Taxonomic Abundance at Panxian Dadong, a Middle Pleistocene Cave in South China

The faunal assemblage from the site of Panxian Dadong provides evidence for a general continuity in species representation throughout a period of approximately 120 kya. Taxonomically, faunal material from Dadong includes classic taxa of the Middle Pleistocene Ailuropoda-Stegodon faunal complex of South China. Taxonomic abundance measures document a sample that is rich in large ungulate species including rhinoceros, stegodonts, and large bovids. These data are further examined in light of assemblage formation processes, temporal distribution, and environmental context. Taphonomic data that demonstrate the presence and activities of bonecollecting species (including porcupines, hominids, and large and small carnivores) suggest that Dadong Cave was an attractive shelter that saw many uses during the period analyzed. These include hominid foraging, porcupine bone collecting, and carnivore scavenging and hunting. KEYWORDS: Middle Pleistocene, South China, Ailuropoda-Stegodon fauna, hominid

Lithic Raw Material Use at the Late Middle Pleistocene Site of Panxian Dadong

The possibility of selective use of lithic raw material in the Middle Pleistocene cave deposits of Panxian Dadong is examined in order to evaluate hominid strategies of resource management. Limestone, chert, and basalt, available in or nearby the cave, were differentially used for the production of tools and unretouched flakes. Limestone was predominantly used to produce expedient tools, unretouched flakes were most commonly made of basalt, and chert was most frequently used to produce retouched flakes and tools. Patterns in the reduction sequence for each raw material also indicate that these lithic resources were selectively used. The early stages of core reduction are clearly represented in basalt flakes, whereas chert artifacts exhibit the later stages of tool production and the greatest degree of resharpening. When the selection of raw material is examined through time, over a span of more than 100,000 years, two patterns are clear. The proportion of chert and basalt and the overall frequency of artifacts increases. These changes in the frequency and selection of raw material occur without a techno-typological change. The major shifts in raw material usage correlate with a colder climatic regime and may relate to the intensified use of the cave for animal carcass processing and shelter. KEYWORDS: Middle Pleistocene, lithics, reduction sequence, hominid

Beta-peptides with improved affinity for hDM2 and hDMX

We previously described a series of 314-helical β-peptides that bind the hDM2 protein and inhibit its interaction with a p53-derived peptide in vitro. Here we present a detailed characterization of the interaction of these peptides with hDM2 and report two new β-peptides in which non-natural side chains have been substituted into the hDM2-recognition epitope. These peptides feature both improved affinity and inhibitory potency in fluorescence polarization and ELISA assays. Additionally, one of the new β-peptides also binds the hDM2-related protein, hDMX, which has been identified as another key therapeutic target for activation of the p53 pathway in tumors

Infectious disease in the ancient Aegean: Intestinal parasitic worms in the Neolithic to Roman Period inhabitants of Kea, Greece

Little is known about infectious disease and parasites in the prehistoric inhabitants of the islands of the Aegean, in contrast to later time periods. It is only with the development of Greek medical texts in the 5th and 4th centuries BC we start to find evidence for the diseases that affected the population of region. Foremost amongst these authors was the medical practitioner Hippocrates, who lived on the island of Kos. The descriptions of the many diseases he and his students encountered were recorded in their medical texts in the 4th and 3rd centuries BC, known as the Hippocratic Corpus. These important texts provided the core philosophy underpinning medical theories in Europe and the Arab world for the following 2,000 years. Past research to determine which species of intestinal parasitic worms were described in the Hippocratic Corpus has suggested they indicate roundworm, pinworm and Taenia tapeworm. However, until now, there has been no archaeological evidence for which species of helminths were present in ancient Greece. In this study, we analysed soil sediment adherent to the sacrum and iliac bones of the pelvis of 25 burials dating from the Neolithic to Byzantine period on the Greek island of Kea, not far from Kos. Four individuals (16%) were positive for the eggs of intestinal helminths, dating from the Neolithic (4th millennium BC), Late Bronze Age, and the Roman Period. The species identified were whipworm (Trichuris trichiura) and roundworm (Ascaris lumbricoides). We consider reasons as to why fewer species of parasite appear to have been present on Kea than was the case for northern Europe at the same time period. This study of ancient parasites shows how we can combine archaeology with history of medicine to better understand the discoveries of key early scientists and medical practitioners

Packaged delivery of CRISPR–Cas9 ribonucleoproteins accelerates genome editing

Effective genome editing requires a sufficient dose of CRISPR-Cas9 ribonucleoproteins (RNPs) to enter the target cell while minimizing immune responses, off-target editing, and cytotoxicity. Clinical use of Cas9 RNPs currently entails electroporation into cells ex vivo, but no systematic comparison of this method to packaged RNP delivery has been made. Here we compared two delivery strategies, electroporation and enveloped delivery vehicles (EDVs), to investigate the Cas9 dosage requirements for genome editing. Using fluorescence correlation spectroscopy, we determined that >1300 Cas9 RNPs per nucleus are typically required for productive genome editing. EDV-mediated editing was >30-fold more efficient than electroporation, and editing occurs at least 2-fold faster for EDV delivery at comparable total Cas9 RNP doses. We hypothesize that differences in efficacy between these methods result in part from the increased duration of RNP nuclear residence resulting from EDV delivery. Our results directly compare RNP delivery strategies, showing that packaged delivery could dramatically reduce the amount of CRISPR-Cas9 RNPs required for experimental or clinical genome editing

Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign www.bjcancer.co

Thioesters Support Efficient Protein Biosynthesis by the Ribosome

Thioesters are critical chemical intermediates in numerous extant biochemical reactions and are invoked as key reagents during prebiotic peptide synthesis on an evolving Earth. Here we asked if a thioester could replace the native oxo-ester in acyl-tRNA substrates during protein biosynthesis by the ribosome. We prepared 3'-thio-3'-deoxyadenosine triphosphate in 10 steps from xylose and demonstrated that it is an effective substrate for the Escherichia&nbsp;coli CCA-adding enzyme, which appends 3'-thio-3'-deoxyadenosine to truncated tRNAs ending with 3'-CC. Using a variety of aminoacyl-tRNA synthetases, flexizymes, or a direct thioester exchange reaction, we prepared a suite of 3'-thio-tRNAs acylated with α- and non-α-amino acids. All were recognized and utilized by wild-type E. coli ribosomes during in vitro translation reactions to generate oligopeptides in yields commensurate with native oxo-ester tRNAs. These results indicate that thioester intermediates widely used in Nature can be co-opted to support the incorporation of natural α-amino acids as well as noncanonical monomers by the extant translational machinery for sequence-defined polymer synthesis

The genetic prehistory of southern Africa

Southern and eastern African populations that speak non-Bantu languages with click consonants are known to harbour some of the most ancient genetic lineages in humans, but their relationships are poorly understood. Here, we report data from 23 populations analyzed at over half a million single nucleotide polymorphisms, using a genome-wide array designed for studying human history. The southern African Khoisan fall into two genetic groups, loosely corresponding to the northwestern and southeastern Kalahari, which we show separated within the last 30,000 years. We find that all individuals derive at least a few percent of their genomes from admixture with non-Khoisan populations that began approximately 1,200 years ago. In addition, the east African Hadza and Sandawe derive a fraction of their ancestry from admixture with a population related to the Khoisan, supporting the hypothesis of an ancient link between southern and eastern AfricaComment: To appear in Nature Communication

Labeling Strategies Matter for Super-Resolution Microscopy: A Comparison between HaloTags and SNAP-tags

Super-resolution microscopy requires that subcellular structures are labeled with bright and photostable fluorophores, especially for live-cell imaging. Organic fluorophores may help here as they can yield more photons—by orders of magnitude—than fluorescent proteins. To achieve molecular specificity with organic fluorophores in live cells, self-labeling proteins are often used, with HaloTags and SNAP-tags being the most common. However, how these two different tagging systems compare with each other is unclear, especially for stimulated emission depletion (STED) microscopy, which is limited to a small repertoire of fluorophores in living cells. Herein, we compare the two labeling approaches in confocal and STED imaging using various proteins and two model systems. Strikingly, we find that the fluorescent signal can be up to 9-fold higher with HaloTags than with SNAP-tags when using far-red rhodamine derivatives. This result demonstrates that the labeling strategy matters and can greatly influence the duration of super-resolution imaging