Evolution of Reproductive Tract Interactions in Cactophilic Drosophila

Reproductive traits evolve rapidly at the morphological, physiological and molecular levels, a taxonomically robust pattern that is thought to arise from sexual selection. In internally fertilizing organisms, female promiscuity results in competition between multiple male ejaculates for fertilizations in the same female reproductive tract, extending sexual selection past courtship and copulation. In this post-copulatory arena, biochemical interaction between male ejaculates and female reproductive tracts form a dynamic molecular interface that modulates female post-mating responses essential to reproductive fitness. Consistent with the hypothesis that these interactions are subject to sexual selection, sperm and seminal proteins are known to evolve rapidly in a broad range of taxa. The female role in this process, however, in terms of both molecular mechanisms and evolutionary dynamics, remains unclear.The presented dissertation research examines the biochemical nature and evolutionary consequences of post-copulatory sexual selection in two sister-species of cactophilic Drosophila, D. mojavensis and D. arizonae. I first present data that female post-mating response in crosses between these to species is perturbed, severely reducing the reproductive output of heterospecific crosses. A breakdown of reproductive tract interactions in matings between divergent lineages suggests that male and female contributions to reproductive outcomes are coadapted. Next, I use a combination of bioinformatic analyses, comparative sequence analyses, and biochemical assays to elucidate candidate female reproductive tract proteins that may be involved in ejaculate-female dynamics. 241 candidate female reproductive proteins are identified, the most intriguing of which are recently-duplicated secreted proteases. Finally, I explore the evolutionary history of two families of secreted proteases within geographically isolated populations of D. mojavensis. I show that both families evolve rapidly through a complex process involving gene duplication, gene conversion, pseudogenation and positive selection, a unique pattern never before documented in reproductive proteins.Collectively, my dissertation research suggests that females are active participants in the evolution of reproductive tract interactions. Further exploration of how sexual reproduction coevolves between males and females, both in terms of interacting biomolecules, and dynamic evolutionary histories, remains an important challenge for future research

Gene Duplication and Adaptive Evolution of Digestive Proteases in Drosophila arizonae Female Reproductive Tracts

It frequently has been postulated that intersexual coevolution between the male ejaculate and the female reproductive tract is a driving force in the rapid evolution of reproductive proteins. The dearth of research on female tracts, however, presents a major obstacle to empirical tests of this hypothesis. Here, we employ a comparative EST approach to identify 241 candidate female reproductive proteins in Drosophila arizonae, a repleta group species in which physiological ejaculate–female coevolution has been documented. Thirty-one of these proteins exhibit elevated amino acid substitution rates, making them candidates for molecular coevolution with the male ejaculate. Strikingly, we also discovered 12 unique digestive proteases whose expression is specific to the D. arizonae lower female reproductive tract. These enzymes belong to classes most commonly found in the gastrointestinal tracts of a diverse array of organisms. We show that these proteases are associated with recent, lineage-specific gene duplications in the Drosophila repleta species group, and exhibit strong signatures of positive selection. Observation of adaptive evolution in several female reproductive tract proteins indicates they are active players in the evolution of reproductive tract interactions. Additionally, pervasive gene duplication, adaptive evolution, and rapid acquisition of a novel digestive function by the female reproductive tract points to a novel coevolutionary mechanism of ejaculate–female interaction

Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen

SummaryTo understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland—but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance—allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation

Protein expression based multimarker analysis of breast cancer samples

<p>Abstract</p> <p>Background</p> <p>Tissue microarray (TMA) data are commonly used to validate the prognostic accuracy of tumor markers. For example, breast cancer TMA data have led to the identification of several promising prognostic markers of survival time. Several studies have shown that TMA data can also be used to cluster patients into clinically distinct groups. Here we use breast cancer TMA data to cluster patients into distinct prognostic groups.</p> <p>Methods</p> <p>We apply weighted correlation network analysis (WGCNA) to TMA data consisting of 26 putative tumor biomarkers measured on 82 breast cancer patients. Based on this analysis we identify three groups of patients with low (5.4%), moderate (22%) and high (50%) mortality rates, respectively. We then develop a simple threshold rule using a subset of three markers (p53, Na-KATPase-β1, and TGF β receptor II) that can approximately define these mortality groups. We compare the results of this correlation network analysis with results from a standard Cox regression analysis.</p> <p>Results</p> <p>We find that the rule-based grouping variable (referred to as WGCNA*) is an independent predictor of survival time. While WGCNA* is based on protein measurements (TMA data), it validated in two independent Affymetrix microarray gene expression data (which measure mRNA abundance). We find that the WGCNA patient groups differed by 35% from mortality groups defined by a more conventional stepwise Cox regression analysis approach.</p> <p>Conclusions</p> <p>We show that correlation network methods, which are primarily used to analyze the relationships between gene products, are also useful for analyzing the relationships between patients and for defining distinct patient groups based on TMA data. We identify a rule based on three tumor markers for predicting breast cancer survival outcomes.</p

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures

Enquiring About Tolerance (EAT) study: Feasibility of an early allergenic food introduction regimen.

BACKGROUND: The influence of early exposure to allergenic foods on the subsequent development of food allergy remains uncertain. OBJECTIVE: We sought to determine the feasibility of the early introduction of multiple allergenic foods to exclusively breast-fed infants from 3 months of age and the effect on breastfeeding performance. METHODS: We performed a randomized controlled trial. The early introduction group (EIG) continued breastfeeding with sequential introduction of 6 allergenic foods: cow's milk, peanut, hard-boiled hen's egg, sesame, whitefish (cod), and wheat; the standard introduction group followed the UK infant feeding recommendations of exclusive breastfeeding for around 6 months with no introduction of allergenic foods before 6 months of age. RESULTS: One thousand three hundred three infants were enrolled. By 5 months of age, the median frequency of consumption of all 6 foods was 2 to 3 times per week for every food in the EIG and no consumption for every food in the standard introduction group (P < .001 for every comparison). By 6 months of age, nonintroduction of the allergenic foods in the EIG was less than 5% for each of the 6 foods. Achievement of the stringent per-protocol consumption target for the EIG proved more difficult (42% of evaluable EIG participants). Breastfeeding rates in both groups significantly exceeded UK government data for equivalent mothers (P < .001 at 6 and at 9 months of age). CONCLUSION: Early introduction, before 6 months of age, of at least some amount of multiple allergenic foods appears achievable and did not affect breastfeeding. This has important implications for the evaluation of food allergy prevention strategies

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (&lt;380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Review of Electric News in Colonial Algeria (2019) by Arthur Asseraf

Histor

Targeted identification of TE insertions in a Drosophila genome through hemi-specific PCR

Abstract Background Transposable elements (TEs) are major components of eukaryotic genomes and drivers of genome evolution, producing intraspecific polymorphism and interspecific differences through mobilization and non-homologous recombination. TE insertion sites are often highly variable within species, creating a need for targeted genome re-sequencing (TGS) methods to identify TE insertion sites. Methods We present a hemi-specific PCR approach for TGS of P-elements in Drosophila genomes on the Illumina platform. We also present a computational framework for identifying new insertions from TGS reads. Finally, we describe a new method for estimating the frequency of TE insertions from WGS data, which is based precise insertion sites provided by TGS annotations. Results By comparing our results to TE annotations based on whole genome re-sequencing (WGS) data for the same Drosophila melanogaster strain, we demonstrate that TGS is powerful for identifying true insertions, even in repeat-rich heterochromatic regions. We also demonstrate that TGS offers enhanced annotation of precise insertion sites, which facilitates estimation of TE insertion frequency. Conclusions TGS by hemi-specific PCR is a powerful approach for identifying TE insertions of particular TE families in species with a high-quality reference genome, at greatly reduced cost as compared to WGS. It may therefore be ideal for population genomic studies of particular TE families. Additionally, TGS and WGS can be used as complementary approaches, with TGS annotations identifying more annotated insertions with greater precision for a target TE family, and WGS data allowing for estimates of TE insertion frequencies, and a broader picture of the location of non-target TEs across the genome