Human preterm birth (PTB), a multifactorial syndrome affecting offspring born before 37 completed weeks of gestation, is the leading cause of newborn death worldwide. Remarkably, the degree to which early parturition contributes to mortality in other placental mammals remains unclear. To gain insights on whether PTB is a human-specific syndrome, we examined within- and between-species variation in gestation length across placental mammals and the impact of early parturition on offspring fitness. Within species, gestation length is normally distributed, and all species appear to occasionally give birth before the ‘optimal’ time. Furthermore, human gestation length, like that of many mammalian species, scales proportionally to body mass, suggesting that this trait, like many others, is constrained by body size. Premature humans suffer from numerous cognitive impairments, but little is known of cognitive impairments in other placental mammals. Human gestation differs in the timing of the ‘brain growth spurt’, where unlike many mammals, including closely related primates, the trajectory of human brain growth directly overlaps with the parturition time window. Thus, although all mammals experience early parturition, the fitness costs imposed by the cognitive impairments may be unique to our species. Describing PTB broadly in mammals opens avenues for comparative studies on the physiological and genetic regulators of birth timing as well as the development of new mammalian models of the disease.

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Healthy pregnancy depends on proper placentation—including proliferation, differentiation, and invasion of trophoblast cells—which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of Inverted formin 2 (INF2) alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of Inf2 in mice recapitulates maternal and fetal phenotypes of placental insufficiency. Inf2−/− dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. Inf2−/− fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of Inf2 increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for INF2 in trophoblast invasion—a necessary process for placentation—representing a possible future target for improving placentation and fetal outcomes.

Background and objectives The diversity of eutherian reproductive strategies has led to variation in many traits, such as number of offspring, age of reproductive maturity and gestation length. While reproductive trait variation has been extensively investigated and is well established in mammals, the genetic loci contributing to this variation remain largely unknown. The domestic dog, Canis lupus familiaris is a powerful model for studies of the genetics of inherited disease due to its unique history of domestication. To gain insight into the genetic basis of reproductive traits across domestic dog breeds, we collected phenotypic data for four traits, cesarean section rate, litter size, stillbirth rate and gestation length, from primary literature and breeders' handbooks. Methodology By matching our phenotypic data to genomic data from the Cornell Veterinary Biobank, we performed genome-wide association analyses for these four reproductive traits, using body mass and kinship among breeds as covariates. Results We identified 12 genome-wide significant associations between these traits and genetic loci, including variants near CACNA2D3 with gestation length, MSRB3 and MSANTD1 with litter size, SMOC2 with cesarean section rate and UFM1 with stillbirth rate. A few of these loci, such as CACNA2D3 and MSRB3 , have been previously implicated in human reproductive pathologies, whereas others have been associated with domestication-related traits, including brachycephaly ( SMOC2 ) and coat curl ( KRT71 ). Conclusions and implications We hypothesize that the artificial selection that gave rise to dog breeds also influenced the observed variation in their reproductive traits. Overall, our work establishes the domestic dog as a system for studying the genetics of reproductive biology and disease. LAY SUMMARY The genetic contributors to variation in mammalian reproductive traits remain largely unknown. We took advantage of the domestic dog, a powerful model system, to test for associations between genome-wide variants and four reproductive traits (cesarean section rate, litter size, stillbirth rate and gestation length) that vary extensively across breeds. We identified associations at a dozen loci, including ones previously associated with domestication-related traits, suggesting that selection on dog breeds also influenced their reproductive traits.

Decades of research has yet to provide a vaccine for HIV, the virus which causes AIDS. Recent theoretical research has turned attention to mucosa pH levels over systemic pH levels. Previous research in this field developed a computational approach for determining pH sensitivity that indicated higher potential for transmission at mucosa pH levels present during intercourse. The process was extended to incorporate a principal component analysis (PCA)-based machine learning technique for classification of gp120 proteins against a known transmitted variant called Biomolecular Electro-Static Indexing (BESI). The original process has since been extended to the residue level by a process we termed Electrostatic Variance Masking (EVM) and used in conjunction with BESI to determine structural differences present among various subspecies across Clades A1 and C. Results indicate that structures outside of the core selected by EVM may be responsible for binding affinity observed in many other studies and that pH modulation of select substructures indicated by EVM may influence specific regions of the viral envelope protein (Env) involved in protein-protein interactions.

Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation of discoveries from model organisms to humans. GEneSTATION is built using tools from the Generic Model Organism Database project, including the biology-aware database CHADO, new tools for rapid data integration, and algorithms that streamline synthesis and user access. GEneSTATION contains curated life history information on pregnancy and reproduction from 23 high-quality mammalian genomes. For every human gene, GEneSTATION contains diverse evolutionary (e.g. gene age, population genetic and molecular evolutionary statistics), organismal (e.g. tissue-specific gene and protein expression, differential gene expression, disease phenotype), and molecular data types (e.g. Gene Ontology Annotation, protein interactions), as well as links to many general (e.g. Entrez, PubMed) and pregnancy disease-specific (e.g. PTBgene, dbPTB) databases. By facilitating the synthesis of diverse functional and evolutionary data in pregnancy-associated tissues and phenotypes and enabling their quick, intuitive, accurate and customized meta-analysis, GEneSTATION provides a novel platform for comprehensive investigation of the function and evolution of mammalian pregnancy.

W hat is systems biology? Aspects of the field can be traced to the mid-20th century, but its recent growth was sparked by the integration of theoretical and structural molecular biology to answer new questions arising from high-throughput, data-rich, functional genomics. New collaborations, institutes, and at least one new research university (our own) established at the turn of this century embraced systems biology to transform "largely descriptive" biology practiced along disciplinary lines into "a quantitative, predictive" interdisciplinary endeavor (1). Almost ten years on, what is systems biology now? As students and faculty drawn together from tissue engineering, molecular and cell biology, physiology, ecology, and evolution into a current topics class of the Quantitative and Systems Biology graduate group at UC Merced, we sought to answer this question to define our course and possibly our futures.Systems Biology: Philosophical Foundations, a collection of papers arising from a 2005 symposium convened by the Department of Molecular Cell Physiology, Vrije Universiteit, Amsterdam, and the first book on the philosophy of systems biology, was a natural starting point. The editors' "Introduction" describes systems biology as the combination of sciences from "physics to ecology, mathematics to medicine and linguistics to chemistry" and the field's purview as "functional biology." Yet, they see systems biology as largely cell biology. In their view the field primarily studies processes that occur in extant life forms; they also note the importance of research into minimal life ("the smallest unit of life among autonomous cells") and the origin of life.Surprisingly, given systems biology's supposed broad embrace, the editors explicitly exclude one discipline: evolutionary biology. They explain, quoting Ernst Mayr (2), that functional and evolutionary biology are "two largely separate fields which differ greatly in methods, Fragestellung [types of questions] and basic concepts." That sentiment is echoed in a chapter on methodologies by Hans Westerhoff and Douglas Kell and again in the editors' "Conclusion" ("systems biology is functional and mechanistic rather than evolutionary biology"), which supposedly summarizes findings of all of the chapters. However, seven of the other 11 chapters discuss the evolution of systems, albeit not always at length. These include thoughtful contributions by William Wimsatt on research programs, Alvaro Moreno on the origin of biological organization, and Evelyn Fox Keller on selforganizing systems.This discrepancy seems to result from the editors'position that functional systems biologists "may use reasoning derived from evolutionary biology" but ignore the evolution of systems. That claim is at best whimsical, and the editors themselves cite homology of DNA sequences as evidence of the "unity of biochemistry," praise "the successes of … phylogenetics," and foresee synergy with "evo-devo." A more convincing exclusion of evolutionary biology could have been damaging. The mantra that...