An early modern human presence in Sumatra 73,000-63,000 years ago.

Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93-61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications. Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel-dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.

Inkjet printing and electrical characterisation of DNA-templated cadmium sulphide nanowires.

Cadmium sulphide can be templated on λ-DNA molecules to form an aqueous dispersion of CdS/λ-DNA nanowires. Subsequent addition of ethylene glycol to 50% v/v is sufficient to formulate an ink suitable for printing using piezoelectric drop-on-demand technology. Printed droplet arrays show a coffee-ring morphology of individual deposits by fluorescence and Raman microscopy, but upon increasing the number of layers of printed material by repeated printing over each droplet, the dry deposit approaches closer to a disc shape. It is also possible to print parallel tracks by reducing the droplet separation in the array until neighbouring droplets overlap before they dry. The droplets coalesce to form a strip of width roughly equal to the diameter of the droplets. Evaporation-driven capillary flow sends the nanowires to the edges of the strip and when dry they form parallel tracks of CdS/λ-DNA nanowire bundles. Both droplets and tracks were printed onto Pt-on-glass interdigitated microelectrodes (10 µm width, 10 µm gap). The current-voltage characteristics of these two-terminal devices were approximately ohmic, but with some hysteresis. The conductance increased with temperature as a simple activated process with activation energies of 0.57 ± 0.02 eV (tracks) and 0.39 ± 0.02 eV (droplets). The impedance spectra of the printed films were consistent with hopping between CdS grains.

Sport science for salmon and other species: ecological consequences of metabolic power constraints.

For metabolically demanding behaviours, power supply (ATP resynthesis per unit time) is an important constraint on performance. Yet ecology as a discipline lacks a framework to account for these power constraints. We developed such a framework (borrowing concepts from sports science) and applied it to the upriver migration of anadromous fish. Our models demonstrate how metabolic power constraints alters optimal migratory behaviour; in response to strong counter flows, fish minimise cost of transport by alternating between rapid, anaerobically fuelled swimming and holding to restore spent fuels. Models ignoring power constraints underestimated the effect of elevated water temperature on migration speed and costs (by up to 60%). These differences were primarily due to a temperature-mediated reduction in aerobic scope that impairs the ability of fish to rapidly migrate through warm waters. Our framework provides a mechanistic link between temperature-induced reductions in aerobic scope and their ecological consequences for individuals, populations and communities.

Wolbachia infection and Lepidoptera of conservation concern.

Conservation of at-risk species requires multi-faceted and carefully-considered management approaches to be successful. For arthropods, the presence of endosymbiotic bacteria, such as Wolbachia (Rickettsiales: Rickettsiaceae), may complicate management plans and exacerbate the challenges faced by conservation managers. Wolbachia poses a substantial and underappreciated threat to the conservation of arthropods because infection may induce a number of phenotypic effects, most of which are considered deleterious to the host population. In this study, the prevalence of Wolbachia infection in lepidopteran species of conservation concern was examined. Using standard molecular techniques, 22 species of Lepidoptera were screened, of which 19 were infected with Wolbachia. This rate is comparable to that observed in insects as a whole. However, this is likely an underestimate because geographic sampling was not extensive and may not have included infected segments of the species' ranges. Wolbachia infections may be particularly problematic for conservation management plans that incorporate captive propagation or translocation. Inadvertent introduction of Wolbachia into uninfected populations or introduction of a new strain may put these populations at greater risk for extinction. Further sampling to investigate the geographic extent of Wolbachia infections within species of conservation concern and experiments designed to determine the nature of the infection phenotype(s) are necessary to manage the potential threat of infection.

Stratigraphic context and direct dating of the Neandertal mandible from Cova del Gegant (Sitges, Barcelona).

Stratigraphic study of the Cova del Gegant's sedimentary fill revealed different cycles of accumulation of typical interior cave and delta facies. A precise chronology for these deposits, the faunal remains and stone tools contained therein was obtained by radiocarbon, U-Th and OSL. Our results indicate that the Upper Pleistocene archaeological sequence dates between 49.3 +/- 1.8 ka BP, the U-Th age of the overlying flowstone, and 60.0 +/- 3.9 ka BP, the OSL age of the basal deposits. We have also directly dated the site's Neandertal mandible to 52.3 +/- 2.3 ka by U-Th.

Recent Canadian efforts to develop population-level pregnancy intervention studies to mitigate effects of natural disasters and other tragedies.

The preconception, pregnancy and immediate postpartum and newborn periods are times for mothers and their offspring when they are especially vulnerable to major stressors - those that are sudden and unexpected and those that are chronic. Their adverse effects can transcend generations. Stressors can include natural disasters or political stressors such as conflict and/or migration. Considerable evidence has accumulated demonstrating the adverse effects of natural disasters on pregnancy outcomes and developmental trajectories. However, beyond tracking outcomes, the time has arrived for gathering more information related to identifying mechanisms, predicting risk and developing stress-reducing and resilience-building interventions to improve outcomes. Further, we need to learn how to encapsulate both the quantitative and qualitative information available and share it with communities and authorities to mitigate the adverse developmental effects of future disasters, conflicts and migrations. This article briefly reviews prenatal maternal stress and identifies three contemporary situations (wildfire in Fort McMurray, Alberta, Canada; hurricane Harvey in Houston, USA and transgenerational and migrant stress in Pforzheim, Germany) where current studies are being established by Canadian investigators to test an intervention. The experiences from these efforts are related along with attempts to involve communities in the studies and share the new knowledge to plan for future disasters or tragedies.

Response to Comment on "U-Th dating of carbonate crusts reveals Neandertal origin of Iberian cave art".

Slimak et al challenge the reliability of our oldest (>65,000 years) U-Th dates on carbonates associated with cave paintings in Spain. They cite a supposed lack of parietal art for the 25,000 years following this date, along with potential methodological issues relating to open-system behavior and corrections to detrital or source water 230Th. We show that their criticisms are unfounded.

U-Th dating of carbonate crusts reveals Neandertal origin of Iberian cave art.

The extent and nature of symbolic behavior among Neandertals are obscure. Although evidence for Neandertal body ornamentation has been proposed, all cave painting has been attributed to modern humans. Here we present dating results for three sites in Spain that show that cave art emerged in Iberia substantially earlier than previously thought. Uranium-thorium (U-Th) dates on carbonate crusts overlying paintings provide minimum ages for a red linear motif in La Pasiega (Cantabria), a hand stencil in Maltravieso (Extremadura), and red-painted speleothems in Ardales (Andalucía). Collectively, these results show that cave art in Iberia is older than 64.8 thousand years (ka). This cave art is the earliest dated so far and predates, by at least 20 ka, the arrival of modern humans in Europe, which implies Neandertal authorship.

Crystal structures of guinea-pig, goat and bovine alpha-lactalbumin highlight the enhanced conformational flexibility of regions that are significant for its action in lactose synthase.

BACKGROUND: The regulation of milk lactose biosynthesis is highly dependent on the action of a specifier protein, alpha-lactalbumin (LA). Together with a glycosyltransferase, LA forms the enzyme complex lactose synthase. LA promotes the binding of glucose to the complex and facilitates the biosynthesis of lactose. To gain further insight into the molecular basis of LA function in lactose synthase we have determined the structures of three species variants of LA. RESULTS: The crystal structures of guinea-pig, goat and a recombinant from of bovine LA have been determined using molecular replacement techniques. Overall, the structures are very similar and reflect their high degree of amino acid sequence identity (66-94%). Nonetheless, the structures show that a portion of the molecule (residues 105-110), known to be important for function, exhibits a variety of distinct conformers. This region lies adjacent to two residues (Phe31 and His32) that have been implicated in monosaccharide binding by lactose synthase and its conformation has significant effects on the environments of these functional groups. The crystal structures also demonstrate that residues currently implicated in LA's modulatory properties are located in a region of the structure that has relatively high thermal parameters and is therefore probably flexible in vivo. CONCLUSIONS: LA's proposed interaction site for the catalytic component of the lactose synthase complex is primarily located in the flexible C-terminal portion of the molecule. This general observation implies that conformational adjustments may be important for the formation and function of lactose synthase.

Structural insights into the mode of action of a pure antiestrogen.

BACKGROUND: Estrogens exert their effects on target tissues by binding to a nuclear transcription factor termed the estrogen receptor (ER). Previous structural studies have demonstrated that each class of ER ligand (agonist, partial agonist, and SERM antagonist) induces distinctive orientations in the receptor's carboxy-terminal transactivation helix. The conformation of this portion of the receptor determines whether ER can recruit and interact with the components of the transcriptional machinery, thereby facilitating target gene expression. RESULTS: We have determined the structure of rat ERbeta ligand binding domain (LBD) in complex with the pure antiestrogen ICI 164,384 at 2.3 A resolution. The binding of this compound to the receptor completely abolishes the association between the transactivation helix (H12) and the rest of the LBD. The structure reveals that the terminal portion of ICI's bulky side chain substituent protrudes from the hormone binding pocket, binds along the coactivator recruitment site, and physically prevents H12 from adopting either its characteristic agonist or AF2 antagonist orientation. CONCLUSIONS: The binding mode adopted by the pure antiestrogen is similar to that seen for other ER antagonists. However, the size and resultant positioning of the ligand's side chain substituent produces a receptor conformation that is distinct from that adopted in the presence of other classes of ER ligands. The novel observation that binding of ICI results in the complete destabilization of H12 provides some indications as to a possible mechanism for pure receptor antagonism.

Changes in mammographic densities induced by a hormonal contraceptive designed to reduce breast cancer risk.

BACKGROUND: It has been known for some time that oral contraceptives substantially reduce the risk of endometrial and ovarian cancer, but they do not reduce the risk of breast cancer. A hormonal contraceptive regimen has been developed which uses a gonadotropin-releasing hormone against (GnRHA) to suppress ovarian function, and this regimen includes the administration of very low doses of both estrogen and progestogen. This hormonal contraceptive regimen attempts to minimize exposure of the breast epithelium to these steroids and to preserve the maximum beneficial effects of estrogen, while still preventing endometrial hyperplasia. PURPOSE: Our purpose was to determine whether changes occurred in mammographic densities between baseline and 1 year for women on this hormonal contraceptive regimen with reduced estrogen and progestogen levels compared with women in a control group. METHODS: Twenty-one women were randomly assigned in a 2:1 ratio to the GnRHA-based contraceptive group (14 women) or to a control group (seven women). The contraceptive group received the following: 7.5 mg leuprolide acetate depot by intramuscular injection every 28 days; 0.625 mg conjugated estrogen by mouth for 6 days out of 7 every week; and 10 mg medroxyprogesterone acetate orally for 13 days every fourth 28-day cycle. The control group received no medication. Baseline and 1-year follow-up mammograms of contraceptive and control subjects were reviewed in a blinded fashion by two radiologists. RESULTS: Comparison of the changes between the baseline and 1-year mammograms in the two groups of women showed significant (P = .039) reduction in mammographic densities at 1 year for women on the contraceptive regimen. Assessing the reduction in mammographic densities by noting the fineness of fibrous septae showed a highly significant (P = .0048) difference in the contraceptive regimen group. One of the women on the contraceptive regimen was withdrawn from the study because of poor compliance. CONCLUSION: The reduced estrogen and progestogen exposures to the breast that were achieved by the hormonal contraceptive regimen resulted in substantial reductions in follow-up mammographic densities at 1 year compared with baseline. Although there is no direct evidence that such a reduction in densities will lead to a reduced risk of breast cancer, indirect evidence for a protective effect of this regimen is that early menopause reduces breast cancer risk, and that menopause is associated with a reduction in mammographic densities.

PIP: In California, physicians randomly assigned 21 women aged 25-40 to either the contraceptive group or the control group as part of a study aimed to determine whether or not a hormonal contraceptive regimen with reduced estrogen and progestogen levels affects mammographic densities. Eligibility criteria included premenopausal women with a 5-fold greater than normal risk of breast cancer, no prior cancer, bone mineral density not less than 2 standard deviations below normal, normal cholesterol, and a normal physical and pelvic examination. The contraceptive group received intramuscular injection of 7.5 mg leuprolide acetate depot every 28 days, 0.625 mg oral conjugated estrogen for 6 out of 7 days every week, and 10 mg oral medroxyprogesterone acetate for 13 days every fourth 28-day cycle. The reduction in mammographic densities in women on the contraceptive regimen between baseline and 1 year was significantly different than that of the controls whose mammographic densities remained essentially the same (p = 0.039). Cases had significantly more change in fibrous septae between baseline and 1 year than did controls (+0.82 units vs. -0.07; p = 0.0048). These results indicate that lower levels of estrogen and progestogen reduces mammographic densities, which may reduce the risk of breast cancer since increased mammographic densities are linked to an increased risk of breast cancer. Reduced mitotic activity in breast epithelial cells during menopause and with lower levels of estrogen and progestogen (i.e., reduced mammographic densities) suggest that early menopause may also protect against breast cancer.

Measurement of diethylstilbestrol in plasma from patients with cancer of the prostate.

A specific radioimmunoassay has been developed for diethylstilbestrol (DES), using an antiserum raised against DES monocarboxymethyl ether and a tritium-labeled radioligand. Prior to radioimmunoassay, a fraction enriched in DES is obtained from a dichloroethane extract of plasma using Sephadex LH-20. The specificity of the assay is good, and the sensitivity (130 pg/ml) is adequate for accurate determination of DES in plasma from prostatic cancer patients treated with the drug. The precision is satisfactory, with an interassay coefficient of variation of approximately 10% at concentrations of approximately 1 ng/ml, and the blank values are negligible. Excellent agreement (r = 0.96) is observed between data obtained by radioimmunoassay and those obtained by a procedure using gas chromatography-high-resolution mass spectrometry. DES concentrations in the plasma of six treated (1 mg DES three times daily) patients were in the range 0.15 to 6.0 ng/ml. Increases in plasma concentration were observed within 2 hr of administration, with secondary rises occurring 5 to 6 hr later. Plasma testosterone concentrations were low in four of the patients; in a single subject, relatively high levels of testosterone were further elevated following administration of luteinizing hormone-releasing hormone.

Development of Dermatophagoides pteronyssinus (Acari: Pyroglyphidae) at constant and simultaneously fluctuating temperature and humidity conditions.

House dust mites are found in almost all dwellings in New Zealand and are a major risk factor in the development of asthma and perennial allergic rhinitis. We studied the longevity, life stage length, and fecundity of a New Zealand strain of European house dust mite, Dermatophagoides pteronyssinus (Trouessart), at constant (23 degrees C, 75% RH) and the fluctuating conditions typically found in dry (18-25 degrees C, 60-38% RH) and damp (18-23 degrees C, 70-55% RH) New Zealand dust mite microhabitats in carpets. All the adult mites placed in the "dry" conditions died within 18 d. Mites in the "da conditions had developmental times, oviposition, and death rates that were not significantly different from constant conditions. These mites are tolerant of fluctuating temperatures, but they are more susceptible to environments that strongly fluctuate in humidity.

A structural basis for the interaction of urea with lysozyme.

The effect of urea on the crystal structure of hen egg-white lysozyme has been investigated using X-ray crystallography. High resolution structures have been determined from crystals grown in the presence of 0, 0.7, 2, 3, 4, and 5 M urea and from crystals soaked in 9 M urea. All the forms are essentially isomorphous with the native type II crystals, and the derived structures exhibit excellent geometry and RMS differences from ideality in bond distances and angles. Comparison of the urea complex structures with the native enzyme (type II form, at 1.5 A resolution) indicates that the effect of urea is minimal over the concentration range studied. The mean difference in backbone conformation between the native enzyme and its urea complexes varies from 0.18 to 0.49 A. Conformational changes are limited to flexible surface loops (Thr 69-Asn 74, Ser 100-Asn 103), the active site loop (Asn 59-Cys 80), and the C-terminus (Cys 127-Leu 129). Urea molecules are bound to distinct sites on the surface of the protein. One molecule is bound to the active site cleft's C subsite, at all concentrations, in a fashion analogous to that of the N-acetyl substituent of substrate and inhibitor sugars normally bound to this site. Occupation of this subsite by urea alone does not appear to induce the conformational changes associated with inhibitor binding.

The effect of lactation on peak adult shaft and ultra-distal forearm bone mass in women.

The effect of long-term vs short-term lactation (three to four children with an average of 10.7 mo vs 2.8 mo duration for each child) on maternal forearm bone-mass sites that are either primarily trabecular or cortical in composition was determined. The habitual calcium intake of each subject exceeded 90% of her recommended dietary allowance (RDA) for nonpregnant, pregnant, and lactating states. Trabecular and cortical bone mass were estimated using single-photon densitometry at ultra-distal and midshift sites on the radius, respectively. Bone mass at both sites was lower in the long-term than in the short-term lactation group and, at the ultra-distal site (trabecular bone), the effect was statistically significant (p less than 0.05). These data indicate that even when women consume the RDA for calcium, long-term lactation can deplete ultra-distal bone mass in the forearm.

Calorie restriction modulates age-dependent changes in the retinas of Brown Norway rats.

The present study examined the effect of a 40% reduction in caloric intake (CR) versus ad libitum (AL) feeding on retinal aging. CR- and AL-fed Brown Norway (BN) rats were obtained at 12, 24 and 30 months of age from the National Center for Toxicological Research (NCTR). Age-dependent declines in outer nuclear layer (ONL=photoreceptor) cell densities, ONL height, inner nuclear layer (INL) cell densities, and thicknesses of the inner retina and whole retina were quantified in thick sections at six loci across the circumference of the sensory retina (four peripheral, two central). Data were analyzed by repeated measures, general linear models. Aging in both diet groups was associated with declines in ONL cell density, ONL height, peripheral INL cell density and total retinal thickness (P< or =0.05). However, ONL cell densities, ONL height and retinal thickness were significantly greater in the CR versus AL diet group at all three ages (P< or =0.005). CR was also associated with a trend for greater peripheral INL cell density (P=0.06) and with greater INL thickness at 30 months (Bonferroni P=0.03). Elevated ONL cell densities in the CR-12 cohort relative to the AL-12 cohort could be explained by diet-associated differences in retinal length, i.e. delayed retinal growth in response to CR. Enhanced ONL cell density, ONL height, INL cell density, INL thickness and total retinal thickness in the CR-30 cohort appear to be as a result of reduced rates of retinal cell loss between 24 and 30 months. However, the protective effect of CR in retinas of older animals may also reflect the initial growth-associated enhancements which were observed in 12 month-old animals. The rat retina may provide a useful model for elucidating the neuroprotective mechanism(s) of CR.

Sealice on salmonids: their biology and control.

Lepeophtheirus salmonis and Caligus elongatus are the two common species of sealice responsible for serious disease problems in salmonid aquaculture. L. salmonis in particular is the most serious parasitic infection on Atlantic salmon farms in the Northern Hemisphere and is the best-known species. This review examines the voluminous literature on the biology and control of sealice and brings together ideas for developing our knowledge of these organisms. Research on the distribution, host range, structure, life cycle, epidemiology, laboratory maintenance, reproductive biology, physiology and pathogenesis is reviewed in depth. The control strategy and economic cost to the industry is discussed. The interactions between wild and cultured salmonids are examined.

Structural insights into the mechanisms of agonism and antagonism in oestrogen receptor isoforms.

Here we summarise the results that have emerged from our structural studies on the oestrogen receptor (ER) ligand-binding domain. We have investigated the conformational effects of a variety of ligands on the structures of both ER isoforms. Each class of ligand (agonists, partial agonists and selective oestrogen receptor modulators) induces a unique conformation in the receptor's ligand-dependent transcriptional activation function. Together these studies have broadened our understanding of ER function by providing a unique insight into ER's ligand specificity and the structural changes that underlie receptor agonism and antagonism.

Juvenile (cellular) adenofibromas. A clinicopathologic study.

"Juvenile" adenofibromas that presented in 25 patients were reviewed. All of the patients were in the second decade of life. The tumors were solitary in 19 patients and multiple and bilateral in six patients. All were distinguished microscopically by prominent cellularity of both epithelium and stroma. Patients who presented with solitary tumors, regardless of size, microscopic pattern, or manner of excision, had no recurrence. In contrast, all patients who presented with multiple tumors developed additional benign masses, often requiring re-excision. We believe that solitary "juvenile adenofibromas," regardless of size, should be excised so as to preserve as much breast tissue as possible. Those patients with multiple, bilateral tumors may anticipate recurrences, but malignant change is not seen. Tumors with this microscopic pattern also may occur, albeit uncommonly, in adults.