Comparative physiological anthropogeny: exploring molecular underpinnings of distinctly human phenotypes.

Anthropogeny is a classic term encompassing transdisciplinary investigations of the origins of the human species. Comparative anthropogeny is a systematic comparison of humans and other living nonhuman hominids (so-called "great apes"), aiming to identify distinctly human features in health and disease, with the overall goal of explaining human origins. We begin with a historical perspective, briefly describing how the field progressed from the earliest evolutionary insights to the current emphasis on in-depth molecular and genomic investigations of "human-specific" biology and an increased appreciation for cultural impacts on human biology. While many such genetic differences between humans and other hominids have been revealed over the last two decades, this information remains insufficient to explain the most distinctive phenotypic traits distinguishing humans from other living hominids. Here we undertake a complementary approach of "comparative physiological anthropogeny," along the lines of the preclinical medical curriculum, i.e., beginning with anatomy and considering each physiological system and in each case considering genetic and molecular components that are relevant. What is ultimately needed is a systematic comparative approach at all levels from molecular to physiological to sociocultural, building networks of related information, drawing inferences, and generating testable hypotheses. The concluding section will touch on distinctive considerations in the study of human evolution, including the importance of gene-culture interactions.

Evolution of Human-Specific Alleles Protecting Cognitive Function of Grandmothers.

The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular V-set domain recognition of sialic acid (Sia)-containing "self-associated molecular patterns" (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against late-onset Alzheimer's Disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific CD33 V-set domain mutations. Due to hominin-specific, fixed loss-of-function mutation in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and molecular dynamics (MD)-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to N-acetylneuraminic acid (Neu5Ac)-recognition. We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind human CD33 (huCD33) as part of immune-evasive molecular mimicry of host SAMPs and that this binding is significantly impacted by amino acid 21 modification. In addition to LOAD-protective CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of 13 SNPs in these human genes (including CD33) are not shared by genomes of archaic hominins: Neanderthals and Denisovans. We present a plausible evolutionary scenario to compile, correlate, and comprehend existing knowledge about huCD33-evolution and suggest that grandmothering emerged in humans.

Glycocalyx crowding with mucin mimetics strengthens binding of soluble and virus-associated lectins to host cell glycan receptors.

Membrane-associated mucins protect epithelial cell surfaces against pathogenic threats by serving as nonproductive decoys that capture infectious agents and clear them from the cell surface and by erecting a physical barrier that restricts their access to target receptors on host cells. However, the mechanisms through which mucins function are still poorly defined because of a limited repertoire of tools available for tailoring their structure and composition in living cells with molecular precision. Using synthetic glycopolymer mimetics of mucins, we modeled the mucosal glycocalyx on red blood cells (RBCs) and evaluated its influence on lectin (SNA) and virus (H1N1) adhesion to endogenous sialic acid receptors. The glycocalyx inhibited the rate of SNA and H1N1 adhesion in a size- and density-dependent manner, consistent with the current view of mucins as providing a protective shield against pathogens. Counterintuitively, increasing the density of the mucin mimetics enhanced the retention of bound lectins and viruses. Careful characterization of SNA behavior at the RBC surface using a range of biophysical and imaging techniques revealed lectin-induced crowding and reorganization of the glycocalyx with concomitant enhancement in lectin clustering, presumably through the formation of a more extensive glycan receptor patch at the cell membrane. Our findings indicate that glycan-targeting pathogens may exploit the biophysical and biomechanical properties of mucins to overcome the mucosal glycocalyx barrier.

GIV/Girdin, a non-receptor modulator for Gαi/s, regulates spatiotemporal signaling during sperm capacitation and is required for male fertility.

For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV (CCDC88A), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men.

Longitudinal antimüllerian hormone and its correlation with pubertal milestones.

OBJECTIVE: To examine the changes in AMH levels longitudinally over time and their relationship with both body composition, particularly abdominal adiposity, and milestones of pubertal development in female children. DESIGN: Secondary analysis of a prospective, longitudinal study. SETTING: University affiliated research center and laboratories. PATIENTS: Eighty-nine females were examined between 1990 and 2015 to study child growth and development. INTERVENTIONS: Demographic, anthropometric, growth, and pubertal milestone data with serum samples stored and subsequently analyzed for AMH. MAIN OUTCOME MEASURES: Longitudinal change in AMH and predicted AMH levels based on body composition, age, and pubertal milestones including, pubarche, thelarche, and menarche. RESULTS: Natural log-transformed AMH (AMHlog) levels appeared to have a nonlinear relationship with age, decreasing between 10 and 14 years of age, increasing until 16 years. A mixed effect linear model demonstrated that increased abdominal adiposity (waist/height ratio, WHtR) was significantly associated with the predicted increased AMHlog levels (ß=1.37). As females progressed through the Tanner stages, the model predicted decreasing AMHlog values when adjusting for age and WHtR. CONCLUSIONS: Declining AMH levels during puberty may not be reflective of diminished ovarian reserve as observed in adults, but may suggest a permissive role of AMH in the activation of the hypothalamic-pituitary-ovarian axis.

Mucin-mimetic glycan arrays integrating machine learning for analyzing receptor pattern recognition by influenza A viruses.

Influenza A viruses (IAVs) exploit host glycans in airway mucosa for entry and infection. Detection of changes in IAV glycan-binding phenotype can provide early indication of transmissibility and infection potential. While zoonotic viruses are monitored for mutations, the influence of host glycan presentation on viral specificity remains obscured. Here, we describe an array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation and density in the mucinous glycocalyx may impact IAV recognition. H1N1 and H3N2 binding in arrays of α2,3- and α2,6-sialyllactose receptors confirmed their known sialic acid-binding specificities and revealed their different sensitivities to receptor presentation. Further, the transition of H1N1 from avian to mammalian cell culture improved the ability of the virus to recognize mucin-like displays of α2,6-sialic acid receptors. Support vector machine (SVM) learning efficiently characterized this shift in binding preference and may prove useful to study viral evolution to a new host.

Multiple Genomic Events Altering Hominin SIGLEC Biology and Innate Immunity Predated the Common Ancestor of Humans and Archaic Hominins.

Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface "self-associated molecular patterns" that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed ∼2-3 Ma, possibly contributing to the origins of the genus Homo. The mutation likely altered human self-associated molecular patterns, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some gene-encoding Sia-sensing proteins suggested a "hotspot" in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence ∼0.6 Ma. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, Natural Killer(NK) cells, and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6 and 2 Ma, potentially affecting human evolution.

Maximum reproductive lifespan correlates with CD33rSIGLEC gene number: Implications for NADPH oxidase-derived reactive oxygen species in aging.

Humans and orcas are among the very rare species that have a prolonged post-reproductive lifespan (PRLS), during which the aging process continues. Reactive oxygen species (ROS) derived from mitochondria and from the NADPH oxidase (NOX) enzymes of innate immune cells are known to contribute to aging, with the former thought to be dominant. CD33-related-Siglecs are immune receptors that recognize self-associated-molecular-patterns and modulate NOX-derived-ROS. We herewith demonstrate a strong correlation of lifespan with CD33rSIGLEC gene number in 26 species, independent of body weight or phylogeny. The correlation is stronger when considering total CD33rSIGLEC gene number rather than those encoding inhibitory and activating subsets, suggesting that lifetime balancing of ROS is important. Combining independent lines of evidence including the short half-life and spontaneous activation of neutrophils, we calculate that even without inter-current inflammation, a major source of lifetime ROS exposure may actually be neutrophil NOX-derived. However, genomes of human supercentenarians (>110 years) do not harbor a significantly higher number of functional CD33rSIGLEC genes. Instead, lifespan correlation with CD33rSIGLEC gene number was markedly strengthened by excluding the post-reproductive lifespan of humans and orcas (R2  = 0.83; P < .0001). Thus, CD33rSIGLEC modulation of ROS likely contributes to maximum reproductive lifespan, but other unknown mechanisms could be important to PRLS.

The New Science of Practical Wisdom.

Wisdom has been discussed for centuries in religious and philosophical texts. It is often viewed as a fuzzy psychological construct analogous to consciousness, stress, and resilience. This essay provides an understanding of wisdom as a scientific construct, based on empirical research starting in the 1970s. The focus is on practical rather than theoretical wisdom. While there are different conceptualizations of wisdom, it is best defined as a complex human characteristic or trait with specific components: social decision-making, emotional regulation, prosocial behavior (such as empathy and compassion), self-reflection, acceptance of uncertainty, decisiveness, and spirituality. These psychological processes involve the fronto-limbic circuitry. Wisdom is associated with positive life outcomes including better health, well-being, happiness, life satisfaction, and resilience. Wisdom tends to increase with active aging, facilitating a contribution of wise grandparents to promoting fitness of younger kin. Despite the loss of their own fertility and physical health, older adults help enhance their children's and grandchildren's well-being, health, longevity, and fertility-the "grandmother hypothesis" of wisdom. Wisdom has important implications at individual and societal levels and is a major contributor to human thriving. We need to place a greater emphasis on promoting wisdom through our educational systems from elementary to professional schools.

The female reproductive tract contains multiple innate sialic acid-binding immunoglobulin-like lectins (Siglecs) that facilitate sperm survival.

A sperm that fertilizes an egg has successfully survived multiple checkpoints within the female reproductive tract, termed pre-fertilization events. The leukocytic response is a pre-fertilization event in which sperm trigger an immune response that promotes homing of circulating leukocytes to the uterine lumen to destroy most sperm. Various glycoconjugates decorate the sperm surface, including sialic acids, which are abundant at the sperm surface where they cap most glycan chains and regulate sperm migration through cervical mucus, formation of the sperm oviductal reservoir, and sperm capacitation. However, the role of sperm-associated sialic acids in the leukocytic reaction remains unknown. The cognate endogenous binding partners of sialic acids, sialic acid-binding immunoglobulin-like lectins (Siglecs) play a pivotal role in regulating many immune responses. Here we investigated whether sperm-associated sialic acids inhibit activation of neutrophils, one of the major immune cells involved in the leukocytic reaction. We used in vitro interactions between sperm and neutrophils as well as binding assays between sperm and recombinant Siglec-Fc chimeric proteins to measure interactions. Moreover, we examined whether Siglecs are expressed on human and mouse endometria, which have a role in initiating the leukocytic reaction. Surprisingly less sialylated, capacitated, sperm did not increase neutrophil activation in vitro However, we observed expression of several Siglecs on the endometrium and that these receptors interact with sialylated sperm. Our results indicate that sperm sialic acids may interact with endometrial Siglecs and that these interactions facilitate sperm survival in the face of female immunity.

Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans-An Evolutionary Perspective.

The glycocalyx of human cells differs from that of many other mammals by the lack of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and increased abundance of its precursor N-acetylneuraminic acid (Neu5Ac). Most humans also have circulating antibodies specifically targeting the non-human sialic acid Neu5Gc. Recently, several additional mammalian species have been found to also lack Neu5Gc. In all cases, loss-of-function mutations in the gene encoding the sialic acid-modifying enzyme CMAH are responsible for the drastic change in these species. Unlike other glycan antigens, Neu5Gc apparently cannot be produced by microbes, raising the question about the origin of these antibodies in humans. Dietary exposure and presentation on bacteria coating themselves with Neu5Gc from the diet are distinct possibilities. However, the majority of the non-human species that lack Neu5Gc do not consume diets rich in Neu5Gc, making it unlikely that they will have been immunized against this sialic acid. A notable exception are mustelids (ferrets, martens and their relatives) known for preying on various small mammal species rich in Neu5Gc. No studies exist on levels of anti-Neu5Gc antibodies in non-human species. Evolutionary scenarios for the repeated, independent fixation of CMAH loss-of-function mutations at various time points in the past include strong selection by parasites, especially enveloped viruses, stochastic effects of genetic drift, and directional selection via female immunity to paternal Neu5Gc. Convergent evolution of losses of the vertebrate-specific self-glycan Neu5Gc are puzzling and may represent a prominent way in which glycans become agents of evolutionary change in their own right. Such change may include the reconfiguration of innate immune lectins that use self-sialic acids as recognition patterns.

Humans and Chimpanzees Display Opposite Patterns of Diversity in Arylamine N-Acetyltransferase Genes.

Among the many genes involved in the metabolism of therapeutic drugs, human arylamine N-acetyltransferases (NATs) genes have been extensively studied, due to their medical importance both in pharmacogenetics and disease epidemiology. One member of this small gene family, NAT2, is established as the locus of the classic human acetylation polymorphism in drug metabolism. Current hypotheses hold that selective processes favoring haplotypes conferring lower NAT2 activity have been operating in modern humans' recent history as an adaptation to local chemical and dietary environments. To shed new light on such hypotheses, we investigated the genetic diversity of the three members of the NAT gene family in seven hominid species, including modern humans, Neanderthals and Denisovans. Little polymorphism sharing was found among hominids, yet all species displayed high NAT diversity, but distributed in an opposite fashion in chimpanzees and bonobos (Pan genus) compared to modern humans, with higher diversity in Pan species at NAT1 and lower at NAT2, while the reverse is observed in humans. This pattern was also reflected in the results returned by selective neutrality tests, which suggest, in agreement with the predicted functional impact of mutations detected in non-human primates, stronger directional selection, presumably purifying selection, at NAT1 in modern humans, and at NAT2 in chimpanzees. Overall, the results point to the evolution of divergent functions of these highly homologous genes in the different primate species, possibly related to their specific chemical/dietary environment (exposome) and we hypothesize that this is likely linked to the emergence of controlled fire use in the human lineage.

Ovulation Induction for the General Gynecologist.

The practice of ovulation induction often falls to the reproductive endocrinology and infertility specialist. However, attitudes toward the evaluation and treatment of infertility has shifted among general obstetrician-gynecologists (OB-GYN). This review discusses the underlying scientific basis of anovulation and clinical guidelines regarding the use of different medications for the purpose of promoting follicular recruitment and ovulation for the general OB-GYN.

Cesarean Scar Ectopic Pregnancy: Current Management Strategies.

IMPORTANCE: Cesarean scar ectopic pregnancy (CSEP) has a high rate of morbidity with nonspecific signs and symptoms making identification difficult. The criterion-standard treatment of CSEP has been subject to debate. OBJECTIVE: This review defines CSEP, discusses pathogenesis and diagnosis, and compares treatment options and outcomes. EVIDENCE ACQUISITION: A literature review was performed utilizing the term cesarean scar ectopic pregnancy and subsequently selecting only meta-analyses and systematic reviews. Only articles published in English were included. Relevant articles within the reviews were analyzed as necessary. RESULTS: Five basic pathways have been identified in treatment of CSEP: expectant management, medical therapy, surgical intervention, uterine artery embolization, or a combination approach. Expectant management has the highest probability of morbid outcomes, including hemorrhage, uterine rupture, and preterm delivery. Medical management often requires further treatment with additional medication or surgery. Different surgical methods have been explored including uterine artery embolization; dilation and curettage; surgical removal via vaginal, laparoscopic, or laparotomic approach; and hysterectomy. Each method has various levels of success and depends on surgeon skill and patient presentation. CONCLUSIONS: Recent research supports any method that removes the pregnancy and scar to reduce morbidity and promote future fertility. Laparoscopic and transvaginal approaches are options for CSEP treatment, although continued research is required to identify the optimal approach. RELEVANCE: As cesarean delivery numbers rise, a subsequent increase in CSEPs can be anticipated. The ability to accurately diagnose and treat this morbid condition is vital to the practice of any specialist in general obstetrics and gynecology.

Evolutionary expansion of DNA hypomethylation in the mammalian germline genome.

DNA methylation in the germline is among the most important factors influencing the evolution of mammalian genomes. Yet little is known about its evolutionary rate or the fraction of the methylome that has undergone change. We compared whole-genome, single-CpG DNA methylation profiles in sperm of seven species-human, chimpanzee, gorilla, rhesus macaque, mouse, rat, and dog-to investigate epigenomic evolution. We developed a phylo-epigenetic model for DNA methylation that accommodates the correlation of states at neighboring sites and allows for inference of ancestral states. Applying this model to the sperm methylomes, we uncovered an overall evolutionary expansion of the hypomethylated fraction of the genome, driven both by the birth of new hypomethylated regions and by extensive widening of hypomethylated intervals in ancestral species. This expansion shows strong lineage-specific aspects, most notably that hypomethylated intervals around transcription start sites have evolved to be considerably wider in primates and dog than in rodents, whereas rodents show evidence of a greater trend toward birth of new hypomethylated regions. Lineage-specific hypomethylated regions are enriched near sets of genes with common developmental functions and significant overlap across lineages. Rodent-specific and primate-specific hypomethylated regions are enriched for binding sites of similar transcription factors, suggesting that the plasticity accommodated by certain regulatory factors is conserved, despite substantial change in the specific sites of regulation. Overall our results reveal substantial global epigenomic change in mammalian sperm methylomes and point to a divergence in trans-epigenetic mechanisms that govern the organization of epigenetic states at gene promoters.

N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils.

Biosynthesis of the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) was lost during human evolution due to inactivation of the CMAH gene, possibly expediting divergence of the Homo lineage, due to a partial fertility barrier. Neu5Gc catabolism generates N-glycolylhexosamines, which are potential precursors for glycoconjugate biosynthesis. We carried out metabolic labeling experiments and studies of mice with human-like Neu5Gc deficiency to show that Neu5Gc degradation is the metabolic source of UDP-GlcNGc and UDP-GalNGc and the latter allows an unexpectedly selective incorporation of N-glycolyl groups into chondroitin sulfate (CS) over other potential glycoconjugate products. Partially N-glycolylated-CS was chemically synthesized as a standard for mass spectrometry to confirm its natural occurrence. Much lower amounts of GalNGc in human CS can apparently be derived from Neu5Gc-containing foods, a finding confirmed by feeding Neu5Gc-rich chow to human-like Neu5Gc-deficient mice. Unlike the case with Neu5Gc, N-glycolyl-CS was also stable enough to be detectable in animal fossils as old as 4 My. This work opens the door for investigating the biological and immunological significance of this glycosaminoglycan modification and for an "ancient glycans" approach to dating of Neu5Gc loss during the evolution of Homo.

Vulvodynia: What We Know and Where We Should Be Going.

OBJECTIVE: The aim of the study was to review the current nomenclature and literature examining microbiome cytokine, genomic, proteomic, and glycomic molecular biomarkers in identifying markers related to the understanding of the pathophysiology and diagnosis of vulvodynia (VVD). MATERIALS AND METHODS: Computerized searches of MEDLINE and PubMed were conducted focused on terminology, classification, and "omics" variations of VVD. Specific MESH terms used were VVD, vestibulodynia, metagenomics, vaginal fungi, cytokines, gene, protein, inflammation, glycomic, proteomic, secretomic, and genomic from 2001 to 2016. Using combined VVD and vestibulodynia MESH terms, 7 references were identified related to vaginal fungi, 15 to cytokines, 18 to gene, 43 to protein, 38 to inflammation, and 2 to genomic. References from identified publications were manually searched and cross-referenced to identify additional relevant articles. A narrative synthesis of the articles was conducted; however, meta-analysis was not conducted because of substantial heterogeneity in the studies and limited numbers of control-matched studies. RESULTS: Varying definitions of VVD complicate a meta-analysis, and standard definitions will better allow for comparisons of studies and enhance the applicability of evidence to patient populations. Although data are still limited, genomic and molecular diagnostic testings continue to be investigated as potential tools for the diagnosis of VVD. CONCLUSIONS: Standardized nomenclature will allow for comparability of studies and progress in research related to the pathophysiology of VVD and to facilitate clinical decision making and treatment choices. Although the current understanding of the pathogenesis of VVD is limited, there are new opportunities to explore potential diagnostic markers differences in women with VVD, which may lead to targeted therapy.

Synthetic Mucus Nanobarriers for Identification of Glycan-Dependent Primary Influenza A Infection Inhibitors.

Current drugs against the influenza A virus (IAV) act by inhibiting viral neuraminidase (NA) enzymes responsible for the release of budding virions from sialoglycans on infected cells. Here, we describe an approach focused on a search for inhibitors that reinforce the protective functions of mucosal barriers that trap viruses en route to the target cells. We have generated mimetics of sialo-glycoproteins that insert into the viral envelope to provide a well-defined mucus-like environment encapsulating the virus. By introducing this barrier, which the virus must breach using its NA enzymes to infect a host cell, into a screening platform, we have been able to identify compounds that provide significant protection against IAV infection. This approach may facilitate the discovery of potent new IAV prophylactics among compounds with NA activities too weak to emerge from traditional drug screens.