Late Pleistocene age and archaeological context for the hominin calvaria from GvJm-22 (Lukenya Hill,Kenya)

Kenya National Museums Lukenya Hill Hominid 1 (KNM-LH 1) is a Homo sapiens partial calvaria from site GvJm-22 at Lukenya Hill, Kenya, associated with Later Stone Age (LSA) archaeological deposits. KNM-LH 1 is securely dated to the Late Pleistocene, and samples a time and region important for understanding the origins of modern human diversity. A revised chronology based on 26 accelerator mass spectrometry radiocarbon dates on ostrich eggshells indicates an age range of 23,576–22,887 y B.P. for KNM-LH 1, confirming prior attribution to the Last Glacial Maximum. Additional dates extend the maximum age for archaeological deposits at GvJm-22 to >46,000 y B.P. (>46 kya). These dates are consistent with new analyses identifying both Middle Stone Age and LSA lithic technologies at the site, making GvJm-22 a rare eastern African record of major human behavioral shifts during the Late Pleistocene. Comparative morphometric analyses of the KNM-LH 1 cranium document the temporal and spatial complexity of early modern human morphological variability. Features of cranial shape distinguish KNM-LH 1 and other Middle and Late Pleistocene African fossils from crania of recent Africans and samples from Holocene LSA and European Upper Paleolithic sites.For Late Pleistocene African populations of modern humans, the constellation of behavioral changes encapsulated in the transition from the Middle Stone Age (MSA) to the Later Stone Age (LSA) ∼70–20 kya represents a series of some of the most pronounced changes in the archaeological record before the adoption of domesticated animals and plants and the use of ceramics for cooking and storage. It is among LSA sites that the strongest parallels with ethnographic and historic foragers are observed. Typical archaeological signatures include lithic technologies focused on the production of microliths (small flakes, blades, and bladelets with one edge blunted or “backed”) from bipolar, single-, and opposed-platform cores; an increased use of ground-stone tools; and implements made of wood and bone. These new technologies occur with the appearance of material correlates of social identity and networks of long-distance exchange, including ostrich eggshell (OES) beads, ochre, and nonlocal stone raw material, as well as increased dietary breadth, all consistent with larger, more dense, or more interconnected populations (1–9).This same interval of ∼70–20 kya witnessed a number of human dispersals across Africa, with eastern Africa host to one or more candidate populations for the expansion of Homo sapiens out of Africa (10–15). However, the eastern African hominin fossil record for this interval is extremely sparse and poorly dated, and it consists largely of isolated teeth or highly fragmentary crania and postcrania (16–18). Here, we reassess the age and context of the Kenya National Museums Lukenya Hill Hominid 1 (KNM-LH 1) partial calvaria from site GvJm-22 at Lukenya Hill, Kenya, the only eastern African fossil hominin from a Last Glacial Maximum [LGM; 19–26.4 kya (19)] LSA archaeological context. We construct a revised accelerator mass spectrometry (AMS) radiocarbon chronology built on 26 new dates on OES fragments. The revised chronology confirms the LGM age of KNM-LH 1 and expands the maximum age of the site to beyond the limits of the radiocarbon method. Increased radiometric age is consistent with new technological analyses that demonstrate previously unrecognized MSA elements that indicate assemblages spanning the MSA/LSA transition from deposits underlying KNM-LH 1. Morphometric analyses using a robust comparative dataset demonstrate the variability among African Late Pleistocene hominins, including candidate populations for out-of-Africa dispersals. They indicate that KNM-LH 1 is distinct from (i) modern Africans, (ii) H. sapiens from Holocene LSA sites, and (iii) European Upper Paleolithic modern humans, suggesting that it may sample a now extinct lineage.     

Association of prion protein with cognitive functioning in humans

Objectives

Recent animal studies have suggested a key role for cellular prion protein (PrPc) in the pathological consequences of amyloid plaque formation, the hallmark of Alzheimer's disease. This epidemiological study investigated whether serum concentrations of PrPc are associated with cognitive functioning in humans.

Design, Setting, Participants

Cross-sectional study of 1,322 participants from the elderly general population in Germany, aged 65 + years at baseline (2000–2002).

Measurements

Cognitive functioning was assessed by the COGTEL phone interview 5 years after baseline. Serum PrPc was determined by a commercial immunoassay.

Results

In multiple linear regression adjusted for important confounders, subjects in higher PrPc quintiles appeared to have lower cognitive functioning scores than those in the lowest PrPc quintile. Spline regression suggested pronounced non-linearity with an inverse association between PrPc and cognitive functioning levelling off beyond median PrPc. Cognitive subdomain-specific models produced somewhat heterogeneous results.

Conclusion

The findings are suggestive of an independent association of PrPc with cognitive functioning in humans. Confirmatory and longitudinal studies are needed to elucidate the potential of PrPc for applications in early risk stratification for cognitive impairment.     

A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results

We describe a patient with a Homo sapiens mutL homolog 1 (MLH1)-associated Lynch syndrome with previous diagnoses of two distinct primary cancers: a sigmoid colon cancer at the age of 39 years, and a right colon cancer at the age of 50 years. The mutation identified in his blood and buccal cells, c.1771delG, p.Asp591Ilefs*25, appears to be a de novo event, as it was not transmitted by either of his parents. This type of de novo event is rare in MLH1 as only three cases have been reported in the literature so far. Furthermore, the discordant results observed between replication error phenotyping and immunohistochemistry highlight the importance of the systematic use of both pre-screening tests in the molecular diagnosis of Lynch syndrome.     

Exploring the biomechanics of taurodontism

Taurodontism (i.e. enlarged pulp chamber with concomitant apical displacement of the root bi/trifurcation) is considered a dental anomaly with relatively low incidence in contemporary societies, but it represents a typical trait frequently found in Neandertal teeth. Four hypotheses can be envisioned to explain the high frequency in Neandertals: adaptation to a specific occlusal loading regime (biomechanical advantage), adaptation to a high attrition diet, pleiotropic or genetic drift effects. In this contribution we used finite element analysis (FEA) and advanced loading concepts based on macrowear information to evaluate whether taurodontism supplies some dental biomechanical advantages. Loads were applied to the digital model of the lower right first molar (RM₁) of the Neandertal specimen Le Moustier 1, as well as to the digital models of both a shortened and a hyper-taurodontic version of Le Moustier RM₁. Moreover, we simulated a scenario where an object is held between teeth and pulled in different directions to investigate whether taurodontism might be useful for para-masticatory activities. Our results do not show any meaningful difference among all the simulations, pointing out that taurodontism does not improve the functional biomechanics of the tooth and does not favour para-masticatory pulling activities. Therefore, taurodontism should be considered either an adaptation to a high attrition diet or most likely the result of pleiotropic or genetic drift effects. Finally, our results have important implications for modern dentistry during endodontic treatments, as we observed that filling the pulp chamber with dentine-like material increases tooth stiffness, and ultimately tensile stresses in the crown, thus favouring tooth failure.     

Recent origin of low trabecular bone density in modern humans

Humans are unique, compared with our closest living relatives (chimpanzees) and early fossil hominins, in having an enlarged body size and lower limb joint surfaces in combination with a relatively gracile skeleton (i.e., lower bone mass for our body size). Some analyses have observed that in at least a few anatomical regions modern humans today appear to have relatively low trabecular density, but little is known about how that density varies throughout the human skeleton and across species or how and when the present trabecular patterns emerged over the course of human evolution. Here, we test the hypotheses that (i) recent modern humans have low trabecular density throughout the upper and lower limbs compared with other primate taxa and (ii) the reduction in trabecular density first occurred in early Homo erectus, consistent with the shift toward a modern human locomotor anatomy, or more recently in concert with diaphyseal gracilization in Holocene humans. We used peripheral quantitative CT and microtomography to measure trabecular bone of limb epiphyses (long bone articular ends) in modern humans and chimpanzees and in fossil hominins attributed to Australopithecus africanus, Paranthropus robustus/early Homo from Swartkrans, Homo neanderthalensis, and early Homo sapiens. Results show that only recent modern humans have low trabecular density throughout the limb joints. Extinct hominins, including pre-Holocene Homo sapiens, retain the high levels seen in nonhuman primates. Thus, the low trabecular density of the recent modern human skeleton evolved late in our evolutionary history, potentially resulting from increased sedentism and reliance on technological and cultural innovations.Obligate bipedalism—a defining feature of humans that distinguishes us from our closest living relatives, the African apes—has transformed the human skeleton. Among these unique features are long lower limbs with large joint surfaces. These large joint surfaces help distribute loads over a larger surface area and thus are better at resisting the high forces incurred during locomotion on two limbs instead of four (1–5). Early African Homo erectus at 1.8–1.5 Ma had enlarged lower limb joint surfaces (1, 3) and a larger stature (6) and body mass (7, 8) than many earlier hominins, and this pattern often is considered to reflect the emergence of a more modern human-like body plan (1, 3, 5, 6, 9; but also see ref. 7).Recent modern human (Holocene Homo sapiens) skeletons also appear to be gracile as compared with earlier hominins (10–14). Here, “gracilization” refers to the reduction in strength and bone mass relative to body mass inferred from osseous tissue and overall bone size and has been studied mainly using diaphyseal cortical bone cross-sections (10–16). Although the relationship between mechanical loading during life and bone strength is likely to be complex (17), there is much evidence that increased mechanical loading leads to increases in relative bone strength (18). Thus, diaphyseal skeletal gracilization in recent modern humans relative to earlier hominins generally has been attributed to a decrease in daily physical activity via technological and cultural innovations (6, 10, 13–15, 19–22).There also is evidence that increased activity level and mechanical loading increases trabecular bone mineral density within limb bones (ref. 23 and references therein). However, although there currently is extensive literature on the variation and evolution of long bone shaft strength in humans and fossil hominins (10, 15, 16, 24–27), there has been comparatively less research on trabecular bone (28–30) because of the technical challenges in quantifying its structure: limited access to high-resolution CT (microCT), problems with preservation and/or imaging of fine trabecular structures, particularly in fossils, and intensive processing time. A few studies examining individual limb elements have reported low trabecular density, as measured by volumetric density (the trabecular bone fraction, TBF, or bone volume relative to total volume), in recent modern human epiphyses. The recent modern human arm (humerus) and hand (metacarpals) have low TBF (31, 32) and mineral density (33) compared with chimpanzees and orangutans. This finding might be expected, because humans rarely use their upper limbs for locomotion and therefore do not habitually expose their upper limb bones to the high loads of body-weight support. Indeed, recent modern human upper limb bones have relatively low diaphyseal strengths compared with the lower limbs (34). However, recent modern humans also have low TBF in the calcaneus (35) and metatarsals (36) compared with great apes, despite the increased proportionate loading and full body-weight support incurred during bipedal locomotion.To our knowledge, this study is the first to examine how trabecular density varies throughout the human appendicular skeleton, how that variation compares with other primates, and how trabecular density evolved in the hominin lineage. We test the hypotheses that (i) recent modern humans have lower TBF throughout the upper and lower limbs compared with that of other primates and (ii) the reduction in TBF first occurred in African Homo erectus, consistent with the shift toward a modern human locomotor anatomy, or more recently in concert with diaphyseal gracilization in recent modern humans. This study is the first, to our knowledge, to evaluate TBF in upper and lower limb joints in fossil hominins from late Pliocene Australopithecus to recent Homo.To assess whether low trabecular density is a systemic phenomenon throughout the human skeleton, we examined trabecular density in seven epiphyseal elements throughout the upper limb (humeral head, proximal ulna, distal radius, metacarpal heads) and lower limb (femoral head, distal tibia, and metatarsal heads) (Tables S1 and S2). We measured trabecular density in a 2D image as the ratio of bone pixels/total pixels (i.e., the TBF) within a defined region of interest (ROI) for each epiphysis (Fig. S1). We first compared TBF across extant primate (baboon, orangutan, chimpanzee, and recent modern human) limb epiphyses (Table S2). We also compared TBF in late Pliocene and Pleistocene hominins (n = 42) within the context of changes in body form in early Homo at 1.8 Ma and throughout the Pleistocene (Table S2).

Table 1.

Sample size of taxa studied

Sutural growth restriction and modern human facial evolution: an experimental study in a pig model

Facial size reduction and facial retraction are key features that distinguish modern humans from archaic Homo. In order to more fully understand the emergence of modern human craniofacial form, it is necessary to understand the underlying evolutionary basis for these defining characteristics. Although it is well established that the cranial base exerts considerable influence on the evolutionary and ontogenetic development of facial form, less emphasis has been placed on developmental factors intrinsic to the facial skeleton proper. The present analysis was designed to assess anteroposterior facial reduction in a pig model and to examine the potential role that this dynamic has played in the evolution of modern human facial form. Ten female sibship cohorts, each consisting of three individuals, were allocated to one of three groups. In the experimental group (n = 10), microplates were affixed bilaterally across the zygomaticomaxillary and frontonasomaxillary sutures at 2 months of age. The sham group (n = 10) received only screw implantation and the controls (n = 10) underwent no surgery. Following 4 months of post‐surgical growth, we assessed variation in facial form using linear measurements and principal components analysis of Procrustes scaled landmarks. There were no differences between the control and sham groups; however, the experimental group exhibited a highly significant reduction in facial projection and overall size. These changes were associated with significant differences in the infraorbital region of the experimental group including the presence of an infraorbital depression and an inferiorly and coronally oriented infraorbital plane in contrast to a flat, superiorly and sagittally infraorbital plane in the control and sham groups. These altered configurations are markedly similar to important additional facial features that differentiate modern humans from archaic Homo, and suggest that facial length restriction via rigid plate fixation is a potentially useful model to assess the developmental factors that underlie changing patterns in craniofacial form associated with the emergence of modern humans.     

Human origins: Out of Africa

Our species, Homo sapiens, is highly autapomorphic (uniquely derived) among hominids in the structure of its skull and postcranial skeleton. It is also sharply distinguished from other organisms by its unique symbolic mode of cognition. The fossil and archaeological records combine to show fairly clearly that our physical and cognitive attributes both first appeared in Africa, but at different times. Essentially modern bony conformation was established in that continent by the 200–150 Ka range (a dating in good agreement with dates for the origin of H. sapiens derived from modern molecular diversity). The event concerned was apparently short-term because it is essentially unanticipated in the fossil record. In contrast, the first convincing stirrings of symbolic behavior are not currently detectable until (possibly well) after 100 Ka. The radical reorganization of gene expression that underwrote the distinctive physical appearance of H. sapiens was probably also responsible for the neural substrate that permits symbolic cognition. This exaptively acquired potential lay unexploited until it was “discovered” via a cultural stimulus, plausibly the invention of language. Modern humans appear to have definitively exited Africa to populate the rest of the globe only after both their physical and cognitive peculiarities had been acquired within that continent.     

The spread of modern humans in Europe

The earliest credible evidence of Homo sapiens in Europe is an archaeological proxy in the form of several artifact assemblages (Bohunician) found in South-Central and possibly Eastern Europe, dating to ≤48,000 calibrated radiocarbon years before present (cal BP). They are similar to assemblages probably made by modern humans in the Levant (Emiran) at an earlier date and apparently represent a population movement into the Balkans during a warm climate interval [Greenland Interstadial 12 (GI 12)]. A second population movement may be represented by a diverse set of artifact assemblages (sometimes termed Proto-Aurignacian) found in the Balkans, parts of Southwest Europe, and probably in Eastern Europe, and dating to several brief interstadials (GI 11–GI 9) that preceded the beginning of cold Heinrich Event 4 (HE4) (≈40,000 cal BP). They are similar to contemporaneous assemblages made by modern humans in the Levant (Ahmarian). The earliest known human skeletal remains in Europe that may be unequivocally assigned to H. sapiens (Peçstera cu Oase, Romania) date to this time period (≈42,000 cal BP) but are not associated with artifacts. After the Campanian Ignimbrite volcanic eruption (40,000 cal BP) and the beginning of HE4, artifact assemblages assigned to the classic Aurignacian, an industry associated with modern human skeletal remains that seems to have developed in Europe, spread throughout the continent.     

靶向封闭EEF1A2对胰腺癌细胞凋亡的作用及其机制研究

目的 观察靶向封闭EEF1A2基因对胰腺癌细胞株凋亡的影响,并探讨其可能的作用机制.方法 体外转录制备2对EEF1A2 siRNA,应用脂质体技术转染胰腺癌细胞株BxPC-3,半定量RT-PCR、蛋白质印迹法检测转染前后EEF1A2基因表达的变化.运用膜联蛋白V/碘化丙啶法检测细胞凋亡率;蛋白质印迹法检测细胞中caspase-3、caspase-8、caspase-9、聚二磷酸腺苷核糖多聚酶(PARP)细胞色素C和Bid等凋亡相关蛋白表达变化.结果 2对EEF1A2 siRNA均能有效降低BxPC-3细胞中EEF1A2的表达,其中第2对siRNA静默效果更佳,EEF1A2在mRNA和蛋白质水平的表达抑制率均达75%左右.抑制BxPC-3细胞中EEF1A2的表达后,细胞的早期凋亡率为15.28%±3.65%,显著高于阴性对照组的10.11%±3.05%和空白组的9.41%±4.14%,同时伴随出现caspase-3、caspase-8、caspase-9、PARP和Bid的蛋白活化增强和细胞色素C表达增加.结论 抑制EEF1A2表达能明显诱导胰腺癌细胞BxPC-3的凋亡,而死亡受体途径和线粒体途径的激活可能均参与凋亡的发生.     

The XY gene hypothesis of psychosis: Origins and current status

Sex differences in psychosis and their interaction with laterality (systematic departures from 50:50 left‐right symmetry across the antero‐posterior neural axis) are reviewed in the context of the X‐Y gene hypothesis. Aspects of laterality (handedness/cerebral asymmetry/the torque) predict (1) verbal and non‐verbal ability in childhood and across adult life and (2) anatomical, physiological, and linguistic variation relating to psychosis. Neuropsychological and MRI evidence from individuals with sex chromosome aneuploidies indicates that laterality is associated with an X‐Y homologous gene pair. Within each mammalian species the complement of such X‐Y gene pairs reflects their potential to account for taxon‐specific sexual dimorphisms. As a consequence of the mechanism of meiotic suppression of unpaired chromosomes <MSUC> such X‐Y gene pairs generate epigenetic variation around a species defining motif that is carried to the zygote with potential to initiate embryonic gene expression in XX or XY format. The Protocadherin11XY (PCDH11XY) gene pair in Xq21.3/Yp11.2 in probable coordination with a gene or genes within PAR2 (the second pseudo‐autosomal region) is the prime candidate in relation to cerebral asymmetry and psychosis in Homo sapiens. The lately‐described pattern of sequence variation associated with psychosis on the autosomes may reflect a component of the human genome's adjustment to selective pressures generated by the sexually dimorphic mate recognition system. © 2013 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by John Wiley and Sons, Ltd.