High Performance Web Servers: A Study In Concurrent Programming Models

With the advent of commodity large-scale multi-core computers, the performance of software running on these computers has become a challenge to researchers and enterprise developers. While academic research and industrial products have moved in the direction of writing scalable and highly available services using distributed computing, single machine performance remains an active domain, one which is far from saturated. This thesis selects an archetypal software example and workload in this domain, and describes software characteristics affecting performance. The example is highly-parallel web-servers processing a static workload. Particularly, this work examines concurrent programming models in the context of high-performance web-servers across different architectures — threaded (Apache, Go and μKnot), event-driven (Nginx, μServer) and staged (WatPipe) — compared with two static workloads in two different domains. The two workloads are a Zipf distribution of file sizes representing a user session pulling an assortment of many small and a few large files, and a 50KB file representing chunked streaming of a large audio or video file. Significant effort is made to fairly compare eight web-servers by carefully tuning each via their adjustment parameters. Tuning plays a significant role in workload-specific performance. The two domains are no disk I/O (in-memory file set) and medium disk I/O. The domains are created by lowering the amount of RAM available to the web-server from 4GB to 2GB, forcing files to be evicted from the file-system cache. Both domains are also restricted to 4 CPUs. The primary goal of this thesis is to examine fundamental performance differences between threaded and event-driven concurrency models, with particular emphasis on user-level threading models. Additionally, a secondary goal of the work is to examine high-performance software under restricted hardware environments. Over-provisioned hardware environments can mask architectural and implementation shortcomings in software – the hypothesis in this work is that restricting resources stresses the application, bringing out important performance characteristics and properties. Experimental results for the given workload show that memory pressure is one of the most significant factors for the degradation of web-server performance, because it forces both the onset and amount of disk I/O. With an ever increasing need to support more content at faster rates, a web-server relies heavily on in-memory caching of files and related content. In fact, personal and small business web-servers are even run on minimal hardware, like the Raspberry Pi, with only 1GB of RAM and a small SD card for the file system. Therefore, understanding behaviour and performance in restricted contexts should be a normal aspect of testing a web server (and other software systems)

Shared genes related to aggression, rather than chemical communication, are associated with reproductive dominance in paper wasps (Polistes metricus)

BackgroundIn social groups, dominant individuals may socially inhibit reproduction of subordinates using aggressive interactions or, in the case of highly eusocial insects, pheromonal communication. It has been hypothesized these two modes of reproductive inhibition utilize conserved pathways. Here, we use a comparative framework to investigate the chemical and genomic underpinnings of reproductive dominance in the primitively eusocial wasp Polistes metricus. Our goals were to first characterize transcriptomic and chemical correlates of reproductive dominance and second, to test whether dominance-associated mechanisms in paper wasps overlapped with aggression or pheromone-related gene expression patterns in other species. To explore whether conserved molecular pathways relate to dominance, we compared wasp transcriptomic data to previous studies of gene expression associated with pheromonal communication and queen-worker differences in honey bees, and aggressive behavior in bees, Drosophila, and mice. ResultsBy examining dominant and subordinate females from queen and worker castes in early and late season colonies, we found that cuticular hydrocarbon profiles and genome-wide patterns of brain gene expression were primarily associated with season/social environment rather than dominance status. In contrast, gene expression patterns in the ovaries were associated primarily with caste and ovary activation. Comparative analyses suggest genes identified as differentially expressed in wasp brains are not related to queen pheromonal communication or caste in bees, but were significantly more likely to be associated with aggression in other insects (bees, flies), and even a mammal (mice). ConclusionsThis study provides the first comprehensive chemical and molecular analysis of reproductive dominance in paper wasps. We found little evidence for a chemical basis for reproductive dominance in P. metricus, and our transcriptomic analyses suggest that different pathways regulate dominance in paper wasps and pheromone response in bees. Furthermore, there was a substantial impact of season/social environment on gene expression patterns, indicating the important role of external cues in shaping the molecular processes regulating behavior. Interestingly, genes associated with dominance in wasps were also associated with aggressive behavior in bees, solitary insects and mammals. Thus, genes involved in social regulation of reproduction in Polistes may have conserved functions associated with aggression in insects and other taxa

Physical Mapping and Refinement of the Painted Turtle Genome (Chrysemys picta) Inform Amniote Genome Evolution and Challenge Turtle-Bird Chromosomal Conservation

Comparative genomics continues illuminating amniote genome evolution, but for many lineages our understanding remains incomplete. Here, we refine the assembly (CPI 3.0.3 NCBI AHGY00000000.2) and develop a cytogenetic map of the painted turtle (Chrysemys picta—CPI) genome, the first in turtles and in vertebrates with temperature-dependent sex determination. A comparison of turtle genomes with those of chicken, selected nonavian reptiles, and human revealed shared and novel genomic features, such as numerous chromosomal rearrangements. The largest conserved syntenic blocks between birds and turtles exist in four macrochromosomes, whereas rearrangements were evident in these and other chromosomes, disproving that turtles and birds retain fully conserved macrochromosomes for greater than 300 Myr. C-banding revealed large heterochromatic blocks in the centromeric region of only few chromosomes. The nucleolar-organizing region (NOR) mapped to a single CPI microchromosome, whereas in some turtles and lizards the NOR maps to nonhomologous sex-chromosomes, thus revealing independent translocations of the NOR in various reptilian lineages. There was no evidence for recent chromosomal fusions as interstitial telomeric-DNA was absent. Some repeat elements (CR1-like, Gypsy) were enriched in the centromeres of five chromosomes, whereas others were widespread in the CPI genome. Bacterial artificial chromosome (BAC) clones were hybridized to 18 of the 25 CPI chromosomes and anchored to a G-banded ideogram. Several CPI sex-determining genes mapped to five chromosomes, and homology was detected between yet other CPI autosomes and the globally nonhomologous sex chromosomes of chicken, other turtles, and squamates, underscoring the independent evolution of vertebrate sex-determining mechanisms

The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage

Background: We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing.Results: Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented.Conclusions: Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders

Studies on the causes and consequences of sex determination in turtles

Sex determination is a crucial decision of commitment of an individual's sexual fate into either a male or a female. In vertebrates, sex determination modes span a spectrum of extremes: genotypic sex determination (GSD), where sex is genetically determined, often due to the presence of sex chromosomes and temperature-dependent sex determination (TSD), where environmental temperature during a critical period of embryonic development establishes sexual fate. The evolution of this diversity in sex determining mechanisms is one that has defied scientific explanation for decades. An ideal system to demystify this conundrum includes turtle lineages, where both TSD and GSD co-occur. This dissertation addresses two big questions on this topic: firstly, what are the underlying molecular causes of sex determination? Our knowledge of molecular components that could transduce the external temperature cue in TSD systems remains incomplete. Is sex determined by direct thermal responses of certain key elements in the gonadal network in TSD vertebrates? Are there epigenetic underpinnings regulating gene expression in response to temperature? Secondly, what are the consequences of possessing sex chromosomes? Upon acquiring a sex-determining factor, sex-linked sequences are hypothesized to evolve at a faster rate than autosomes owing to multiple factors, with no supporting evidence stemming from mainly from Drosophila and some mammals. However, any reptilian evidence to test this hypothesis is still forthcoming. In Chapter 1, I analyze a time-series of embryonic transcriptomes of TSD and GSD turtles to characterize the composition of the transcriptional network that regulates male and female gonadal development, and test how it responds to temperature in TSD and GSD systems. In Chapter 2, I test for the involvement of epigenetic modification in TSD and whether it mediates the differential gene expression patterns detected via transcriptomics in Chapter 1. In Chapter 3, I test the effect of sex chromosome evolution on the molecular evolution of coding regions of genes by comparing genes that are sex-linked in some amniotes while being autosomal in others. Together, these chapters shed light on the genetic and epigenetic basis of a complex system (sexual phenotype), its environmental susceptibility (TSD v GSD), and evolution (divergence among species).</p

MeDIP-seq and nCpG analyses illuminate sexually dimorphic methylation of gonadal development genes with high historic methylation in turtle hatchlings with temperature-dependent sex determination

Background: DNA methylation alters gene expression but not DNA sequence and mediates some cases of phenotypic plasticity. Temperature-dependent sex determination (TSD) epitomizes phenotypic plasticity where environmental temperature drives embryonic sexual fate, as occurs commonly in turtles. Importantly, the temperature-specific transcription of two genes underlying gonadal differentiation is known to be induced by differential methylation in TSD fish, turtle and alligator. Yet, how extensive is the link between DNA methylation and TSD remains unclear. Here we test for broad differences in genome-wide DNA methylation between male and female hatchling gonads of the TSD painted turtle Chrysemys picta using methyl DNA immunoprecipitation sequencing, to identify differentially methylated candidates for future study. We also examine the genome-wide nCpG distribution (which affects DNA methylation) in painted turtles and test for historic methylation in genes regulating vertebrate gonadogenesis. Results: Turtle global methylation was consistent with other vertebrates (57% of the genome, 78% of all CpG dinucleotides). Numerous genes predicted to regulate turtle gonadogenesis exhibited sex-specific methylation and were proximal to methylated repeats. nCpG distribution predicted actual turtle DNA methylation and was bimodal in gene promoters (as other vertebrates) and introns (unlike other vertebrates). Differentially methylated genes, including regulators of sexual development, had lower nCpG content indicative of higher historic methylation. Conclusions: Ours is the first evidence suggesting that sexually dimorphic DNA methylation is pervasive in turtle gonads (perhaps mediated by repeat methylation) and that it targets numerous regulators of gonadal development, consistent with the hypothesis that it may regulate thermosensitive transcription in TSD vertebrates. However, further research during embryogenesis will help test this hypothesis and the alternative that instead, most differential methylation observed in hatchlings is the by-product of sexual differentiation and not its cause.This article is published as Radhakrishnan, Srihari, Robert Literman, Beatriz Mizoguchi, and Nicole Valenzuela. "MeDIP-seq and nCpG analyses illuminate sexually dimorphic methylation of gonadal development genes with high historic methylation in turtle hatchlings with temperature-dependent sex determination." Epigenetics & chromatin 10 (2017): 28. doi: 10.1186/s13072-017-0136-2.</p

MOESM1 of MeDIP-seq and nCpG analyses illuminate sexually dimorphic methylation of gonadal development genes with high historic methylation in turtle hatchlings with temperature-dependent sex determination

Additional file 1. Table S1: Genes with distinct hypermethylated sex-specific windows within the same gene. Table S2: Categories enriched (p = 0.05) in hypermethylated genes at male-producing temperature (26 °C). Table S3: Categories enriched (p = 0.05) in hypermethylated genes at female-producing temperature (31 °C). Tables S4 through S11—differentially methylated genes in C. picta hatchling methylomes along with RPKM, fold change and edgeR p value: Table S4: Heat shock genes. Table S5: Androgen-/estrogen-related genes. Table S6: Kinases. Table S7: Histone-related genes. Table S8: Ubiquitin-related genes. Table S9: Transient receptor potential genes. Table S10: Genes involved in cell proliferation. Table S11: Germline-related genes. Table S12: Number of differentially methylated genes by GO term present in testis and ovaries of C. picta hatchlings. Table S13: Comprehensive list of differentially methylated genes and associated GO pathways between testis and ovaries of C. picta hatchlings. Table S14: Statistics of all differentially methylated genes between testis and ovaries of C. picta hatchlings. Table S15: Genes differentially expressed in the C. picta transcriptome (stage 22) [42] and differentially methylated in the hatchling methylome (this study). Table S16: Relative abundance distribution of repeat categories as a fraction of the genome. Table S17: Overlapping genes between C. picta hatchling methylomes and the methylomes of tongue sole [18]

Shared genes related to aggression, rather than chemical communication, are associated with reproductive dominance in paper wasps (Polistes metricus)

BackgroundIn social groups, dominant individuals may socially inhibit reproduction of subordinates using aggressive interactions or, in the case of highly eusocial insects, pheromonal communication. It has been hypothesized these two modes of reproductive inhibition utilize conserved pathways. Here, we use a comparative framework to investigate the chemical and genomic underpinnings of reproductive dominance in the primitively eusocial wasp Polistes metricus. Our goals were to first characterize transcriptomic and chemical correlates of reproductive dominance and second, to test whether dominance-associated mechanisms in paper wasps overlapped with aggression or pheromone-related gene expression patterns in other species. To explore whether conserved molecular pathways relate to dominance, we compared wasp transcriptomic data to previous studies of gene expression associated with pheromonal communication and queen-worker differences in honey bees, and aggressive behavior in bees, Drosophila, and mice. ResultsBy examining dominant and subordinate females from queen and worker castes in early and late season colonies, we found that cuticular hydrocarbon profiles and genome-wide patterns of brain gene expression were primarily associated with season/social environment rather than dominance status. In contrast, gene expression patterns in the ovaries were associated primarily with caste and ovary activation. Comparative analyses suggest genes identified as differentially expressed in wasp brains are not related to queen pheromonal communication or caste in bees, but were significantly more likely to be associated with aggression in other insects (bees, flies), and even a mammal (mice). ConclusionsThis study provides the first comprehensive chemical and molecular analysis of reproductive dominance in paper wasps. We found little evidence for a chemical basis for reproductive dominance in P. metricus, and our transcriptomic analyses suggest that different pathways regulate dominance in paper wasps and pheromone response in bees. Furthermore, there was a substantial impact of season/social environment on gene expression patterns, indicating the important role of external cues in shaping the molecular processes regulating behavior. Interestingly, genes associated with dominance in wasps were also associated with aggressive behavior in bees, solitary insects and mammals. Thus, genes involved in social regulation of reproduction in Polistes may have conserved functions associated with aggression in insects and other taxa.This article is from BMC Genomics 15 (2014): 75, doi:10.1186/1471-2164-15-75. Posted with permission.</p