Fingerprinting facies of the Tuff IF marker,with implications for early hominin palaeoecology,Olduvai Gorge,Tanzania

The top of Tuff IF marks the upper boundary of the Plio-/Pleistocene Bed I succession exposed in Olduvai Gorge, NE Tanzania, a tephrostratigraphic interval that is well known for remarkable Oldowan archaeological and vertebrate fossil assemblages, including early hominins. Geochemically, Tuff IF is characterized by a relatively consistent silica-undersaturated trachytic to phonolitic composition that relates both in terms of numerical ages (1.79 Ma) and compositional constraints to Olmoti volcano, located 22–38 km E of Olduvai Gorge.Measured Tuff IF sections are characterized by a thick unwelded pyroclastic flow in proximal settings and a succession of surges and ashfalls that interfingers with fluvio-lacustrine deposits of the Olduvai Basin in the medial to distal settings. Only in those areas with a relatively low topographic gradient, in distal reaches and beyond the toe of an Olmoti-sourced volcaniclastic fan, did the Tuff IF marker develop a typical threefold subdivision comprising: (1) primary surges and minor fallout, (2) reworked pumice units as lateral correlatives of proximally emplaced pyroclastic flows and (3) a succession of mass flows in conjunction with aeolian and fluvially reworked units.The pyroclastic marker unit is thus highly heterogeneous with regard to its vertical and lateral facies architecture and this has immediate effects on its preservation potential and in situ burial of fossils and stone artifacts. Even though the volcanically-related environmental perturbations were probably more severe at the eastern lake margin, the evidence for at least temporary freshwater sources and trees suggests environments conducive to hominin activities, but not during emplacement of Tuff IF pyroclastic flows and surges. This inference is supported by the presence of rich Oldowan stone artifact assemblages immediately preceding and following the deposition of Tuff IF, but only extremely sparse archaeological traces from one site in Tuff IF, restricted to the upper, fluvially reworked portion of Tuff IF.Tuff IF facies record the maximum of a regressive (drying) cycle that correlates with regional marine arid indicators. An ecological crisis covering ～ 2000–3500 a of time during Tuff IF deposition resulted not only from the lethal effects of explosive volcanism but also from its coincidence with a pronounced period of climate induced drought. These combined effects appear to have made at least the eastern basin uninhabitable by hominins and other vertebrates for most of the time during which Tuff IF accumulated.     

Chemotherapy-resistant osteosarcoma is highly susceptible to IL-15-activated allogeneic and autologous NK cells

High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell-mediated therapies for chemotherapy-resistant and chemotherapy-sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell-mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell-mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient-derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell-activating agents in patients with high-grade osteosarcoma.     

Lack of low frequency variants masks patterns of non-neutral evolution following domestication

Detecting artificial selection in the genome of domesticated species can not only shed light on human history but can also be beneficial to future breeding strategies. Evidence for selection has been documented in domesticated species including maize and rice, but few studies have to date detected signals of artificial selection in the Sorghum bicolor genome. Based on evidence that domesticated S. bicolor and its wild relatives show significant differences in endosperm structure and quality, we sequenced three candidate seed storage protein (kafirin) loci and three candidate starch biosynthesis loci to test whether these genes show non-neutral evolution resulting from the domestication process. We found strong evidence of non-neutral selection at the starch synthase IIa gene, while both starch branching enzyme I and the beta kafirin gene showed weaker evidence of non-neutral selection. We argue that the power to detect consistent signals of non-neutral selection in our dataset is confounded by the absence of low frequency variants at four of the six candidate genes. A future challenge in the detection of positive selection associated with domestication in sorghum is to develop models that can accommodate for skewed frequency spectrums.     

Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive x chromosome

X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation?pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development.     

HSPG-deficient zebrafish uncovers dental aspect of multiple osteochondromas

Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2^−/− fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2^−/− fish. Histological analysis reveals that ext2^−/− fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2^−/− fish have a single tooth at the end of the 5^th pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2^−/− teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2^+/− adults. The tooth morphology in ext2^−/− was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.