Predicting Hip Fracture Type With Cortical Bone Mapping (CBM) in the Osteoporotic Fractures in Men (MrOS) Study.

Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual-energy X-ray (DXA)-based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have subdivided fracture into types, because this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The Osteoporotic Fractures in Men (MrOS) study is a predictive case-cohort study of men over 65 years old: we analyze 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5994. To our knowledge, this is the largest QCT-based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We show that both cortical mass surface density and endocortical trabecular BMD are significantly different in fracture cases versus cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA-based BMD leads to a small but significant (p < 0.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave-one-out cross-validation. For specific fracture types, the improvement is more significant (p < 0.0001), with AUC increasing from 0.71 to 0.77 for trochanteric fractures and 0.76 to 0.82 for femoral neck fractures. In contrast, adding DXA-based BMD to a CBM-based predictive model does not result in any significant improvement.The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Ageing (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. GMT, AHG, DMB and KESP contributed to the conception and design of the study. All authors were involved in the analysis or interpretation of the data, contributed to the manuscript, and approved the final version. KESP acknowledges the support of the NIHR Biomedical Research Centre, Cambridge. KESP received funding from Arthritis Research UK (ARUK ref. no. 20109). GMT takes responsibility for the integrity of the data analysis.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/jbmr.255

Liquid-liquid critical point in supercooled silicon

A novel liquid-liquid phase transition has been proposed and investigated in a wide variety of pure substances recently, including water, silica and silicon. From computer simulations using the Stillinger-Weber classical empirical potential, Sastry and Angell [1] demonstrated a first order liquid-liquid transition in supercooled silicon, subsequently supported by experimental and simulation studies. Here, we report evidence for a liquid-liquid critical end point at negative pressures, from computer simulations using the SW potential. Compressibilities exhibit a growing maximum upon lowering temperature below 1500 K and isotherms exhibit density discontinuities below 1120 K, at negative pressure. Below 1120 K, isotherms obtained from constant volume-temperature simulations exhibit non-monotonic, van der Waals-like behavior signaling a first order transition. We identify Tc ~ 1120 +/- 12 K, Pc -0.60 +/- 0.15 GPa as the critical temperature and pressure for the liquid-liquid critical point. The structure of the liquid changes dramatically upon decreasing the temperature and pressure. Diffusivities vary over 4 orders of magnitude, and exhibit anomalous pressure dependence near the critical point. A strong relationship between local geometry quantified by the coordination number, and diffusivity, is seen, suggesting that atomic mobility in both low and high density liquids can usefully be analyzed in terms of defects in the tetrahedral network structure. We have constructed the phase diagram of supercooled silicon. We identify the lines of compressibility, density extrema (maxima and minima) and the spinodal which reveal the interconnection between thermodynamic anomalies and the phase behaviour of the system as suggested in previous works [2-9]Comment: (to be published in revised form); small corrections to previous version; Nature Physics 201

Risk and Ethical Concerns of Hunting Male Elephant: Behavioural and Physiological Assays of the Remaining Elephants

BACKGROUND: Hunting of male African elephants may pose ethical and risk concerns, particularly given their status as a charismatic species of high touristic value, yet which are capable of both killing people and damaging infrastructure. METHODOLOGY/PRINCIPAL FINDINGS: We quantified the effect of hunts of male elephants on (1) risk of attack or damage (11 hunts), and (2) behavioural (movement dynamics) and physiological (stress hormone metabolite concentrations) responses (4 hunts) in Pilanesberg National Park. For eleven hunts, there were no subsequent attacks on people or infrastructure, and elephants did not break out of the fenced reserve. For three focal hunts, there was an initial flight response by bulls present at the hunting site, but their movements stabilised the day after the hunt event. Animals not present at the hunt (both bulls and herds) did not show movement responses. Physiologically, hunting elephant bulls increased faecal stress hormone levels (corticosterone metabolites) in both those bulls that were present at the hunts (for up to four days post-hunt) and in the broader bull and breeding herd population (for up to one month post-hunt). CONCLUSIONS/SIGNIFICANCE: As all responses were relatively minor, hunting male elephants is ethically acceptable when considering effects on the remaining elephant population; however bulls should be hunted when alone. Hunting is feasible in relatively small enclosed reserves without major risk of attack, damage, or breakout. Physiological stress assays were more effective than behavioural responses in detecting effects of human intervention. Similar studies should evaluate intervention consequences, inform and improve best practice, and should be widely applied by management agencies

Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance

10.1371/journal.pone.0076230PLOS ONE8101-1

The RNA Polymerase PB2 Subunit of Influenza A/HongKong/156/1997 (H5N1) Restrict the Replication of Reassortant Ribonucleoprotein Complexes

BACKGROUND: Genetic reassortment plays a critical role in the generation of pandemic strains of influenza virus. The influenza virus RNA polymerase, composed of PB1, PB2 and PA subunits, has been suggested to influence the efficiency of genetic reassortment. However, the role of the RNA polymerase in the genetic reassortment is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: Here, we reconstituted reassortant ribonucleoprotein (RNP) complexes, and demonstrated that the PB2 subunit of A/HongKong/156/1997 (H5N1) [HK PB2] dramatically reduced the synthesis of mRNA, cRNA and vRNA when introduced into the polymerase of other influenza strains of H1N1 or H3N2. The HK PB2 had no significant effect on the assembly of the polymerase trimeric complex, or on promoter binding activity or replication initiation activity in vitro. However, the HK PB2 was found to remarkably impair the accumulation of RNP. This impaired accumulation and activity of RNP was fully restored when four amino acids at position 108, 508, 524 and 627 of the HK PB2 were mutated. CONCLUSIONS/SIGNIFICANCE: Overall, we suggest that the PB2 subunit of influenza polymerase might play an important role for the replication of reassortant ribonucleoprotein complexes

Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells.

Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo

Detection and characterization of subvisible aggregates of monoclonal lgG in serum

To detect and characterize the aggregation of therapeutic monoclonal antibodies in undiluted biological fluids. Fluorescently labeled subvisible IgG aggregates formed by applying either heat stress or by pH-shift were investigated immediately after addition to human serum, and after 24 h. Unstressed and stressed IgG formulations were analyzed by fluorescence single particle tracking, confocal laser scanning microscopy and flow cytometry. Unstressed formulations remained free from subvisible aggregates in serum, whereas heat-stressed and pH-shift stressed formulations showed dissimilar aggregation behaviors. The aggregation profile of the heat-stressed formulation diluted in serum remained practically the same as the one diluted in buffer, even after the 24 h incubation period. The pH-shift stressed formulation had strikingly smaller and more numerous subvisible aggregates immediately after dilution in serum compared to buffer. These aggregates became noticeably larger in both diluents after 24 h, but in serum they appeared to be formed by other types of constituents than the labeled protein itself. These results show that subvisible therapeutic protein aggregates may undergo changes in number, type and size distribution upon contact with human serum. This emphasizes the importance of analytical strategies for monitoring aggregation in undiluted biological fluids

Derivation of High Purity Neuronal Progenitors from Human Embryonic Stem Cells

The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use