Postcard from W. C. Overall to B. R. Colson

Postcard from W. C. Overall to B. R. Colson. The hand-written note is dated 4 September 1912. There is a transcript of the postcard in the item PDF

Sex Differences in Sexual Arousal and Finger Length Ratio

Most men show sexual arousal to one, preferred sex, whereas most women respond to both sexes, regardless of their sexual orientation. A different research program indicates that men have lower second-to-fourth finger length ratios (2D:4D) than women, possibly because men are exposed to higher levels of androgens during prenatal development. We hypothesized that sex differences in sexual arousal patterns are influenced by prenatal androgen exposure and would thus be explained by sex differences in 2D:4D. We measured the sexual response patterns of 139 men and 179 women via genital arousal and pupil dilation to erotic videos, in addition to their 2D:4D. Compared to women, men showed stronger responses to one sex over the other, although this pattern was clearer in genital arousal than pupil dilation. Men also had lower 2D:4D than women. However, there was no evidence that sex differences in sexual arousal related to sex differences in 2D:4D. Thus, whichever factor explains sex differences in sexual arousal patterns may not be reflected in 2D:4D

Sexual Orientation, Sexual Arousal, and Finger Length Ratios in Women

In general, women show physiological sexual arousal to both sexes. However, compared with heterosexual women, homosexual women are more aroused to their preferred sex, a pattern typically found in men. We hypothesized that homosexual women’s male-typical arousal is due to their sex-atypical masculinization during prenatal development. We measured the sexual responses of 199 women (including 67 homosexual women) via their genital arousal and pupil dilation to female and male sexual stimuli. Our main marker of masculinization was the ratio of the index to ring finger, which we expected to be lower (a masculine pattern) in homosexual women due to increased levels of prenatal androgens. We further measured observer- and self-ratings of psychological masculinity–femininity as possible proxies of prenatal androgenization. Homosexual women responded more strongly to female stimuli than male stimuli and therefore had more male-typical sexual responses than heterosexual women. However, they did not have more male-typical digit ratios, even though this difference became stronger if analyses were restricted to white participants. Still, variation in women's digit ratios did not account for the link between their sexual orientation and their male-typical sexual responses. Furthermore, homosexual women reported and displayed more masculinity than heterosexual women, but their masculinity was not associated with their male-typical sexual arousal. Thus, women’s sexual and behavioral traits, and potential anatomical traits, are possibly masculinized at different stages of gestation

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection.

The interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the α2 domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α2 domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α1/α2 helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens

Microarray tools and analysis methods to better characterize biological networks

To accurately model a biological system (e.g. cell), we first need to characterize each of its distinct networks. While omics data has given us unprecedented insight into the structure and dynamics of these networks, the associated analysis routines are more involved and the accuracy and precision of the experimental technologies not sufficiently examined. The main focus of our research has been to develop methods and tools to better manage and interpret microarray data. How can we improve methods to store and retrieve microarray data from a relational database? What experimental and biological factors most influence our interpretation of a microarray's measurements? By accounting for these factors, can we improve the accuracy and precision of microarray measurements? It's essential to address these last two questions before using 'omics data for downstream analyses, such as inferring transciption regulatory networks from microarray data. While answers to such questions are vital to microarray research in particular, they are equally relevant to systems biology in general. We developed three studies to investigate aspects of these questions when using Affymetrix expression arrays. In the first study, we develop the Data-FATE framework to improve the handling of large scientific data sets. In the next two studies, we developed methods and tools that allow us to examine the impact of physical and technical factors known or suspected to dramatically alter the interpretation of a microarray experiment. In the second study, we develop ArrayInitiative -- a tool that simplifies the process of creating custom CDFs -- so that we can easily re-design the array specifications for Affymetrix 3' IVT expression arrays. This tool is essential for testing the impact of the various factors, and for making the framework easy to communicate and re-use. We then use ArrayInitiative in a case study to illustrate the impact of several factors known to distort microarray signals. In the third study, we systematically and exhaustively examine the effect of physical and technical factors -- both generally accepted and novel -- on our interpretation of dozens of experiments using hundreds of E. coli Affymetrix microarrays

Patterns of Genital Sexual Arousal in Transgender Men

Most men show genital sexual arousal to one preferred gender. Most women show genital arousal to both genders, regardless of their sexual preferences. There is limited knowledge of whether this difference is driven by biological sex or gender identity. Transgender individuals, whose birth sex and gender identity are incongruent, provide a unique opportunity to address this question. We tested whether the genital responses of 25 (female-to-male) transgender men followed their female birth sex or male gender identity. Depending on their surgical status, arousal was assessed with penile gauges or vaginal plethysmographs. Transgender men’s sexual arousal showed both male-typical and female-typical patterns. Across measures, they responded more strongly to their preferred gender than to the other gender, similar to (but not entirely like) 145 cisgender (nontransgender) men. However, they still responded to both genders, similar to 178 cisgender women. In birth-assigned women, both gender identity and biological sex may influence sexual-arousal patterns

Microarray Detection Call Methodology as a Means to Identify and Compare Transcripts Expressed within Syncytial Cells from Soybean (Glycine max) Roots Undergoing Resistant and Susceptible Reactions to the Soybean Cyst Nematode (Heterodera glycines)

Background. A comparative microarray investigation was done using detection call methodology (DCM) and differential expression analyses. The goal was to identify genes found in specific cell populations that were eliminated by differential expression analysis due to the nature of differential expression methods. Laser capture microdissection (LCM) was used to isolate nearly homogeneous populations of plant root cells. Results. The analyses identified the presence of 13,291 transcripts between the 4 different sample types. The transcripts filtered down into a total of 6,267 that were detected as being present in one or more sample types. A comparative analysis of DCM and differential expression methods showed a group of genes that were not differentially expressed, but were expressed at detectable amounts within specific cell types. Conclusion. The DCM has identified patterns of gene expression not shown by differential expression analyses. DCM has identified genes that are possibly cell-type specific and/or involved in important aspects of plant nematode interactions during the resistance response, revealing the uniqueness of a particular cell population at a particular point during its differentiation process

ArrayInitiative - a tool that simplifies creating custom Affymetrix CDFs

<p>Abstract</p> <p>Background</p> <p>Probes on a microarray represent a frozen view of a genome and are quickly outdated when new sequencing studies extend our knowledge, resulting in significant measurement error when analyzing any microarray experiment. There are several bioinformatics approaches to improve probe assignments, but without in-house programming expertise, standardizing these custom array specifications as a usable file (e.g. as Affymetrix CDFs) is difficult, owing mostly to the complexity of the specification file format. However, without correctly standardized files there is a significant barrier for testing competing analysis approaches since this file is one of the required inputs for many commonly used algorithms. The need to test combinations of probe assignments and analysis algorithms led us to develop ArrayInitiative, a tool for creating and managing custom array specifications.</p> <p>Results</p> <p>ArrayInitiative is a standalone, cross-platform, rich client desktop application for creating correctly formatted, custom versions of manufacturer-provided (default) array specifications, requiring only minimal knowledge of the array specification rules and file formats. Users can import default array specifications, import probe sequences for a default array specification, design and import a custom array specification, export any array specification to multiple output formats, export the probe sequences for any array specification and browse high-level information about the microarray, such as version and number of probes. The initial release of ArrayInitiative supports the Affymetrix 3' IVT expression arrays we currently analyze, but as an open source application, we hope that others will contribute modules for other platforms.</p> <p>Conclusions</p> <p>ArrayInitiative allows researchers to create new array specifications, in a standard format, based upon their own requirements. This makes it easier to test competing design and analysis strategies that depend on probe definitions. Since the custom array specifications are easily exported to the manufacturer's standard format, researchers can analyze these customized microarray experiments using established software tools, such as those available in Bioconductor.</p