Canine sexual dimorphism in Ardipithecus ramidus was nearly human-like.

Body and canine size dimorphism in fossils inform sociobehavioral hypotheses on human evolution and have been of interest since Darwin's famous reflections on the subject. Here, we assemble a large dataset of fossil canines of the human clade, including all available Ardipithecus ramidus fossils recovered from the Middle Awash and Gona research areas in Ethiopia, and systematically examine canine dimorphism through evolutionary time. In particular, we apply a Bayesian probabilistic method that reduces bias when estimating weak and moderate levels of dimorphism. Our results show that Ar. ramidus canine dimorphism was significantly weaker than in the bonobo, the least dimorphic and behaviorally least aggressive among extant great apes. Average male-to-female size ratios of the canine in Ar. ramidus are estimated as 1.06 and 1.13 in the upper and lower canines, respectively, within modern human population ranges of variation. The slightly greater magnitude of canine size dimorphism in the lower than in the upper canines of Ar. ramidus appears to be shared with early Australopithecus, suggesting that male canine reduction was initially more advanced in the behaviorally important upper canine. The available fossil evidence suggests a drastic size reduction of the male canine prior to Ar. ramidus and the earliest known members of the human clade, with little change in canine dimorphism levels thereafter. This evolutionary pattern indicates a profound behavioral shift associated with comparatively weak levels of male aggression early in human evolution, a pattern that was subsequently shared by Australopithecus and Homo.

The earliest hylobatid from the Late Miocene of China.

Yuanmoupithecus xiaoyuan, a small catarrhine from the Late Miocene of Yunnan in southern China, was initially suggested to be related to Miocene proconsuloids or dendropithecoids from East Africa, but subsequent reports indicated that it might be more closely related to hylobatids. Here, detailed comparisons of the material, including seven newly discovered teeth and a partial lower face of a juvenile individual, provide crucial evidence to help establish its phylogenetic relationships. Yuanmoupithecus exhibits a suite of synapomorphies that support a close phylogenetic relationship with extant hylobatids. Furthermore, based on the retention of several primitive features of the dentition, Yuanmoupithecus can be shown to be the sister taxon of crown hylobatids. The contention that Kapi ramnagarensis from the Middle Miocene of India might represent an earlier species of hylobatid is not supported here. Instead, Kapi is inferred to be a specialized pliopithecoid more closely related to Krishnapithecus krishnaii from the Late Miocene of India. Currently then, Yuanmoupithecus represents the earliest known definitively identified hylobatid and the only member of the clade predating the Pleistocene. It extends the fossil record of hylobatids back to 7-8 Ma and fills a critical gap in the evolutionary history of hominoids that has up until now remained elusive. Even so, molecular estimates of a divergence date of hylobatids from other hominoids at about 17-22 Ma signifies that there is still a substantial gap in the fossil record of more than 10 million years that needs to be filled in order to document the biogeographic origins and early evolution of hylobatids.

Evolutionary trend in dental size in fossil orangutans from the Pleistocene of Chongzuo, Guangxi, southern China.

More than 800 isolated teeth of fossil Pongo have been recovered from cave sites in the vicinity of Chongzuo in Guangxi, southern China, ranging from the Early to Late Pleistocene (2.0-0.1 Ma). These collections provide a unique regional window into the evolutionary history of orangutans over a two-million-year period at the northernmost extent of their former geographic range. Here we investigate the nature and timing of the evolutionary change in the dental size of fossil orangutans from Chongzuo. Fossil tooth size (mesiodistal length∗buccolingual breadth) was compared against an extant Pongo pygmaeus standard (n = 106 individuals). During the course of the Pleistocene, orangutans from southern China exhibited a progressive reduction in overall dental size. Early Pleistocene Pongo has cheek teeth with occlusal areas that are 38.1% larger than those of extant P. pygmaeus. Those from the Middle and Late Pleistocene are 25.2% and 18.9% larger, respectively. Previously, the size difference in dentition between the Early to Middle Pleistocene and Middle to Late Pleistocene samples was used to differentiate time-successive species of Pongo, namely Pongo weidenreichi and Pongo devosi. However, with access to larger samples and better representation of populations through time, the evidence in support of this taxonomic arrangement requires reconsideration. Diminution of the teeth now appears to be a gradual evolutionary transformation rather than a punctuated event. Moreover, the morphological features that distinguish the Chongzuo fossil orangutans from extant Pongo spp. remain uniform throughout the Pleistocene. Retaining P. weidenreichi and P. devosi as anagenetic species remains an option, but, given the current evidence, we consider it preferable to assign all of the fossil orangutans from Chongzuo to P. weidenreichi. Beyond resolving questions of alpha taxonomy, the study of fossil orangutan dental size provides a basis for estimating body mass, which has implications for interpreting the paleobiology of Pleistocene Pongo in southern China.

A new genus of pliopithecoid from the late Early Miocene of China and its implications for understanding the paleozoogeography of the Pliopithecoidea.

A diversity of pliopithecoids is known from Miocene localities in Europe, but until recently, this group was relatively poorly represented in China. However, new discoveries have shown that Chinese pliopithecoids were taxonomically diverse and geographically widespread. The earliest pliopithecoids in China (and Eurasia) are Dionysopithecus and Platodontopithecus from the Early Miocene of Sihong, Jiangsu (∼19-18 Ma). During the Middle Miocene (∼15-12 Ma), several species of pliopithecoids are recorded at localities in Gansu Province (Laogou), Inner Mongolia (Damiao), Xinjiang Uygur Autonomous Region (Tieersihabahe), and Ningxia Hui Autonomous Region (Tongxin). Finally, a late-surviving anapithecine crouzeliid, Laccopithecus robustus, is known from the Late Miocene (∼7 Ma) of Shihuiba in Yunnan, which postdates the extinction of pliopithecoids in Europe (during MN 10). Paleontological investigations at a late Early Miocene locality near Fanchang in Anhui Province have yielded a large sample of isolated teeth (more than one hundred) of a previously unknown species of pliopithecoid. The associated micromammals indicate an age contemporaneous with the Shanwang Formation in Shandong Province (MN 3-4, ∼18-17 Ma). All of the permanent teeth are represented except for I2. With its unique suite of dental features, the Fanchang pliopithecoid can be attributed to a new species and genus. Shared derived features of the lower molars confirm that the Fanchang pliopithecoid has its closest affinities with European crouzeliids, but a number of primitive traits indicate that it is a stem member of the clade. The evidence points to China as an important center for the early diversification of pliopithecoids. Contrary to previous zoogeographic scenarios, the occurrence of an early crouzeliid in China implies that the Pliopithecidae and Crouzeliidae may have diverged from a stem pliopithecoid in Asia during the Early Miocene before their arrival in Europe.

Identification of Tumor Specific Peptide as EpCAM Ligand and Its Potential Diagnostic and Therapeutic Clinical Application.

Tumor targeting agents are being developed for early tumor detection and therapeutics. We previously identified the peptide SNFYMPL (SNF*) and demonstrated its specific binding to human esophageal specimens of high-grade dysplasia (HGD) and adenocarcinoma with imaging ex vivo. Here, we aim to identify the target for this peptide and investigate its potential applications in imaging and drug delivery. With SNF* conjugated affinity chromatography, mass spectrum, Western blot, enzyme-linked immunosorbent assay (ELISA), and molecular docking, we found that the epithelial cell adhesion molecule (EpCAM) was the potential target of SNF*. Next, we showed that FITC-labeled SNF* (SNF*-FITC) colocalized with EpCAM antibody on the surface of esophageal adenocarcinoma cells OE33, and SNF*-FITC binding patterns significantly changed after EpCAM knockdown or exogenous EpCAM transfection. With the data from TCGA, we demonstrated that EpCAM was overexpressed in 17 types of cancers. Using colon and gastric adenocarcinoma cells and tissues as examples, we found that SNF*-FITC bound in a pattern was colocalized with EpCAM antibody, and the SNF* binding did not upregulate the EpCAM downstream Wnt signals. Subsequently, we conjugated SNF* with our previously constructed poly(histidine)-PEG/DSPE copolymer micelles. SNF* labeling significantly improved the micelle binding with colon and gastric adenocarcinoma cells in vitro, and enhanced the antitumor effects and decreased the toxicities of the micelles in vivo. In conclusion, we identified and validated SNF* as a specific peptide for EpCAM. The future potential use of SNF* peptide in multiple tumor surveillance and tumor-targeted therapeutics was demonstrated.

A distinguishing feature of Pongo upper molars and its implications for the taxonomic identification of isolated hominid teeth from the Pleistocene of Asia.

OBJECTIVES: The taxonomic status of isolated hominoid teeth from the Asian Pleistocene has long been controversial due to difficulties distinguishing between pongine and hominin molars given their high degree of morphometrical variation and overlap. Here, we combine nonmetric and geometric morphometric data to document a dental pattern that appears to be taxonomically diagnostic among Pongo. We focus on the protoconule, a cuspule of well-documented evolutionary history, as well as on shape differences of the mesial fovea of the upper molars. MATERIALS AND METHODS: We examined 469 upper molars of eight hominid genera (Australopithecus, Paranthropus, Homo, Meganthropus, Sivapithecus, Pan, Gorilla, and Pongo), including representatives of Homo erectus and extinct and recent Pongo. Analyses were conducted at the enamel-dentine junction to overcome the limitations introduced by dental wear. RESULTS: We found that a moderate or large protoconule is present in ~80% of Pleistocene and extant Pongo. Conversely, a moderate to pronounced protoconule in hominins, Meganthropus, and African great apes occurs in low frequencies (~0-20%). Canonical variate analyses for the mesial fovea show that Pleistocene and extant Pongo cluster together and are clearly differentiated from all other groups, except for Sivapithecus. DISCUSSION: This study suggests that the protoconule and the shape of the mesial fovea in upper molars are useful features for the taxonomic identification of isolated hominid teeth. By identifying these new features, our results can contribute to the better understanding of hominoid evolutionary history and biogeography during the Asian Pleistocene. However, we emphasize that the reported features should be used in combination with other diagnostic variables for the most accurate taxonomic assessments.

Gigantopithecus blacki: a giant ape from the Pleistocene of Asia revisited.

Gigantopithecus blacki is the largest hominoid that ever lived. The consensus view is that it is a specialized pongine and late-surviving member of the Sivapithecus-Indopithecus lineage. It is known primarily from Early and Middle Pleistocene cave sites in southern China, dating from 2.0 Ma to almost 300 ka. The cause of its extinction in the late Middle Pleistocene is unknown, but ecological change or the arrival of Homo erectus may have been contributing factors. Gigantopithecus is highly specialized in its dentognathic anatomy, with a unique combination of features that distinguish it from all other hominoids. Based on the size of its dentition and mandible, a reasonable estimate of its body mass would be 200-300 kg. There was a progressive increase in dental size from the Early Pleistocene to the Middle Pleistocene, and possibly a shift towards greater complexity of the cheek teeth. Gigantopithecus exhibits a relatively high degree of sexual dimorphism, implying a high level of male-male competition, but the relatively small canines in both sexes suggest that these teeth were not important in agonistic behaviors. The species inhabited a subtropical monsoon forest with a closed canopy and dense understory. Foraging was focused on the forest floor and its diet included a broad range of C3 plants, including fruits, leaves and stems, and possibly tubers. The cheek teeth and jaws were adapted for processing a wide variety of bulky, fibrous, and abrasive food items, but the small incisors indicate that incisal preparation was not an important part of its feeding repertoire.

Hominin teeth from the Middle Pleistocene site of Yiyuan, Eastern China.

In 1981-1982, some hominin fossils, including a relatively complete skull and seven isolated teeth, were recovered from the Middle Pleistocene site of Yiyuan in Eastern China. In the present study we provide a detailed metric and morphological comparison of the Yiyuan dental sample in order to characterize better the variability of the human populations that inhabited China during the Middle Pleistocene. Aside from taxonomic and phylogenetic questions, the lack of understanding and/or knowledge about the morphological variability of these populations have caused concern about the human versus non-human nature of some of the hominin dental remains found in East Asia during the Early and the Middle Pleistocene. Thus, our study aims to present a detailed description and comparison of the Yiyuan isolated teeth to 1) discuss and support their human nature and 2) to explore their taxonomic affinities with regard to other penecontemporaneous populations from Asia. Our results clearly differentiate the Yiyuan sample from Pongo specimens and support a human attribution for the Yiyuan material. Our analyses also suggest that the Yiyuan teeth form a morphologically coherent group together with samples from Zhoukoudian, Chaoxian and Hexian. They are different from the more derived specimens from Panxian Dadong, suggesting a pattern of biogeographic isolation and different evolutionary trends between northern and southern China during the Middle Pleistocene. In addition, and despite sharing a common morphological bauplan with Homo erectus sensu stricto (s.s.), the Yiyuan, Zhoukoudian and Hexian teeth are also different from the Indonesian Early Pleistocene samples. In particular, the expression of a highly crenulated or dendritic enamel-dentine surface could be unique to these groups. Our study supports the notion that the taxonomy of the Pleistocene hominins from Asia may have been oversimplified. Future studies should explore the variability of the Asian specimens and reconsider whether all the samples can be attributed to H. erectus s.s.

Evolutionary trend in dental size in Gigantopithecus blacki revisited.

Previous analyses of dental size in Gigantopithecus blacki indicated marked sexual dimorphism and a trend towards increasing size through time. These studies were based on a sample of over 700 teeth from five localities excavated prior to 1990. Since then, 12 additional cave sites have been discovered in southern China, yielding hundreds of isolated teeth of G. blacki. Most of these sites are well dated by a combination of biochronology and absolute dating methods, so we now have a much better understanding of the chronology of G. blacki. Here, we reexamine the degree of sexual dimorphism and the question of dental size increase through time in G. blacki based on the expanded collections now available. Our results show that sexual dimorphism is not as marked as indicated in previous studies and confirm earlier analyses suggesting that the postcanine teeth of G. blacki tend to become larger through time from the beginning of the Early Pleistocene to the Middle Pleistocene.

Human remains from Zhirendong, South China, and modern human emergence in East Asia.

The 2007 discovery of fragmentary human remains (two molars and an anterior mandible) at Zhirendong (Zhiren Cave) in South China provides insight in the processes involved in the establishment of modern humans in eastern Eurasia. The human remains are securely dated by U-series on overlying flowstones and a rich associated faunal sample to the initial Late Pleistocene, >100 kya. As such, they are the oldest modern human fossils in East Asia and predate by >60,000 y the oldest previously known modern human remains in the region. The Zhiren 3 mandible in particular presents derived modern human anterior symphyseal morphology, with a projecting tuber symphyseos, distinct mental fossae, modest lateral tubercles, and a vertical symphysis; it is separate from any known late archaic human mandible. However, it also exhibits a lingual symphyseal morphology and corpus robustness that place it close to later Pleistocene archaic humans. The age and morphology of the Zhiren Cave human remains support a modern human emergence scenario for East Asia involving dispersal with assimilation or populational continuity with gene flow. It also places the Late Pleistocene Asian emergence of modern humans in a pre-Upper Paleolithic context and raises issues concerning the long-term Late Pleistocene coexistence of late archaic and early modern humans across Eurasia.

Preliminary description of a late Middle Pleistocene mammalian fauna prior to the extinction of Gigantopithecus blacki from the Yixiantian Cave, Guangxi ZAR, South China.

In recent years, nearly 20 cave sites with rich assemblages of mammalian fossils have been found and excavated in the Chongzuo area, Guangxi Zhuang Autonomous Region, China. Their ages are distributed throughout the entire Pleistocene Epoch. These discoveries have greatly facilitated our understanding of the evolution of the Stegodon-Ailuropoda fauna and the environmental context of human evolution in southern China. Here, we present a preliminary report on a diverse late Middle Pleistocene mammalian fauna from the Yixiantian Cave in southern China, which is a typical representative of the Stegodon-Ailuropoda fauna (sensu lato). The fossil mammals are represented by isolated dental remains only. In 2010 and 2011, two seasons of systematic excavations at the Yixiantian Cave yielded a total of 4,958 identifiable mammalian teeth. They were identified as belonging to 37 species and 6 orders of mammals. In addition, the tooth type of all the teeth representing each species was also determined where possible. A single fragmentary molar was identified as belonging to Gigantopithecus blacki, indicating that its population had declined sharply at this time and was on the brink of extinction. Description of the Yixiantian fauna will not only help better characterize the composition of the Stegodon-Ailuropoda fauna during the late Middle Pleistocene, but also clarify our understanding of the paleoenvironmental context at a time just prior to the extinction of G. blacki.

Lactoferrin and Its Detection Methods: A Review.

Lactoferrin (LF) is one of the major functional proteins in maintaining human health due to its antioxidant, antibacterial, antiviral, and anti-inflammatory activities. Abnormal levels of LF in the human body are related to some serious diseases, such as inflammatory bowel disease, Alzheimer's disease and dry eye disease. Recent studies indicate that LF can be used as a biomarker for diagnosis of these diseases. Many methods have been developed to detect the level of LF. In this review, the biofunctions of LF and its potential to work as a biomarker are introduced. In addition, the current methods of detecting lactoferrin have been presented and discussed. We hope that this review will inspire efforts in the development of new sensing systems for LF detection.

Anti-beta 2 glycoprotein 1 domain IgA positive antiphospholipid syndrome secondary to incomplete Behcet's disease: a case report.

Antiphospholipid syndrome (APS) is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis, and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity. APS is induced by persistent positive antiphospholipid antibodies (aPL), the main being lupus anticoagulant (LA), and/or anticardiolipin (aCL) antibodies, and/or anti-beta 2 glycoprotein 1 (ß2-GP1) antibodies. Some studies have shown that the incidence of APS is about 5 new cases per 100,000 persons per year, and the prevalence is around 40-50 cases per 100,000 persons. APS can be primary or secondary. Secondary APS often coexists with another autoimmune disorder, most commonly systemic lupus erythematosus (SLE). Behcet's disease (BD) is usually characterized by recurrent oral and genital aphthous ulcers and ocular involvement. It can occasionally affect the venous system. BD usually affects small vessels, but can sometimes affect large veins or even a variety of veins. Because most of APS is secondary to SLE, APS secondary to incomplete BD is quite rare. This report describes a case in which a 15-year-old male experienced bilateral leg swelling and pain. The patient had a long history of self-healing recurrent mouth ulcers. Laboratory tests revealed positive ß2-GP1 immunoglobulin A (IgA). His symptoms improved by using steroids, prednisolone, uro-kinase, and hirudin. In this rare case of secondary APS, the patient was diagnosed with anti-ß2-GP-1 IgA positive to incomplete BD. It is a rare case of secondary APS with positive anti-ß2-GP1 IgA to incomplete BD. It is suggested that patients with recurrent mouth ulcers should be closely examined to prevent thrombosis, and more laboratory markers should be used to avoid a risk of misdiagnosing patients with APS.

Nasal anatomy of Paradolichopithecus gansuensis (early Pleistocene, Longdan, China) with comments on phyletic relationships among the species of this genus.

Paradolichopithecus was a large cercopithecine primate that existed in Eurasia from the middle Pliocene to the early Pleistocene. Para. arvernensis from the late Pliocene of Senèze, France, shows no maxillary sinus, whereas Para.sushkini from the late Pliocene of Kuruksay, Tajikistan, has this feature. In this study, we examined a new maxillary specimen of Para. gansuensis from the early Pleistocene of Longdan, China. The Longdan maxilla had lost its facial part, which exposed the internal floor of the nasal region. The nasal floor expands laterally, making the maxillary body thin at the P3-M2 level and thick at the M3 level and extending to the maxillary tubercle. Such a topography is seen in the Senèze and Kuruksay crania. The Longdan maxilla shows no evidence of the formation of a maxillary sinus within the inferior portion of the thick maxillary body, as is seen in the Senèze cranium. Such a configuration could reflect the absence of a maxillary sinus in the Longdan specimen. Eastern Para. gansuensis might have dispersed eastward retaining a primitive condition, while central Para. sushkini would have acquired this feature independently in central Eurasia.

Middle Pleistocene hominin teeth from Longtan Cave, Hexian, China.

Excavations at the Longtan Cave, Hexian, Anhui Province of Eastern China, have yielded several hominin fossils including crania, mandibular fragments, and teeth currently dated to 412 ± 25 ka. While previous studies have focused on the cranial remains, there are no detailed analyses of the dental evidence. In this study, we provide metric and morphological descriptions and comparisons of ten teeth recovered from Hexian, including microcomputed tomography analyses. Our results indicate that the Hexian teeth are metrically and morphologically primitive and overlap with H. ergaster and East Asian Early and mid-Middle Pleistocene hominins in their large dimensions and occlusal complexities. However, the Hexian teeth differ from H. ergaster in features such as conspicuous vertical grooves on the labial/buccal surfaces of the central incisor and the upper premolar, the crown outline shapes of upper and lower molars and the numbers, shapes, and divergences of the roots. Despite their close geological ages, the Hexian teeth are also more primitive than Zhoukoudian specimens, and resemble Sangiran Early Pleistocene teeth. In addition, no typical Neanderthal features have been identified in the Hexian sample. Our study highlights the metrical and morphological primitive status of the Hexian sample in comparison to contemporaneous or even earlier populations of Asia. Based on this finding, we suggest that the primitive-derived gradients of the Asian hominins cannot be satisfactorily fitted along a chronological sequence, suggesting complex evolutionary scenarios with the coexistence and/or survival of different lineages in Eurasia. Hexian could represent the persistence in time of a H. erectus group that would have retained primitive features that were lost in other Asian populations such as Zhoukoudian or Panxian Dadong. Our study expands the metrical and morphological variations known for the East Asian hominins before the mid-Middle Pleistocene and warns about the possibility that the Asian hominin variability may have been taxonomically oversimplified.

The effect of direct translocation across endosomes on the cytotoxicity of the recombinant protein e23sFv-Fdt-casp6 to HER2 positive gastric cancer cells.

HER2-positive cancers represent a class of malignancies with high metastasis and poor prognosis. We previously generated the e23sFv-PEA II-casp6 recombinant, which contains an anti-HER2 single-chain antibody (e23sFv), a Pseudomonas exotoxin A translocation domain (PEA II), and a constitutively active caspase-6 (casp6), and demonstrated its potent selective anti-tumor activities. In this study, we generated a smaller-sized recombinant e23sFv-Fdt-casp6, in which the PEA II domain was replaced with the furin cleavage sequence from diphtheria toxin (Fdt), and explored its translocation pathway and specific killing mechanism. We found that e23sFv-Fdt-casp6 proteins, following their receptor-mediated endocytosis in HER2-positive gastric cancer cells, underwent furin-mediated cleavage in endosome and engaged in direct translocation of the released C-terminal fragment (active caspase-6) instead of via the trans-Golgi and the endoplasmic reticulum (ER) pathway. The active caspase-6 cleaved its well-documented substrate, Lamin A, and subsequently triggered the apoptosis of cancer cells. The e23sFv-Fdt-casp6 proteins produced from genetically modified cells showed a selective cytotoxicity to cultured HER2-positive gastric cancer cells. Similar to the results of our previous research on e23sFv-PEA II-casp6, the delivery of liposome-encapsulated e23sFv-Fdt-casp6 constructs in tumor-adjacent muscles also inhibited tumor growth and prolonged animal survival in a nude mouse xenograft tumor model. Moreover, e23sFv-Fdt-casp6 proteins were also cytotoxic to trastuzumab-resistant gastric cancer cells characterized by downregulated HER2 expression. Accordingly, e23sFv-Fdt-casp6 recombinant provides a promising therapeutic alternative for HER2-positive and trastuzumab-resistant gastric cancers.