Long-term patterns of body mass and stature evolution within the hominin lineage.

Body size is a central determinant of a species' biology and adaptive strategy, but the number of reliable estimates of hominin body mass and stature have been insufficient to determine long-term patterns and subtle interactions in these size components within our lineage. Here, we analyse 254 body mass and 204 stature estimates from a total of 311 hominin specimens dating from 4.4 Ma to the Holocene using multi-level chronological and taxonomic analytical categories. The results demonstrate complex temporal patterns of body size variation with phases of relative stasis intermitted by periods of rapid increases. The observed trajectories could result from punctuated increases at speciation events, but also differential proliferation of large-bodied taxa or the extinction of small-bodied populations. Combined taxonomic and temporal analyses show that in relation to australopithecines, early Homo is characterized by significantly larger average body mass and stature but retains considerable diversity, including small body sizes. Within later Homo, stature and body mass evolution follow different trajectories: average modern stature is maintained from ca 1.6 Ma, while consistently higher body masses are not established until the Middle Pleistocene at ca 0.5-0.4 Ma, likely caused by directional selection related to colonizing higher latitudes. Selection against small-bodied individuals (less than 40 kg; less than 140 cm) after 1.4 Ma is associated with a decrease in relative size variability in later Homo species compared with earlier Homo and australopithecines. The isolated small-bodied individuals of Homo naledi (ca 0.3 Ma) and Homo floresiensis (ca 100-60 ka) constitute important exceptions to these general patterns, adding further layers of complexity to the evolution of body size within the genus Homo. At the end of the Late Pleistocene and Holocene, body size in Homo sapiens declines on average, but also extends to lower limits not seen in comparable frequency since early Homo

Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling

Gallium-68 (68Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. 68Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex 68Ga3+. Ideally, the chelator will rapidly, quantitatively and stably coordinate 68Ga3+ at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based 68Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with 68Ga3+ is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for 68Ga3+ under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5–50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective 68Ga3+ chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for 68Ga3+ complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of 68Ga-biomolecules for molecular PET imaging. LC-MS and 1H, 13C{1H} and 71Ga NMR studies of HBED complexes of Ga3+ showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral [Ga(HBED)(H2O)], with HBED coordinated in a pentadentate N2O3 mode, with only one phenolic group coordinated to Ga3+, and the remaining coordination site occupied by a water molecule

The Underestimation Of Egocentric Distance: Evidence From Frontal Matching Tasks

There is controversy over the existence, nature, and cause of error in egocentric distance judgments. One proposal is that the systematic biases often found in explicit judgments of egocentric distance along the ground may be related to recently observed biases in the perceived declination of gaze (Durgin & Li, Attention, Perception, & Psychophysics, in press), To measure perceived egocentric distance nonverbally, observers in a field were asked to position themselves so that their distance from one of two experimenters was equal to the frontal distance between the experimenters. Observers placed themselves too far away, consistent with egocentric distance underestimation. A similar experiment was conducted with vertical frontal extents. Both experiments were replicated in panoramic virtual reality. Perceived egocentric distance was quantitatively consistent with angular bias in perceived gaze declination (1.5 gain). Finally, an exocentric distance-matching task was contrasted with a variant of the egocentric matching task. The egocentric matching data approximate a constant compression of perceived egocentric distance with a power function exponent of nearly 1; exocentric matches had an exponent of about 0.67. The divergent pattern between egocentric and exocentric matches suggests that they depend on different visual cues

Supernova 2007bi as a pair-instability explosion

Stars with initial masses 10 M_{solar} < M_{initial} < 100 M_{solar} fuse progressively heavier elements in their centres, up to inert iron. The core then gravitationally collapses to a neutron star or a black hole, leading to an explosion -- an iron-core-collapse supernova (SN). In contrast, extremely massive stars (M_{initial} > 140 M_{solar}), if such exist, have oxygen cores which exceed M_{core} = 50 M_{solar}. There, high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs prior to oxygen ignition, and leads to a violent contraction that triggers a catastrophic nuclear explosion. Tremendous energies (>~ 10^{52} erg) are released, completely unbinding the star in a pair-instability SN (PISN), with no compact remnant. Transitional objects with 100 M_{solar} < M_{initial} < 140 M_{solar}, which end up as iron-core-collapse supernovae following violent mass ejections, perhaps due to short instances of the pair instability, may have been identified. However, genuine PISNe, perhaps common in the early Universe, have not been observed to date. Here, we present our discovery of SN 2007bi, a luminous, slowly evolving supernova located within a dwarf galaxy (~1% the size of the Milky Way). We measure the exploding core mass to be likely ~100 M_{solar}, in which case theory unambiguously predicts a PISN outcome. We show that >3 M_{solar} of radioactive 56Ni were synthesized, and that our observations are well fit by PISN models. A PISN explosion in the local Universe indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic limit, perhaps resulting from star formation processes similar to those that created the first stars in the Universe.Comment: Accepted version of the paper appearing in Nature, 462, 624 (2009), including all supplementary informatio

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Potential role of differential medication use in explaining excess risk of cardiovascular events and death associated with chronic kidney disease: A cohort study

<p>Abstract</p> <p>Background</p> <p>Patients with chronic kidney disease (CKD) are less likely to receive cardiovascular medications. It is unclear whether differential cardiovascular drug use explains, in part, the excess risk of cardiovascular events and death in patients with CKD and coronary heart disease (CHD).</p> <p>Methods</p> <p>The ADVANCE Study enrolled patients with new onset CHD (2001-2003) who did (N = 159) or did not have (N = 1088) CKD at entry. The MDRD equation was used to estimate glomerular filtration rate (eGFR) using calibrated serum creatinine measurements. Patient characteristics, medication use, cardiovascular events and death were ascertained from self-report and health plan electronic databases through December 2008.</p> <p>Results</p> <p>Post-CHD event ACE inhibitor use was lower (medication possession ratio 0.50 vs. 0.58, P = 0.03) and calcium channel blocker use higher (0.47 vs. 0.38, P = 0.06) in CKD vs. non-CKD patients, respectively. Incidence of cardiovascular events and death was higher in CKD vs. non-CKD patients (13.9 vs. 11.5 per 100 person-years, P < 0.001, respectively). After adjustment for patient characteristics, the rate of cardiovascular events and death was increased for eGFR 45-59 ml/min/1.73 m²(hazard ratio [HR] 1.47, 95% CI: 1.10 to 2.02) and eGFR < 45 ml/min/1.73 m²(HR 1.58, 95% CI: 1.00 to 2.50). After further adjustment for statins, β-blocker, calcium channel blocker, ACE inhibitor/ARB use, the association was no longer significant for eGFR 45-59 ml/min/1.73 m²(HR 0.82, 95% CI: 0.25 to 2.66) or for eGFR < 45 ml/min/1.73 m²(HR 1.19, 95% CI: 0.25 to 5.58).</p> <p>Conclusions</p> <p>In adults with CHD, differential use of cardiovascular medications may contribute to the higher risk of cardiovascular events and death in patients with CKD.</p

Early readmission and length of hospitalization practices in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background:  Rising hospital care costs have created pressure to shorten hospital stays and emphasize outpatient care. This study tests the hypothesis that shorter median length of stay (LOS) as a dialysis facility practice is associated with higher rates of early readmission. Methods:  Readmission within 30 days of each hospitalization was evaluated for participants in the Dialysis Outcomes and Practice Patterns Study, an observational study of randomly selected hemodialysis patients in the United States (142 facilities, 5095 patients with hospitalizations), five European countries (101 facilities, 2281 patients with hospitalizations), and Japan (58 facilities, 883 patients with hospitalizations). Associations between median facility LOS (estimated from all hospitalizations at the facility and interpreted as a dialysis facility practice pattern) and odds of readmission were assessed using logistic regression, adjusted for patient characteristics and the LOS of each index hospitalization. Results:  Risk of readmission was directly and significantly associated with LOS of the index hospitalization (adjusted odds ratio [AOR] 1.005 per day in median facility LOS, p = 0.007) and inversely associated with median facility LOS (AOR = 0.974 per day, p = 0.016). This latter association was strongest for US hemodialysis centers (AOR = 0.954 per day, p = 0.015). Conclusions:  Dialysis facilities with shorter median hospital LOS for their patients have higher odds of readmission, particularly in the United States, where there is greater pressure to shorten LOS. The determinants and consequences of practices related to hospital LOS for hemodialysis patients should be further studied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73641/1/j.1492-7535.2004.01107.x.pd

Assessment of Objectively Measured Physical Activity Levels in Individuals with Intellectual Disabilities with and without Down's Syndrome

Objective: To investigate, using accelerometers, the levels of physical activity being undertaken by individuals with intellectual disabilities with and without Down’s syndrome. Methods: One hundred and fifty two individuals with intellectual disabilities aged 12–70 years from East and South-East England. Physical activity levels in counts per minute (counts/min), steps per day (steps/day), and minutes of sedentary, light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) measured with a uni-axial accelerometer (Actigraph GT1M) for seven days. Results: No individuals with intellectual disabilities met current physical activity recommendations. Males were more active than females. There was a trend for physical activity to decline and sedentary behaviour to increase with age, and for those with more severe levels of intellectual disability to be more sedentary and less physically active, however any relationship was not significant when adjusted for confounding variables. Participants with Down’s syndrome engaged in significantly less physical activity than those with intellectual disabilities without Down’s syndrome and levels of activity declined significantly with age. Conclusions: Individuals with intellectual disabilities, especially those with Down’s syndrome may be at risk of developing diseases associated with physical inactivity. There is a need for well-designed, accessible, preventive health promotio

The Lipid lowering and Onset of Renal Disease (LORD) Trial: A randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease

Background: There is evidence that dyslipidemia is associated with chronic kidney disease (CKD). Experimental studies have established that lipids are damaging to the kidney and animal intervention studies show statins attenuate this damage. Small clinical trials, meta-analyses, observational studies and post-hoc analyses of cardiovascular intervention studies all support the concept that statins can reduce kidney damage in humans. Based on this background, a double blind randomized placebo controlled trial was designed to assess the effectiveness of atorvastatin 10 mg on slowing the progression of kidney disease in a population of patients with CKD

Nutritional correlates of koala persistence in a low-density population

It is widely postulated that nutritional factors drive bottom-up, resource-based patterns in herbivore ecology and distribution. There is, however, much controversy over the roles of different plant constituents and how these influence individual herbivores and herbivore populations. The density of koala (Phascolarctos cinereus) populations varies widely and many attribute population trends to variation in the nutritional quality of the eucalypt leaves of their diet, but there is little evidence to support this hypothesis. We used a nested design that involved sampling of trees at two spatial scales to investigate how leaf chemistry influences free-living koalas from a low-density population in south east New South Wales, Australia. Using koala faecal pellets as a proxy for koala visitation to trees, we found an interaction between toxins and nutrients in leaves at a small spatial scale, whereby koalas preferred trees with leaves of higher concentrations of available nitrogen but lower concentrations of sideroxylonals (secondary metabolites found exclusively in eucalypts) compared to neighbouring trees of the same species. We argue that taxonomic and phenotypic diversity is likely to be important when foraging in habitats of low nutritional quality in providing diet choice to tradeoff nutrients and toxins and minimise movement costs. Our findings suggest that immediate nutritional concerns are an important priority of folivores in low-quality habitats and imply that nutritional limitations play an important role in constraining folivore populations. We show that, with a careful experimental design, it is possible to make inferences about populations of herbivores that exist at extremely low densities and thus achieve a better understanding about how plant composition influences herbivore ecology and persistence.IW and WF received a grant from New South Wales (NSW) Department of Environment, Climate Change & Water