Middle and later Pleistocene hominins in Africa and Southwest Asia

Approximately 700,000 years ago, Homo erectus in Africa was giving way to populations with larger brains accompanied by structural adjustments to the vault, cranial base, and face. Such early Middle Pleistocene hominins were not anatomically modern. Their skulls display strong supraorbital tori above projecting faces, flattened frontals, and less parietal expansion than is the case for Homo sapiens. Postcranial remains seem also to have archaic features. Subsequently, some groups evolved advanced skeletal morphology, and by ca. 200,000 years ago, individuals more similar to recent humans are present in the African record. These fossils are associated with Middle Stone Age lithic assemblages and, in some cases, Acheulean tools. Crania from Herto in Ethiopia carry defleshing cutmarks and superficial scoring that may be indicative of mortuary practices. Despite these signs of behavioral innovation, neither the Herto hominins, nor others from Late Pleistocene sites such as Klasies River in southern Africa and Skhūl/Qafzeh in Israel, can be matched in living populations. Skulls are quite robust, and it is only after ≈35,000 years ago that people with more gracile, fully modern morphology make their appearance. Not surprisingly, many questions concerning this evolutionary history have been raised. Attention has centered on systematics of the mid-Pleistocene hominins, their paleobiology, and the timing of dispersals that spread H. sapiens out of Africa and across the Old World. In this report, I discuss structural changes characterizing the skulls from different time periods, possible regional differences in morphology, and the bearing of this evidence on recognizing distinct species.     

Degenerate evolution of the hedgehog gene in a hemichordate lineage

The discovery of a set of highly conserved genes implicated in patterning during animal development represents one of the most striking findings from the field of evolutionary developmental biology. Existence of these “developmental toolkit” genes in diverse taxa, however, does not necessarily imply that they always perform the same functions. Here, we demonstrate functional evolution in a major toolkit gene. hedgehog (hh) encodes a protein that undergoes autocatalytic cleavage, releasing a signaling molecule involved in major developmental processes, notably neural patterning. We find that the hh gene of a colonial pterobranch hemichordate, Rhabdopleura compacta, is expressed in a dramatically different pattern to its ortholog in a harrimaniid enteropneust hemichordate, Saccoglossus kowalevskii. These represent two of the three major hemichordate lineages, the third being the indirect developing ptychoderid enteropneusts. We also show that the normally well-conserved amino acid sequence of the autoproteolytic cleavage site has a derived change in S. kowalevskii. Using ectopic expression in Drosophila, we find that this amino acid substitution reduces the efficiency of Hh autocatalytic cleavage and its signaling function. We conclude that the Hh sequence and expression in S. kowalevskii represent the derived state for deuterostomes, and we argue that functional evolution accompanied secondary reduction of the central nervous system in harrimaniids.     

Global view of the evolution and diversity of metazoan neuropeptide signaling

Neuropeptides are signaling molecules that commonly act via G protein-coupled receptors (GPCRs) and are generated in neurons by proneuropeptide (pNP) cleavage. Present in both cnidarians and bilaterians, neuropeptides represent an ancient and widespread mode of neuronal communication. Due to the inherent difficulties of analyzing highly diverse and repetitive pNPs, the relationships among different families are often elusive. Using similarity-based clustering and sensitive similarity searches, I obtained a global view of metazoan pNP diversity and evolution. Clustering revealed a large and diffuse network of sequences connected by significant sequence similarity encompassing one-quarter of all families. pNPs belonging to this cluster were also identified in the early-branching neuronless animal Trichoplax adhaerens. Clustering of neuropeptide GPCRs identified several orthology groups and allowed the reconstruction of the phyletic distribution of receptor families. GPCR phyletic distribution closely paralleled that of pNPs, indicating extensive conservation and long-term coevolution of receptor–ligand pairs. Receptor orthology and intermediate sequences also revealed the homology of pNPs so far considered unrelated, including allatotropin and orexin. These findings, together with the identification of deuterostome achatin and luqin and protostome opioid pNPs, extended the neuropeptide complement of the urbilaterian. Several pNPs were also identified from the hemichordate Saccoglossus kowalevskii and the cephalochordate Branchiostoma floridae, elucidating pNP evolution in deuterostomes. Receptor–ligand conservation also allowed ligand predictions for many uncharacterized GPCRs from nonmodel species. The reconstruction of the neuropeptide-signaling repertoire at deep nodes of the animal phylogeny allowed the formulation of a testable scenario of the evolution of animal neuroendocrine systems.     

Characterization of MADS-box genes in charophycean green algae and its implication for the evolution of MADS-box genes

The MADS-box genes of land plants are extensively diverged to form a superfamily and are important in various aspects of development including the specification of floral organs as homeotic selector genes. The closest relatives of land plants are the freshwater green algae charophyceans. To study the origin and evolution of land plant MADS-box genes, we characterized these genes in three charophycean green algae: the stonewort Chara globularis, the coleochaete Coleochaete scutata, and the desmid Closterium peracerosum-strigosum-littorale complex. Phylogenetic analyses suggested that MADS-box genes diverged extensively in the land plant lineage after the separation of charophyceans from land plants. The stonewort C. globularis mRNA was specifically detected in the oogonium and antheridium together with the egg and spermatozoid during their differentiation. The expression of the C. peracerosum-strigosum-littorale-complex gene increased when vegetative cells began to differentiate into gametangial cells and decreased after fertilization. These expression patterns suggest that the precursors of land plant MADS-box genes originally functioned in haploid reproductive cell differentiation and that the haploid MADS-box genes were recruited into a diploid generation during the evolution of land plants.     

A guardian of grasses: specific origin and conservation of a unique disease-resistance gene in the grass lineage

The maize Hm1 gene provides protection against a lethal leaf blight and ear mold disease caused by Cochliobolus carbonum race 1 (CCR1). Although it was the first disease-resistance (DR) gene to be cloned, it remains a novelty because, instead of participating in the plant recognition and response system as most DR genes do, Hm1 disarms the pathogen directly. It does so by encoding an NADPH-dependent reductase, whose function is to inactivate Helminthosporium carbonum (HC) toxin, an epoxide-containing cyclic tetrapeptide, which the pathogen produces as a key virulence factor to colonize maize. Although CCR1 is strictly a pathogen of maize, orthologs of Hm1 and the HC-toxin reductase activity are present in the grass family, suggesting an ancient and evolutionarily conserved role of this DR trait in plants. Here, we provide proof for such a role by demonstrating its involvement in nonhost resistance of barley to CCR1. Barley leaves in which expression of the Hm1 homologue was silenced became susceptible to infection by CCR1, but only if the pathogen was able to produce HC toxin. Phylogenetic analysis indicated that Hm1 evolved exclusively and early in the grass lineage. Given the devastating ability of CCR1 to kill maize, these findings imply that the evolution and/or geographical distribution of grasses may have been constrained if Hm1 did not emerge.     

Rapid changes in the gut microbiome during human evolution

Humans are ecosystems containing trillions of microorganisms, but the evolutionary history of this microbiome is obscured by a lack of knowledge about microbiomes of African apes. We sequenced the gut communities of hundreds of chimpanzees, bonobos, and gorillas and developed a phylogenetic approach to reconstruct how present-day human microbiomes have diverged from those of ancestral populations. Compositional change in the microbiome was slow and clock-like during African ape diversification, but human microbiomes have deviated from the ancestral state at an accelerated rate. Relative to the microbiomes of wild apes, human microbiomes have lost ancestral microbial diversity while becoming specialized for animal-based diets. Individual wild apes cultivate more phyla, classes, orders, families, genera, and species of bacteria than do individual humans across a range of societies. These results indicate that humanity has experienced a depletion of the gut flora since diverging from Pan.The human microbiome is shaped by host genetics, environment, and lifestyle (1–3); thus, humanity''s unique evolutionary and cultural histories must have altered our associations with microorganisms (4). Despite intensive investigation of the microbiomes of humans spanning a range of geographic locations and cultures (5–7), how the composition of the microbiome has changed since humans diverged from other species, and since human populations diverged from one another, remains unclear, owing to a lack of knowledge about the microbiomes of ancestral hominid populations.Understanding how the composition of the human microbiome has changed over evolutionary time requires the inclusion of the microbiomes of phylogenetic outgroups (i.e., the African apes) into analyses of human microbiomes. Previous comparisons of the gut microbiomes of humans and the African apes have been restricted to just a few individuals per host species (8), precluding detection of the precise compositional differences that distinguish the microbiomes of the host species. Comparing the microbiomes of populations of chimpanzees, bonobos, gorillas, and humans while considering the phylogenetic relatedness among the hosts can reveal how the composition of the microbiome has changed since the host species diversified.Here we used a phylogenetic approach to identify the shifts in the composition of the microbiome that occurred along the lineages leading to the extant species of Homo and Pan. This analysis shows that humans across a range of cultures and geographies harbor microbiomes that are disproportionately divergent from those within wild apes. In particular, among the living hominid species, humans harbor uncharacteristically low levels of microbial diversity within their gut microbiomes.     

Mitochondrial heteroplasmy and the evolution of insecticide resistance: Non-Mendelian inheritance in action

Genes encoded by mitochondrial DNA (mtDNA) exist in large numbers per cell but can be selected very rapidly as a result of unequal partitioning of mtDNA between germ cells during embryogenesis. However, empirical studies of this “bottlenecking” effect are rare because of the apparent scarcity of heteroplasmic individuals possessing more than one mtDNA haplotype. Here, we report an example of insecticide resistance in an arthropod pest (Tetranychus urticae) being controlled by mtDNA and on its inheritance in a heteroplasmic mite strain. Resistance to the insecticide bifenazate is highly correlated with remarkable mutations in cytochrome b, a mitochondrially encoded protein in the respiratory pathway. Four sites in the Q_o site that are absolutely conserved across fungi, protozoa, plants, and animals are mutated in resistant mite strains. Despite the unusual nature of these mutations, resistant mites showed no fitness costs in the absence of insecticide. Partially resistant strains, consisting of heteroplasmic individuals, transmit their resistant and susceptible haplotypes to progeny in highly variable ratios consistent with a sampling bottleneck of ≈180 copies. Insecticide selection on heteroplasmic individuals favors those carrying resistant haplotypes at a frequency of 60% or more. This combination of factors enables very rapid evolution and accounts for mutations being fixed in most field-collected resistant strains. The results provide a rare insight into non-Mendelian mechanisms of mitochondrial inheritance and evolution, relevant to anticipating and understanding the development of other mitochondrially encoded adaptations in arthropods. They also provide strong evidence of cytochrome b being the target site for bifenazate in spider mites.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Structural insight into the reaction mechanism and evolution of cytokinin biosynthesis

The phytohormone cytokinin regulates plant growth and development. This hormone is also synthesized by some phytopathogenic bacteria, such as Agrobacterium tumefaciens, and is as a key factor in the formation of plant tumors. The rate-limiting step of cytokinin biosynthesis is catalyzed by adenosine phosphate-isopentenyltransferase (IPT). Agrobacterium IPT has a unique substrate specificity that enables it to increase trans-zeatin production by recruiting a metabolic intermediate of the host plant's biosynthetic pathway. Here, we show the crystal structures of Tzs, an IPT from A. tumefaciens, complexed with AMP and a prenyl-donor analogue, dimethylallyl S-thiodiphosphate. The structures reveal that the carbon-nitrogen-based prenylation proceeds by the SN2-reaction mechanism. Site-directed mutagenesis was used to determine the amino acid residues, Asp-173 and His-214, which are responsible for differences in prenyl-donor substrate specificity between plant and bacterial IPTs. IPT and the p loop-containing nucleoside triphosphate hydrolases likely evolved from a common ancestral protein. Despite structural similarities, IPT has evolved a distinct role in which the p loop transfers a prenyl moiety in cytokinin biosynthesis.     

Functional evolution of Erg potassium channel gating reveals an ancient origin for IKr

Mammalian Ether-a-go-go related gene (Erg) family voltage-gated K⁺ channels possess an unusual gating phenotype that specializes them for a role in delayed repolarization. Mammalian Erg currents rectify during depolarization due to rapid, voltage-dependent inactivation, but rebound during repolarization due to a combination of rapid recovery from inactivation and slow deactivation. This is exemplified by the mammalian Erg1 channel, which is responsible for I_Kr, a current that repolarizes cardiac action potential plateaus. The Drosophila Erg channel does not inactivate and closes rapidly upon repolarization. The dramatically different properties observed in mammalian and Drosophila Erg homologs bring into question the evolutionary origins of distinct Erg K⁺ channel functions. Erg channels are highly conserved in eumetazoans and first evolved in a common ancestor of the placozoans, cnidarians, and bilaterians. To address the ancestral function of Erg channels, we identified and characterized Erg channel paralogs in the sea anemone Nematostella vectensis. N. vectensis Erg1 (NvErg1) is highly conserved with respect to bilaterian homologs and shares the I_Kr-like gating phenotype with mammalian Erg channels. Thus, the I_Kr phenotype predates the divergence of cnidarians and bilaterians. NvErg4 and Caenorhabditis elegans Erg (unc-103) share the divergent Drosophila Erg gating phenotype. Phylogenetic and sequence analysis surprisingly indicates that this alternate gating phenotype arose independently in protosomes and cnidarians. Conversion from an ancestral I_Kr-like gating phenotype to a Drosophila Erg-like phenotype correlates with loss of the cytoplasmic Ether-a-go-go domain. This domain is required for slow deactivation in mammalian Erg1 channels, and thus its loss may partially explain the change in gating phenotype.Voltage-gated ion channel families are highly conserved across the Eumetazoa (cnidarians and bilaterians) (1, 2). Vertebrates recently expanded the number of ion channel genes within each of the conserved families because of vertebrate-specific gene duplications. Additionally, phylogenetically restricted duplications of ion channel genes appear common throughout the Eumetazoa (1, 3–5). Thus, there is little 1:1 gene orthology between the eumetazoan phyla (1). However, numerous studies show extremely high functional conservation, including family-specific gating properties. For example, Shaker-related voltage-gated K⁺ channels first cloned in Drosophila show a high fidelity of gating phenotype to their mammalian counterparts (6). Subsequent studies have shown this functional conservation extends to cnidarians (4, 7–10), which separated from bilaterians near the base of the eumetazoan tree over 500 Mya (11). One exception to this pattern of high conservation is the Ether-a-go-go related gene (Erg) family (or Kv11) of voltage-gated K⁺ channels. The three mammalian Erg orthologs show striking gating differences compared with Drosophila Erg (seizure, DmErg).The mammalian Erg gating phenotype is typified by human Erg1 (HsErg1), which underlies I_Kr, a K⁺ current that repolarizes the late plateau phase of ventricular action potentials (12, 13). HsErg1 loss-of-function mutations prolong the QT interval in ECG recordings, indicating impaired action potential repolarization (14). Several key gating features adapt Erg1 for ventricular action potential plateau repolarization. First, Erg1 channels inactivate rapidly in response to depolarization (Fig. 1 A–C). Second, recovery from inactivation through the open state is extremely rapid (Fig. 1B), whereas channel deactivation is slow (Fig. 1D); the combination produces a jump in Erg1 current in response to repolarization (15). The net effect is that peak Erg1 current flow is delayed and specifically accelerates cardiac action potential plateau repolarization (15), and the length of the plateau is dependent on Erg1 current density (16). The physiological role of mammalian Erg2 and Erg3 channels has not been extensively characterized, but they share an I_Kr-like gating phenotype (17).Open in a separate windowFig. 1.Comparison of HsErg1 and DmErg gating phenotypes. (A) Families of outward currents recorded from Xenopus oocytes expressing HsErg1 (Left) and DmErg + DAO (Right) in response to depolarizations (Inset). Scale bars indicate time and current amplitude. Currents elicited by a step to +60 mV are highlighted, and arrows indicate (1) rectification of HsErg1 during depolarization by inactivation, (2) rebound in HsErg1 current in response to repolarization due to rapid recovery and slow deactivation, and (3) rapid DmErg deactivation. (B) Comparison of HsErg1 (black) and DmErg (red) currents during a protocol in which channels were first activated by a 1 s step to +60 mV, returned to –100 mV for 10 ms, and then returned to +60 mV. Currents are normalized in peak amplitude for comparison. HsErg1 is inactivated at the end of the first depolarization, recovers to the open state at −100 mV, and inactivates rapidly from a high peak during the second pulse. DmErg1 remains active throughout the first +60 mV pulse, closes at –100 mV, and reactivates during the second +60 mV pulse. (C) Peak HsErg1 current during an initial depolarization (* in B) normalized to peak current after recovery from inactivation (# in B): inactivation reduces the HsErg1 current >20-fold during the first step. Data show mean ± SEM, n = 6 cells. (D) Time constant of deactivation (Tau_DEACT) measured from tail currents recorded at the indicated voltages for HsErg1 (black) and DmErg (red). Data show mean ± SEM, n = 6–7 cells. (E) Normalized GV curves for HsErg1 and DmErg fit with a single Boltzmann distribution (parameters in SI Methods. Scale bar indicates that time and current amplitudes have been normalized.In contrast, DmErg does not inactivate during depolarization (Fig. 1 A and B) and deactivates rapidly upon repolarization (Fig. 1D) (18). The voltage-activation curve (GV) of DmErg is shifted to hyperpolarized potentials, suggesting influence on subthreshold excitability (Fig. 1E). Modeled HsErg1 and DmErg responses to a crude plateau action potential waveform (Fig. 1F and Fig. S1) point to distinct physiological roles. HsErg1 current is attenuated during the plateau by inactivation and rebounds sharply as the plateau decays. These features allow HsErg1 to accelerate late repolarization without blocking the plateau itself (15). Peak DmErg current flows during the plateau, and the current decays rapidly during repolarization. DmErg would therefore directly combat plateau formation. Loss of HsErg1 inactivation in humans indeed leads to a shortened QT interval based on premature action potential repolarization (16). The specific contribution of DmErg to firing patterns in native cells is unknown, but its gating features are consistent with regulation of subthreshold excitability or rapid action potential repolarization. Temperature-sensitive mutations in the seizure locus that encodes DmErg cause bursts of uncoordinated motor output (19) suggestive of changes in subthreshold excitability. The Caenorhabditis elegans Erg ortholog (CeErg, encoded by unc-103) has not been functionally expressed, but genetic analysis demonstrates that it regulates the excitation threshold of vulva muscles in females and protractor muscles in males (20–23).The Erg, Ether-a-go-go (Eag), and Elk gene families comprise the EAG superfamily of voltage-gated K⁺ channels. These gene families are highly conserved in eumetazoan genomes, and Eag channels display a high functional conservation in the bilaterians. Given the distinct gating phenotypes of the Erg genes in Drosophila and mammals, we decided to explore the functional evolution of the Erg gene family to determine the origins of the distinct I_Kr-like and DmErg gating phenotypes in the Erg gene family. We functionally characterized CeErg and Erg paralogs from the starlet sea anemone Nematostella vectensis. We examined CeErg to determine whether the DmErg gating phenotype was present in multiple protostome invertebrate phyla. We reasoned that comparison of bilaterian and Nematostella Erg channels would provide insight into ancestral Erg gating phenotypes present before the cnidarian/bilaterian divergence. Functional and phylogenetic analysis presented here supports an I_Kr-like phenotype as the ancestral gating pattern. An alternate DmErg-like gating phenotype has emerged independently at least twice during metazoan evolution (once in cnidarians and at least once in protostomes) and correlates with loss of the cytoplasmic eag gating domain.     

Stable isotope evidence for an amphibious phase in early proboscidean evolution

The order Proboscidea includes extant elephants and their extinct relatives and is closely related to the aquatic sirenians (manatees and dugongs) and terrestrial hyracoids (hyraxes). Some analyses of embryological, morphological, and paleontological data suggest that proboscideans and sirenians shared an aquatic or semiaquatic common ancestor, but independent tests of this hypothesis have proven elusive. Here we test the hypothesis of an aquatic ancestry for advanced proboscideans by measuring delta(18)O in tooth enamel of two late Eocene proboscidean genera, Barytherium and Moeritherium, which are sister taxa of Oligocene-to-Recent proboscideans. The combination of low delta(18)O values and low delta(18)O standard deviations in Barytherium and Moeritherium matches the isotopic pattern seen in aquatic and semiaquatic mammals, and differs from that of terrestrial mammals. delta(13)C values of these early proboscideans suggest that both genera are likely to have consumed freshwater plants, although a component of C(3) terrestrial vegetation cannot be ruled out. The simplest explanation for the combined evidence from isotopes, dental functional morphology, and depositional environments is that Barytherium and Moeritherium were at least semiaquatic and lived in freshwater swamp or riverine environments, where they grazed on freshwater vegetation. These results lend new support to the hypothesis that Oligocene-to-Recent proboscideans are derived from amphibious ancestors.     

Antimicrobial activity of bismuth subsalicylate on Clostridium difficile,Escherichia coli O157:H7, norovirus,and other common enteric pathogens

Previous studies have shown bismuth subsalicylate (BSS) has antimicrobial properties, but few studies have addressed the mechanism of action. Furthermore, following BSS ingestion other bismuth salts form throughout the gastrointestinal tract including bismuth oxychloride (BiOCl) that also act upon enteric pathogens. To further understand the antimicrobial activity of bismuth in infectious diarrhea, the antimicrobial effect of BSS and BiOCl on Clostridium difficile, Salmonella, Shigella, Shiga toxin-producing Escherichia coli strains and norovirus (NoV) were measured. Bacterial enteric pathogens in pure culture or in human fecal material were exposed to 35mg/ml BSS or BiOCl with or without a vehicle suspension. BSS and BiOCl treated samples were quantified and visualized by transmission electron microscopy. To measure the effect on NoV, reduction of infectious murine NoV (MNV), a surrogate for human NoV, and Norwalk virus RNA levels were measured by viral plaque assay and RT-qPCR, respectively. BSS and BiOCl reduced bacterial growth by 3–9 logs in all strains with majority resulting in populations of <10 cfu/ml within 24 h. Similar results were found when fecal material was included. Microscopy images detected bismuth on bacterial membranes and within the bacterial organisms at 30 min post-treatment. At 8.8mg/ml BSS and BiOCl reduced infectivity of MNV significantly by 2.7 and 2.0 log after 24 h of exposure. In addition, both BSS and BiOCl slightly reduced the level of Norwalk replicon-bearing cells suggesting that bismuth may inhibit NoV in vivo. Collectively, our results confirm and build on existing data that BSS has antimicrobial properties against a wide-range of diarrhea-causing pathogens.     

Dietary change among hominins and cercopithecids in Ethiopia during the early Pliocene

The incorporation of C₄ resources into hominin diet signifies increased dietary breadth within hominins and divergence from the dietary patterns of other great apes. Morphological evidence indicates that hominin diet became increasingly diverse by 4.2 million years ago but may not have included large proportions of C₄ foods until 800 thousand years later, given the available isotopic evidence. Here we use carbon isotope data from early to mid Pliocene hominin and cercopithecid fossils from Woranso-Mille (central Afar, Ethiopia) to constrain the timing of this dietary change and its ecological context. We show that both hominins and some papionins expanded their diets to include C₄ resources as early as 3.76 Ma. Among hominins, this dietary expansion postdates the major dentognathic morphological changes that distinguish Australopithecus from Ardipithecus, but it occurs amid a continuum of adaptations to diets of tougher, harder foods and to committed terrestrial bipedality. In contrast, carbon isotope data from cercopithecids indicate that C₄-dominated diets of the earliest members of the Theropithecus oswaldi lineage preceded the dental specialization for grazing but occurred after they were fully terrestrial. The combined data indicate that the inclusion of C₄ foods in hominin diet occurred as part of broader ecological changes in African primate communities.The Pliocene is a critical time in human evolution when almost all early hominins became committed terrestrial bipeds and expanded their diets to include a wider range of resources than their ancestors. Recent stable isotope studies of Australopithecus afarensis teeth indicate that hominins had increased their dietary breadth to include significant amounts of C₄ or crassulacean acid metabolism (CAM) resources by 3.4 Ma (1), which is in contrast to its putative ancestor, Australopithecus anamensis, whose diet was limited to predominantly C₃ foods (2). The expansion in hominin diets to include significant amounts of C₄ and CAM resources indicates a transition toward more open-country foods, because C₃ plants include trees, shrubs, forbs, and cool-growing season grasses, whereas C₄ plants are primarily warm-growing season grasses and sedges, and CAM plants include cacti and succulents (3). This dietary expansion may have made it easier for hominins to survive in a greater range of environments or in environments that were more variable. However, we do not know when hominins started to include large proportions of C₄ resources in their diets, nor do we fully understand the ecological context of these changes (1, 4).We use stable carbon isotope ratios of fossil hominin and cercopithecid teeth from Woranso-Mille in the western part of the central Afar Rift in Ethiopia (Fig. S1) to refine the timing of hominin dietary expansion to include C₄ resources. We also report isotope data from other mammals and soil carbonates to evaluate the environmental context and the diagenetic integrity of the isotope data. We use stable carbon isotope ratios, or δ¹³C values, of fossil teeth to evaluate the dietary proportion of plants that use the C₃ vs. C₄ photosynthetic pathway, based on the premise that C₃ and C₄ plants have distinct carbon isotope signatures and that the δ¹³C value of tooth enamel reflects the carbon isotope composition of an animal’s diet (5). Fossil teeth from the Woranso-Mille paleontological study area are well-suited to fill the temporal gap in the isotopic record of hominin diet because they are part of a record of Pliocene mammalian fossils that spans 3.76–3.2 Ma (6–11). The hominin fossils from Woranso-Mille include those that are morphologically intermediate between Au. anamensis and Au. afarensis, some that are definitively Au. afarensis, and others that represent additional species (7–9, 12). The cercopithecids include multiple species of colobines and at least two papionins (10). Theropithecus oswaldi cf. darti is the most common cercopithecid in the assemblages (>90% of identifiable cercopithecid specimens; 40% of the total identifiable mammal specimens) (6, 10); it represents the oldest and most primitive representative of the long-lasting T. oswaldi lineage whose morphology became increasingly specialized for grazing throughout the Pliocene and into the Pleistocene (13). The carbon isotope data from cercopithecids sympatric to hominins at Woranso-Mille make it possible to evaluate the ecological context for dietary changes in hominins.Open in a separate windowFig. S1.Map with locations of sites discussed in text and listed in Datasets S2 and S5. Woranso-Mille, Middle Awash (Aramis, Asa Issie, Asa Koma), Dikika, Gona (Segala Noumou), and Hadar and are in the Afar region in Ethiopia. Lomekwi, Allia Bay, and Kanapoi are in the Omo-Turkana region of Kenya. Imagery is from NASA''s Earth Observatory from August 2004 (72).     

Animal Models,Prophylaxis, and Therapeutics for Arenavirus Infections

Arenaviruses are enveloped, bipartite negative single-stranded RNA viruses that can cause a wide spectrum of disease in humans and experimental animals including hemorrhagic fever. The majority of these viruses are rodent-borne and the arenavirus family can be divided into two groups: the Lassa-Lymphocytic choriomeningitis serocomplex and the Tacaribe serocomplex. Arenavirus-induced disease may include characteristic symptoms ranging from fever, malaise, body aches, petechiae, dehydration, hemorrhage, organ failure, shock, and in severe cases death. Currently, there are few prophylactic and therapeutic treatments available for arenavirus-induced symptoms. Supportive care and ribavirin remain the predominant strategies for treating most of the arenavirus-induced diseases. Therefore, efficacy testing of novel therapeutic and prophylactic strategies in relevant animal models is necessary. Because of the potential for person-to-person spread, the ability to cause lethal or debilitating disease in humans, limited treatment options, and potential as a bio-weapon, the development of prophylactics and therapeutics is essential. This article reviews the current arenavirus animal models and prophylactic and therapeutic strategies under development to treat arenavirus infection.     

Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage

BACKGROUND & AIMS: Bone morphogenetic proteins (Bmps) are morphogens known to play key roles in gastrointestinal development and pathology. Most Bmps are produced primarily by the mesenchymal compartment and activate their signaling pathways following a paracrine or autocrine route. The aim of this study was to investigate the role of epithelial Bmp signaling in intestinal morphogenesis and maintenance of adult epithelial cell functions. METHODS: With the use of tissue-specific gene ablation, we generated mice lacking the Bmp receptor type IA (Bmpr1a) exclusively in the intestinal epithelium. Bmpr1a mutant and control mice were sacrificed for histology, immunofluorescence, Western blot analysis, electron microscopy, and quantitative polymerase chain reaction. RESULTS: As well as showing increased proliferation and altered intestinal epithelial morphology, Bmpr1a mutant mice revealed that epithelial Bmp signaling is associated with impaired terminal differentiation of cells from the secretory lineage but not with the determination of cell fate. Loss of Bmp signaling exclusively in the epithelial compartment is not sufficient for the initiation of the de novo crypt phenomenon associated with juvenile polyposis syndrome. CONCLUSIONS: Epithelial Bmp signaling plays an important role in the terminal differentiation of the intestinal secretory cell lineage but not in de novo crypt formation. These findings emphasize the importance of delineating the contribution of the stroma vs the epithelium in gastrointestinal physiology and pathology.