Mutation in Osteoactivin Promotes Receptor Activator of NFκB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function

We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb⁺). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of CTX-1. Contrary to these observations and counterintuitively, temporal gene expression analyses supported up-regulated osteoclastogenesis in D2J mice and increased osteoclast differentiation rates ex vivo, marked by increased number and size. The finding that MAPK was activated in early differentiating and mature D2J osteoclasts and that survival of D2J osteoclasts was enhanced and mediated by activation of the AKT-GSK3β pathway supports this observation. Furthermore, this was abrogated by the addition of recombinant OA to cultures, which restored osteoclastogenesis to wild-type levels. Moreover, mix and match co-cultures demonstrated an induction of osteoclastogenesis in D2J osteoblasts co-cultured with osteoclasts of D2J or wild-type. Last, in functional osteo-assays, we show that bone resorption activity of D2J osteoclasts is dramatically reduced, and these osteoclasts present an abnormal ruffled border over the bone surface. Collectively, these data support a model whereby OA/Gpnmb acts as a negative regulator of osteoclast differentiation and survival but not function by inhibiting the ERK/AKT signaling pathways.     

On optimal Bayesian classification and risk estimation under multiple classes

A recently proposed optimal Bayesian classification paradigm addresses optimal error rate analysis for small-sample discrimination, including optimal classifiers, optimal error estimators, and error estimation analysis tools with respect to the probability of misclassification under binary classes. Here, we address multi-class problems and optimal expected risk with respect to a given risk function, which are common settings in bioinformatics. We present Bayesian risk estimators (BRE) under arbitrary classifiers, the mean-square error (MSE) of arbitrary risk estimators under arbitrary classifiers, and optimal Bayesian risk classifiers (OBRC). We provide analytic expressions for these tools under several discrete and Gaussian models and present a new methodology to approximate the BRE and MSE when analytic expressions are not available. Of particular note, we present analytic forms for the MSE under Gaussian models with homoscedastic covariances, which are new even in binary classification.     

Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012

Background

Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated.

Methods

We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital.

Findings

We estimated that 3709 million people (range: 3440–3878 million) aged 0–49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67–212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific.

Conclusions

The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection.     

Impact and Cost of the HIV/AIDS National Strategic Plan for Mozambique, 2015-2019—Projections with the Spectrum/Goals Model

Introduction

Mozambique continues to face a severe HIV epidemic and high cost for its control, largely born by international donors. We assessed feasible targets, likely impact and costs for the 2015–2019 national strategic HIV/AIDS plan (NSP).

Methods

The HIV epidemic and response was modelled in the Spectrum/Goals/Resource Needs dynamical simulation model, separately for North/Center/South regions, fitted to antenatal clinic surveillance data, household and key risk group surveys, program statistics, and financial records. Intervention targets were defined in collaboration with the National AIDS Council, Ministry of Health, technical partners and implementing NGOs, considering existing commitments.

Results

Implementing the NSP to meet existing coverage targets would reduce annual new infections among all ages from 105,000 in 2014 to 78,000 in 2019, and reduce annual HIV/AIDS-related deaths from 80,000 to 56,000. Additional scale-up of prevention interventions targeting high-risk groups, with improved patient retention on ART, could further reduce burden to 65,000 new infections and 51,000 HIV-related deaths in 2019. Program cost would increase from US$ 273 million in 2014, to US$ 433 million in 2019 for ‘Current targets’, or US$ 495 million in 2019 for ‘Accelerated scale-up’. The ‘Accelerated scale-up’ would lower cost per infection averted, due to an enhanced focus on behavioural prevention for high-risk groups. Cost and mortality impact are driven by ART, which accounts for 53% of resource needs in 2019. Infections averted are driven by scale-up of interventions targeting sex work (North, rising epidemic) and voluntary male circumcision (Center & South, generalized epidemics).

Conclusion

The NSP could aim to reduce annual new HIV infections and deaths by 2019 by 30% and 40%, respectively, from 2014 levels. Achieving incidence and mortality reductions corresponding to UNAIDS’ ‘Fast track’ targets will require increased ART coverage and additional behavioural prevention targeting key risk groups.     

Unexpected Dual Task Benefits on Cycling in Parkinson Disease and Healthy Adults: A Neuro-Behavioral Model

BackgroundWhen performing two tasks at once, a dual task, performance on one or both tasks typically suffers. People with Parkinson’s disease (PD) usually experience larger dual task decrements on motor tasks than healthy older adults (HOA). Our objective was to investigate the decrements in cycling caused by performing cognitive tasks with a range of difficulty in people with PD and HOAs.MethodsTwenty-eight participants with Parkinson’s disease and 20 healthy older adults completed a baseline cycling task with no secondary tasks and then completed dual task cycling while performing 12 tasks from six cognitive domains representing a wide range of difficulty.ResultsCycling was faster during dual task conditions than at baseline, and was significantly faster for six tasks (all p<.02) across both groups. Cycling speed improved the most during the easiest cognitive tasks, and cognitive performance was largely unaffected. Cycling improvement was predicted by task difficulty (p<.001). People with Parkinson’s disease cycled slower (p<.03) and showed reduced dual task benefits (p<.01) than healthy older adults.ConclusionsUnexpectedly, participants’ motor performance improved during cognitive dual tasks, which cannot be explained in current models of dual task performance. To account for these findings, we propose a model integrating dual task and acute exercise approaches which posits that cognitive arousal during dual tasks increases resources to facilitate motor and cognitive performance, which is subsequently modulated by motor and cognitive task difficulty. This model can explain both the improvement observed on dual tasks in the current study and more typical dual task findings in other studies.     

Development and Validation of a Novel Platform-Independent Metastasis Signature in Human Breast Cancer

PurposeThe molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer.ResultsWe identified a broad range of metastatic potential that was independent of intrinsic breast cancer subtypes. 146 genes were significantly associated with metastasis progression and were linked to cancer-related biological functions, including cell migration/adhesion, Jak-STAT, TGF-beta, and Wnt signaling. These genes were used to develop a platform-independent gene expression signature (M-Sig), which was trained and subsequently validated on 5 independent cohorts totaling nearly 1800 breast cancer patients with all p-values < 0.005 and hazard ratios ranging from approximately 2.5 to 3. On multivariate analysis accounting for standard clinicopathologic prognostic variables, M-Sig remained the strongest prognostic factor for metastatic progression, with p-values < 0.001 and hazard ratios > 2 in three different cohorts.ConclusionM-Sig is strongly prognostic for metastatic progression, and may provide clinical utility in combination with treatment prediction tools to better guide patient care. In addition, the platform-independent nature of the signature makes it an excellent research tool as it can be directly applied onto existing, and future, datasets.     

Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light

The veA gene is a light-dependent regulator governing development and secondary metabolism in Aspergillus nidulans. We have identified a putative bipartite nuclear localization signal (NLS) motif in the A. nidulans VeA amino acid sequence and demonstrated its functionality when expressed in yeast. Furthermore, migration of VeA to the nucleus was dependent on the importin alpha. This bipartite NLS is also functional when VeA is expressed in A. nidulans. Interestingly, we found that VeA migration to the nucleus is light-dependent. While in the dark VeA is located mainly in the nuclei, under light VeA is found abundantly in the cytoplasm. The VeA1 mutant protein (lacking the first 36 amino acids at the N-terminus) was found predominantly in the cytoplasm independent of illumination. This indicates that the truncated bipartite NLS in VeA1 is not functional and fails to respond to light. These results might explain the lack of the morphological light-dependent response in strains carrying the veA1 allele. We also evaluated the effect of light on production of the mycotoxin sterigmatocystin in a veA wild-type and the veA1 mutant strains and found that the highest amount of toxin was produced by the veA+ strain growing in the dark, condition favouring accumulation of VeA in the nucleus.     

The discovery of carboline analogs as potent MAPKAP-K2 inhibitors

The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.