Percussive technology continues to play an increasingly important role in understanding the evolution of tool use. Comparing the archaeological record with extractive foraging behaviors in nonhuman ...primates has focused on percussive implements as a key to investigating the origins of lithic technology. Despite this, archaeological approaches towards percussive tools have been obscured by a lack of standardized methodologies. Central to this issue have been the use of qualitative, non-diagnostic techniques to identify percussive tools from archaeological contexts. Here we describe a new morphometric method for distinguishing anthropogenically-generated damage patterns on percussive tools from naturally damaged river cobbles. We employ a geomatic approach through the use of three-dimensional scanning and geographical information systems software to statistically quantify the identification process in percussive technology research. This will strengthen current technological analyses of percussive tools in archaeological frameworks and open new avenues for translating behavioral inferences of early hominins from percussive damage patterns.
Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the ...realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such “cryptic” or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that coculturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis-nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular modeling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled both structural and genomic comparisons to other anthracycline-producing systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin’s MOA, in contrast to many other anthracyclines, does not invoke nucleic acid damage.
Natural products profoundly impact many research areas, including medicine, organic chemistry, and cell biology. However, discovery of new natural products suffers from a lack of high throughput ...analytical techniques capable of identifying structural novelty in the face of a high degree of chemical redundancy. Methods to select bacterial strains for drug discovery have historically been based on phenotypic qualities or genetic differences and have not been based on laboratory production of secondary metabolites. Therefore, untargeted LC/MS-based secondary metabolomics was evaluated to rapidly and efficiently analyze marine-derived bacterial natural products using LC/MS-principal component analysis (PCA). A major goal of this work was to demonstrate that LC/MS-PCA was effective for strain prioritization in a drug discovery program. As proof of concept, we evaluated LC/MS-PCA for strain selection to support drug discovery, for the discovery of unique natural products, and for rapid assessment of regulation of natural product production.
Symbolic gestures, such as pantomimes that signify actions (e.g., threading a needle) or emblems that facilitate social transactions (e.g., finger to lips indicating "be quiet"), play an important ...role in human communication. They are autonomous, can fully take the place of words, and function as complete utterances in their own right. The relationship between these gestures and spoken language remains unclear. We used functional MRI to investigate whether these two forms of communication are processed by the same system in the human brain. Responses to symbolic gestures, to their spoken glosses (expressing the gestures' meaning in English), and to visually and acoustically matched control stimuli were compared in a randomized block design. General Linear Models (GLM) contrasts identified shared and unique activations and functional connectivity analyses delineated regional interactions associated with each condition. Results support a model in which bilateral modality-specific areas in superior and inferior temporal cortices extract salient features from vocal-auditory and gestural-visual stimuli respectively. However, both classes of stimuli activate a common, left-lateralized network of inferior frontal and posterior temporal regions in which symbolic gestures and spoken words may be mapped onto common, corresponding conceptual representations. We suggest that these anterior and posterior perisylvian areas, identified since the mid-19th century as the core of the brain's language system, are not in fact committed to language processing, but may function as a modality-independent semiotic system that plays a broader role in human communication, linking meaning with symbols whether these are words, gestures, images, sounds, or objects.
We have undertaken a deep, wide-field H I imaging survey of M31, reaching a maximum resolution of about 50 pc and 2 km s-1 across a 95 X 48 kpc region. The H I mass and brightness sensitivity at 100 ...pc resolution for a 25 km s-1 wide spectral feature is 1500 M and 0.28 K. Our study reveals ubiquitous H I self-opacity features, discernible in the first instance as filamentary local minima in images of the peak H I brightness temperature. Local minima are organized into complexes of more than kpc length and are particularly associated with the leading edge of spiral arm features. Just as in the Galaxy, there is only patchy correspondence of self-opaque features with CO(1-0) emission. We have produced images of the best-fit physical parameters: spin temperature, opacity-corrected column density, and nonthermal velocity dispersion, for the brightest spectral feature along each line of sight in the M31 disk. Spectroscopically opaque atomic gas is organized into filamentary complexes and isolated clouds down to 100 pc. Localized opacity corrections to the column density exceed an order of magnitude in many cases and add globally to a 30% increase in the atomic gas mass over that inferred from the integrated brightness under the usual assumption of negligible self-opacity. Opaque atomic gas first increases from 20 to 60 K in spin temperature with radius to 12 kpc but then declines again to 20 K beyond 25 kpc. We have extended the resolved star formation law down to physical scales more than an order of magnitude smaller in area and mass than has been possible previously. The relation between total gas mass and star formation rate density is significantly tighter than that with molecular mass and is fully consistent in both slope and normalization with the power-law index of 1.56 found in the molecule-dominated disk of M51 at 500 pc resolution. Below a gas mass density of about 5 M pc-2, there is a downturn in star formation rate density which may represent a real local threshold for massive star formation at a cloud mass of about 5 X 104 M .
This study applies a new three-dimensional measurement technique to determine the major source of variation in the Acheulian bifacial tool collection from the Middle Pleistocene site of ...Elandsfontein, South Africa. This three-dimensional technique is compared with conventional two-dimensional methods to investigate which methods capture morphological variation in the assemblage most comprehensively. Additionally, a set of experimentally produced bifacial tools are incorporated into the analyses to isolate the behavioral pattern underpinning identified variation in the archaeological assemblage. The interpretative breadth of current models explaining morphological variation in bifacial tools is then tested against the pattern identified in the Elandsfontein assemblage. Variation appears to be related to the consistent application of a specific reduction strategy associated with the early stages of bifacial tool manufacture. The intensity with which this strategy was applied seems to have been mediated by the availability of raw material that was suitable for the production of large bifacial tools.
The emergence of lithic technology by ≈ 2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated ...faunal evidence, however, is poorly preserved prior to ≈ 1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to 2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence - spanning hundreds to thousands of years - and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution.
In response to a variety of external signals, the fungal pathogen Candida albicans undergoes a transition between ellipsoidal single cells (blastospores) and filaments composed of elongated cells ...attached end‐to‐end. Here we identify a DNA‐binding protein, Nrg1, that represses filamentous growth in Candida probably by acting through the co‐repressor Tup1. nrg1 mutant cells are predominantly filamentous under non‐filament‐inducing conditions and their colony morphology resembles that of tup1 mutants. We also identify two filament‐specific genes, ECE1 and HWP1, whose transcription is repressed by Nrg1 under non‐inducing conditions. These genes constitute a subset of those under Tup1 control, providing further evidence that Nrg1 acts by recruiting Tup1 to target genes. We show that growth in serum at 37°C, a potent inducer of filamentous growth, causes a reduction of NRG1 mRNA, suggesting that filamentous growth is induced by the down‐regulation of NRG1. Consistent with this idea, expression of NRG1 from a non‐regulated promoter partially blocks the induction of filamentous growth.
The efficacy of novel cancer therapeutics has been hampered by the ability to deliver these agents to the tumor at effective concentrations. Liposomes have been used as a method to overcome some ...delivery issues and, in combination with hyperthermia, have been shown to increase drug delivery to tumors. Particle size has been shown to affect the delivery of liposomes, but it is not known how hyperthermia affects size dependence. This study investigates the effect of hyperthermia (42 degrees C) on the extravasation of different sized nanoparticles (albumin; 100-, 200-, and 400-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in mouse window chambers. In this model (at 34 degrees C), no liposomes were able to extravasate into the tumor interstitium. Hyperthermia enabled liposome extravasation of all sizes. The magnitude of hyperthermia-induced extravasation was inversely proportional to particle size. Thus, at normothermia (34 degrees C), the pore cutoff size for this model was between 7 and 100 nm (e.g., liposomes did not extravasate). At 42 degrees C, the pore cutoff size was increased to >400 nm, allowing all nanoparticles tested to be delivered to the tumor interstitium to some degree. With hyperthermia, the 100-nm liposome experienced the largest relative increase in extravasation from tumor vasculature. Hyperthermia did not enable extravasation of 100-nm liposomes from normal vasculature, potentially allowing for tumor-specific delivery. These experiments indicate that hyperthermia can enable and augment liposomal drug delivery to tumors and potentially help target liposomes specifically to tumors.
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