliferation, DNA synthesis, and anchorage-independent growth using cell-based assays and tumor growth in nude mice. In addition, we demonstrated that EGFR expression was associated with SAHA resistance in the treatment of cancer cells that overexpress EGFR. The knockdown of EGFR in MDA-MB-468 breast cancer cells could sensitize the cells to respond to SAHA. The overexpression of EGFR in SAHA-sensitive MDA-MB-453 breast cancer cells rendered the cells resistant to SAHA. Together, these findings suggest that EGFR plays an important role in SAHA resistance in breast carcinoma cells that we tested. The combination therapy of HDACi with TKI has been proposed for treating cancers with aberrant expression of EGFR. The evidence from pre-clinical or clinical trials demonstrated significant enhancement of therapeutic efficacy by using such a combination therapy. Our in vivo study also demonstrated that the combination of SAHA and TKI for the treatment of breast cancer significantly reduced tumor burden compared with either SAHA or TKI alone. The significance of our study elucidated another possible underlying molecular mechanism by which HDACi mediated sensitization to TKI. Our results unveiled a critical role of EGFR acetylation that regulates EGFR tyrosine phosphorylation and may further provide an experiment-based rationale for combinatorial targeted therapy.

Stromal derived growth factor alpha (SDF-1α) induces the differentiation of bone marrow progenitor cells (BMCs) into pericytes by regulating platelet derived growth factor B (PDGF-B) transcription

We previously demonstrated that bone marrow cells (BMCs) migrate to TC71 and A4573 Ewing’s sarcoma tumors where they can differentiate into endothelial cells (ECs) and pericytes and, participate in the tumor vascular development. This process of neo-vascularization, known as vasculogenesis, is essential for Ewing’s sarcoma growth with the soluble vascular endothelial growth factor, VEGF165, being the chemotactic factor for BMC migration to the tumor site. Inhibiting VEGF165 in TC71 tumors (TC/siVEGF7-1) inhibited BMC infiltration to the tumor site and tumor growth. Introducing the stromal-derived growth factor (SDF-1α) into the TC/siVEGF7-1 tumors partially restored vasculogenesis with infiltration of BMCs to a perivascular area where they differentiated into pericytes and rescued tumor growth. RNA collected from the SDF-1α-treated TC/siVEGF7-1 tumors also revealed an increase in platelet-derived growth factor B (PDGF-B) mRNA levels. PDGF-B expression is elevated in several cancer types and the role of PDGF-B and its receptor, PDGFR-β, has been extensively described in the process of pericyte maturation. However, the mechanisms by which PDGF-B expression is up-regulated during vascular remodeling and the process by which BMCs differentiate into pericytes during tumor vasculogenesis remain areas of investigation. In this study, we are the first to demonstrate that SDF-1α regulates the expression of PDGF-B via a transcriptional mechanism which involves binding of the ELK-1 transcription factor to the pdgf-b promoter. We are also first to validate the critical role of the SDF-1α/PDGF-B pathway in the differentiation of BMCs into pericytes both in vitro and in vivo. SDF-1α up-regulated PDGF-B expression in both TC/siVEGF7-1 and HEK293 cells. In contrast, down-regulating SDF-1α, down-regulated PDGF-B. We cloned the 2 kb pdgf-b promoter fragment into the pGL3 reporter vector and showed that SDF-1α induced pdgf-b promoter activity. We used chromatin immunoprecipitation (ChIP) and demonstrated that the ELK-1 transcription factor bound to the pdgf-b promoter in response to SDF-1α stimulation in both TC/siVEGF7-1 and HEK293 cells. We collected BMCs from the hind femurs of mice and cultured the cells in medium containing SDF-1α and PDGF-B and found that PDGFR-β+ BMCs differentiated into NG2 and desmin positive pericytes in vitro. In contrast, inhibiting SDF-1α and PDGF-B abolished this differentiation process. In vivo, we injected TC71 or A4573 tumor-bearing mice with the SDF-1α antagonist, AMD3100 and found that inhibiting SDF-1α signaling in the tumor microenvironment decreased the tumor microvessel density, decreased the tumor blood vessel perfusion and, increased tumor cell apoptosis. We then analyzed the effect of AMD3100 on vasculogenesis of Ewing’s sarcoma and found that BMCs migrated to the tumor site where they differentiated into ECs but, they did not form thick perivascular layers of NG2 and desmin positive pericytes. Finally, we stained the AMD3100-treated tumors for PDGF-B and showed that inhibiting SDF-1α signaling also inhibited PDGF-B expression. All together, these findings demonstrated that the SDF-1α/PDGF-B pathway plays a critical role in the formation of BM-derived pericytes during vasculogenesis of Ewing’s sarcoma tumors.

The Role of the Androgen Receptor Cofactor p44/WDR77 in Astrocyte Activation

Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to astrogliosis. Our results reveal a novel role of p44/WDR77 in astrocytes, which may explain the well-documented role of androgens in suppression of astrogliosis. While many of detailed mechanisms of astrocyte activation remain to be elucidated, a number pathways have been implicated in astrocyte activation including p21Cip1 and the NF-kB pathway. Astrocytic activation induced by p44/WDR77 gene deletion was associated with a significant increase of p21Cip1 expression and NF-kB activation characterized by p65 nuclear localization. We found that down-regulation of p21Cip1 expression inhibited astrocyte activation induced by the p44/WDR77 deletion and was accompanied by a decreased p65 nuclear localization. While p21Cip1 role in astrocyte activation and NF-kB activation is not well understood, studies of other cell cycle regulators have implicated cell cycle control systems as modulators of astrocyte activation, thus p21Cip1 could induce secondary effect to induce p65 nuclear localization. However, p65 knockdown completely relieved the inhibition of astrocyte growth induced by the p44/WDR77 deletion, while p21Cip1 knockdown only partially recovered this inhibition. Thus, NF-kB activity performs additional regulatory actions not mediated by p21Cip1. These analyses imply that p4/WDR77 suppresses astrocyte activation through modulating p21Cip1 expression and NF-kB activation.

Significance of Increased Tissue Transglutaminase in Hormone Refractory Prostate Cancer

The progression of hormone responsive to hormone refractory prostate cancer poses a major clinical challenge in the successful treatment of prostate cancer. The hormone refractory prostate cancer cells exhibit resistance not only to castrate levels of testosterone, but also to other therapeutic modalities and hence become lethal. Currently, there is no effective treatment available for managing this cancer. These observations underscore the urgency to investigate mechanism(s) that contribute to the progression of hormone-responsive to hormone-refractory prostate cancer and to target them for improved clinical outcomes. Tissue transglutaminase (TG2) is a multifunctional pro-inflammatory protein involved in diverse physiological processes such as inflammation, tissue repair, and wound healing. Its expression is also implicated in pathological conditions such as cancer and fibrosis. Interestingly, we found that the androgen-independent prostate cancer cell lines, which lacked androgen receptor (AR) expression, contained high basal levels of tissue transglutaminase. Inversely, the cell lines that expressed androgen receptor lacked transglutaminase expression. This attracted our attention to investigate the possible role this protein may play in the progression of prostate cancer, especially in view of recent observations that its expression is linked with increased invasion, metastasis, and drug resistance in multiple cancer cell types. The results we obtained were rather surprising and revealed that stable expression of tissue transglutaminase in androgen-sensitive LNCaP prostate cancer cells rendered these cells independent of androgen for growth and survival by silencing the AR expression. The AR silencing in TG2 expressing cells (TG2-infected LNCaP and PC-3 cells) was due to TG2-induced activation of the inflammatory nuclear transcription factor-kB (NF-kB). Thus, TG2 induced NF-kB was found to directly bind to the AR promoter. Importantly, TG2 protein was specifically recruited to the AR promoter in complex with the p65 subunit of NF-kB. Moreover, TG2 expressing LNCaP and PC-3 cells exhibited epithelial-to-mesenchymal transition, as evidenced by gain of mesenchymal (such as fibronectin, vimentin, etc.) and loss of epithelial markers (such as E-cadherin, b-catenin). Taken together, these results suggested a new function for TG2 and revealed a novel mechanism that is responsible for the progression of prostate cancer to the aggressive hormone-refractory phenotype.

NOVEL MECHANISMS OF ANTIGEN PROCESSING THAT ENHANCE BCG VACCINE EFFICACY

Mycobacterium tuberculosis, the causative agent of tuberculosis, is the most lethal single infectious agent afflicting man today causing 2 million deaths per year. The World Health Organization recommends a vaccine as the best option to prevent this disease. The current vaccine, BCG, has a variable efficacy and does not protect adults. It is known that BCG vaccine becomes sequestered in special phagosome compartments of macrophages that do not fuse with lysosomes. Since lysosome fusion is necessary for peptide production and T cell priming leading to protective TH1 immunity, we hypothesized that vaccine efficacy is reduced and occurs perhaps due to non-lysosome dependent mechanisms. We therefore proposed an in depth analysis of phagosome environment, and its proteome to unravel mechanisms of antigen processing and presentation. We initially discovered that three mechanisms of pH regulation including vacuolar proton ATPase, phagocyte oxidase and superoxide dismutase (SOD) secretion from BCG vaccine affect antigen processing within phagosomes. These studies led to the discovery that a mutant of BCG vaccine which lacked SOD was a better vaccine. Subsequently, the proteomic analysis of vaccine phagosomes led to the discovery of novel protease (γ-secretase) enriched on BCG vaccine phagosomes. We then demonstrated that these proteases generated a peptide from the BCG vaccine which was presented through the MHC-II pathway to T cells and induced a TH1 response. The specificity of antigen production from γ-secretase was confirmed through siRNA knockdown of the components of the protease namely, nicastrin, presenilin and APH, which led to a decrease in antigen presentation. We therefore conclude that, even though BCG phagosomes are sequestered and do not fuse with lysosomes to generate peptide antigens, there are complex and novel in situ mechanisms within phagosomes that are capable of generating an immune response. We conclude that TH1 immunity to BCG vaccine arises mostly due to non-lysosome dependent immune mechanisms of macrophages and dendritic cells.

LMW-E MEDIATES MAMMARY TUMORIGENESIS BY DEREGULATING ACINAR MORPHOGENESIS & GENERATING CANCER STEM CELLS

Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in breast cancer generates two low molecular weight (LMW) isoforms that exhibit both enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress LMW-E and associate with poor survival. Therefore, we hypothesize that LMW-E disrupts normal mammary acinar morphogenesis and serves as the initial route into breast tumor development. We first demonstrate that LMW-E overexpression in non-tumorigenic hMECs is sufficient to induce tumor formation in athymic mice significantly more than overexpression of full-length cyclin E and requires CDK2- associated kinase activity. Further in vivo passaging of these tumors augments LMW-E expression and tumorigenic potential. When subjected to acinar morphogenesis in vitro, LMW-E mediates significant morphological disruption by generating hyperproliferative and multi-acinar complexes. Proteomic analysis of patient tissues and tumor cells with high LMW-E expression reveals that the activation of the b-Raf-ERK1/2-mTOR pathway in concert with high LMW-E expression predicts poor patient survival. Combination treatment using roscovitine (CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (b-raf inhibitor) effectively prevented aberrant acinar formation in LMW-E-expressing cells by inducing the G1/S cell cycle arrest. In addition, the LMW-E-expressing tumor cells exhibit phenotypes characteristic of the EMT and enhanced cellular invasiveness. These tumor cells also enrich for cells with CSC phenotypes such as increased CD44hi/CD24lo population, enhanced mammosphere formation, and upregulation of ALDH expression and enzymatic activity. Furthermore, the CD44hi/CD24lo population also shows positive correlation with LMW-E expression in both the tumor cell line model and breast cancer patient samples (p<0.0001 & p=0.0435, respectively). Combination treatment using doxorubicin and salinomycin demonstrates synergistic cytotoxic effects in cells with LMW-E expression but not in those with full-length cyclin E expression. Finally, ProtoArray microarray identifies Hbo1 as a novel substrate of the cyclin E/CDK2 complex and its overexpression results in enrichment for CSCs. Collectively, these data emphasize the strong oncogenic potential of LMW-E in mammary tumorigenesis and suggest possible therapeutic strategies to treat breast cancer patients with high LMW-E expression.

Cognitive Interventions with Children with Special Needs - Transfer effects and multidisciplinary perspectives

Our last study with regularly developed children demonstrated a positive effect of working memory training on cognitive abilities. Building upon these findings, the aim of this multidisciplinary study is to investigate the effects of training of core functions with children who are suffering from different learning disabilities, like AD/HD, developmental dyslexia or specific language impairment. In addition to working memory training (BrainTwister), we apply a perceptual training, which concentrates on auditory-visual matching (Audilex), as well as an implicit concept learning task. We expect differential improvements of mental capacities, specifically of executive functions (working memory, attention, auditory and visual processing), scholastic abilities (language and mathematical skills), as well as of problem solving. With that, we hope to find further directions regarding helpful and individually adapted interventions in educational settings. Interested parties are invited to discuss and comment the design, the research question, and the possibilities in recruiting the subjects.

Estimating Intra-Party Preferences: Comparing Speeches to Votes

Well-established methods exist for measuring party positions, but reliable means for estimating intra-party preferences remain underdeveloped. While most efforts focus on estimating the ideal points of individual legislators based on inductive scaling of roll call votes, this data suffers from two problems: selection bias due to unrecorded votes and strong party discipline, which tends to make voting a strategic rather than a sincere indication of preferences. By contrast, legislative speeches are relatively unconstrained, as party leaders are less likely to punish MPs for speaking freely as long as they vote with the party line. Yet, the differences between roll call estimations and text scalings remain essentially unexplored, despite the growing application of statistical analysis of textual data to measure policy preferences. Our paper addresses this lacuna by exploiting a rich feature of the Swiss legislature: on most bills, legislators both vote and speak many times. Using this data, we compare text-based scaling of ideal points to vote-based scaling from a crucial piece of energy legislation. Our findings confirm that text scalings reveal larger intra-party differences than roll calls. Using regression models, we further explain the differences between roll call and text scalings by attributing differences to constituency-level preferences for energy policy.

Three Experimental Approaches to Measure the Social Context Dependence of Prejudice Communication and Discriminatory Behavior

Empirical research on discrimination is faced with crucial problems stemming from the specific character of its object of study. In democratic societies the communication of prejudices and other forms of discriminatory behavior is considered socially undesirable and depends on situational factors such as whether a situation is considered private or whether a discriminatory consensus can be assumed. Regular surveys thus can only offer a blurred picture of the phenomenon. But also survey experiments intended to decrease the social desirability bias (SDB) so far failed in systematically implementing situational variables. This paper introduces three experimental approaches to improve the study of discrimination and other topics of social (un-)desirability. First, we argue in favor of cognitive context framing in surveys in order to operationalize the salience of situational norms. Second, factorial surveys offer a way to take situational contexts and substitute behavior into account. And third, choice experiments – a rather new method in sociology – offer a more valid method of measuring behavioral characteristics compared to simple items in surveys. All three approaches – which may be combined – are easy to implement in large-scale surveys. Results of empirical studies demonstrate the fruitfulness of each of these approaches.

Na 1 Nachlass Max Horkheimer, 58 - Korrespondenzen u.a. mit Betty Drury (p. I 27, 186-333)

5 Briefe zwischen Konrad Wittwer und Max Horkheimer, 1936, 1938, 1939; 1 Brief von Max Horkheimer an Joseph Wohl, 18.08.1934; 1 Brief von Max Horkheimer an Hedwig Wollenberger, 25.02.1941; 2 Briefe zwischen Richard Wolf und Max Horkheimer, 22.10.1938, 07.11.1938; 2 Briefe zwischen Martha Wolfenstein und Max Horkheimer, 11.10.1937, 19.10.1937; 1 Brief von Clemy Wolff an Leo Löwenthal, 05.03.1941; 2 Briefe zwischen Ilse Wolff und Max Horkheimer, 29.08.1937, 03.09.1937; 1 Brief von Max Horkheimer an Howard Woolston, 25.03.1941; 1 Einladung von der Women's Conference, 1935; 1 Brief von Max Horkheimer an die Women's Conference, 15.03.1935; 1 Brief von der World Foundation an Max Horkheimer, 26.11.1937; 2 Briefe vom World Jewish Congress an Max Horkheimer, 1942, 1945; 1 Brief von Max Horkheimer an Francis Henry Russel, 28.09.1942; 1 Brief von Max Horkheimer an Dr. Opie, 28.09.1942; 1 Brief der Württembergische Hypothekenbank an Max Horkheimer, 24.12.1930; 12 Briefe zwischen Rösle Wuestholz und Max Horkheimer, 1935-1937, 1939; 1 Brief von Max Horkheimer an Frida Wunderlich, 22.11.1937; 1 Brief von Max Horkheimer an die Yale University Library, 22.12.1938; 2 Briefe zwischen Owen D. Young und Max Horkheimer, 22.04.1940, April 1940; 3 Briefe zwischen Hans Zeisel und Max Horkheimer, 21.07.1941, 1941, 1944; 2 Briefe zwischen der Zentrale Hilfsstelle für deutsche Flüchtlingskinder Prag und Max Horkheimer, 01.03.1938, 25.04.1938; 6 Briefe zwischen Gregory Zilboorg und Max Horkheimer, 1939; 16 Briefe und Beilage an Max Horkheimer und F. Pollock von Edgar Zilsel, 1939-1942; 1 Brief vom Social Science Research Counsil an Edgar Zilsel, 01.04.1940; 1 Brief von The Rockefeller Foundation an Edgar Zilsel, 20.06.1939; 9 Briefe und Beilage von Max Horkheimer und F. Pollock an Edgar Zilsel, 1939-1942 sowie Briefwechsel mit Betty Drury; 10 Briefe zwischen The Rockefeller Foundation und Max Horkheimer, 1939-1940; 1 Brief von Max Horkheimer an Edgar Zilsel, 20.06.1939; 12 Briefe zwischen Betty Drury und F. Pollock, 1939-1940; 7 Briefe zwischen Alexander Zinnemann und Max Horkheimer, 1936;

Na 1 Nachlass Max Horkheimer, 57 - Korrespondenzen u.a. mit Hilde Weiss (p. I 27, 1-185)

1 Brief von Max Horkheimer an Weiss, 18.07.1937; 27 Briefe und Beilagen zwischen Hilde Weiss und Max Horkheimer, 1934-1936, 1945 sowie Briefwechsel mit der Commission on Community Interrelations of the American Jewish Congress; 3 Briefe zwischen der Commission on Community Interrelations of the American Jewish Congress und Max Horkheimer, 02.10.1945, 1945; 2 Briefe und Beilage zwischen dem Social Science Research Council und Max Horkheimer, 04.02.1943, 18.03.1943; 1 Brief und 1 Beilage von Leo Löwenthal an Margot von Mendelssohn, 01.03.1943; 2 Briefe zwischen Ernst Weissmann und Max Horkheimer, 07.09.1945; 11 Briefe zwischen Leo H. Weissmann und Max Horkheimer, 1938-1939; 1 Brief von Max Horkheimer an Chaim Weizmann, 06.05.1941; 8 Briefe und 1 Beilage zwischen Karl Georg Wendriner, Anna Wendriner und Max Horkheimer, 1935-1938; 1 Brief von Max Horkheimer an Frederic Wertham, 18.11.1941; 2 Briefe zwischen Wertheimer und Max Horkheimer, 07.11.1934; 2 Briefe von Abr. F. Westermann an Max Horkheimer, 1932, 1934; 1 Brief von Max Horkheimer an die Western Service Corporation, 06.04.1941; 30 Briefe zwischen Wetzel und Max Horkheimer, 1937-1939; 3 Briefe zwischen Helen B. White und Max Horkheimer, 16.03.1939, 1939; 3 Briefe zwischen John Whyte und Max Horkheimer, 01.03.1941, 12.03.1941; 3 Briefe und 1 Beilage zwischen Philip Paul Wiener und Max Horkheimer, 08.12.1938, 1938; 7 Briefe zwischen Maria Wiesengrund und Max Horkheimer, 1942, 1945, 1948; 1 Lebenslauf und 2 Zeugnisse von Ilse Wiesenthal; 1 Brief vom Comité International Pour Le Placement Des Intellectuels Réfugiés an Max Horkheimer in Verbindung mit Ilse Wiesenthal, Dezember 1935; 1 Brief von Max Horkheimer an Willen; 1 Brief vom The Wimbledon Co Master Tailors an Max Horkheimer, 15.06.1937; 5 Briefe zwischen Josef Winternitz und Max Horkheimer, 1938-1939; 7 Briefe zwischen Louis Wirth und Max Horkheimer, 1937-1941; 22 Briefe zwischen Egon Wissing und Max Horkheimer, 1936-1941 sowie Briefwechsel mit dem Georg Washington Hotel, New York; 1 Brief von Lieselotte Karplen an Maidon Horkheimer, 25.04.1940; 2 Briefe zwischen dem Georg Washington Hotel und Max Horkheimer, 07.05.1936, 12.05.1936;

Na 1 Nachlass Max Horkheimer, 532 - Korrespondenzen u.a. mit Otto Kirchheimer und Leo Löwenthal (p. VI 11, 287 - 514)

55 Briefe zwischen Otto Kirchheimer, Anne Kirchheimer und Max Horkheimer, 1937 - 1947; 1 Brief von Otto und Anne Kirchheimer an Frederick Pollock, 06.08.1939; 2 Briefe zwischen der Rockfeller Foundation (New York) und Max Horkheimer, März 1941; 1 Brief von dem Oberlaender Trust an Frederick Pollock, 10.02.1941; 1 Brief von Otto Kirchheimer an Frederick Pollock, 06.08.1939; 1 Brief von Max Horkheimer an das American College Bureau (Chicago), 07.10.1940; 1 Brief von Max Horkheimer an das College and Specialist Bureau (Memphis, T.), 23.09.1939; 2 Briefe zwischen Max Horkheimer und dem Social Science Research Council (New York), 17.12.1938; 73 Briefe zwischen Leo Löwenthal und Max Horkheimer 1933 - 1935; 1 Brief von dem Europa Verlag A. G. (Zürich) an Max Horkheimer, 30.11.1935; 1 Brief von Max Horkheimer an das United States Department of Labor (New York), 03.05.1935; 2 Briefe von Hugo Sinzheimer an Max Horkheimer, 11.06.1934; 1 Brief von Leo Löwenthal an Hugo Sinzheimer, 16.07.1934; 2 Briefe zwischen Leo Löwenthal und Fritz Schiff, 1934/1935;