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1.  Spending of HIV resources in Asia and Eastern Europe: systematic review reveals the need to shift funding allocations towards priority populations 
Introduction
It is increasingly important to prioritize the most cost-effective HIV interventions. We sought to summarize the evidence on which types of interventions provide the best value for money in regions with concentrated HIV epidemics.
Methods
We conducted a systematic review of peer-reviewed and grey literature reporting measurements of cost-effectiveness or cost-benefit for HIV/AIDS interventions in Asia and Eastern Europe. We also collated HIV/AIDS spending assessment data from case-study countries in the region.
Results
We identified 91 studies for inclusion, 47 of which were from peer-reviewed journals. Generally, in concentrated settings, prevention of mother-to-child transmission programmes and prevention programmes targeting people who inject drugs and sex workers had lower incremental cost-effectiveness ratios than programmes aimed at the general population. The few studies evaluating programmes targeting men who have sex with men indicate moderate cost-effectiveness. Collation of prevention programme spending data from 12 countries in the region (none of which had generalized epidemics) indicated that resources for the general population/non-targeted was greater than 30% for eight countries and greater than 50% for five countries.
Conclusions
There is a misalignment between national spending on HIV/AIDS responses and the most affected populations across the region. In concentrated epidemics, scarce funding should be directed more towards most-at-risk populations. Reaching consensus on general principles of cost-effectiveness of programmes by epidemic settings is difficult due to inconsistent evaluation approaches. Adopting a standard costing, impact evaluation, benefits calculation, analysis and reporting framework would enable cross comparisons and improve HIV resource prioritization and allocation.
doi:10.7448/IAS.17.1.18822
PMCID: PMC3936108  PMID: 24572053
HIV; cost-benefit analyses; programme evaluation; systematic review; concentrated epidemics; Asia; Eastern Europe; cost-effectiveness
2.  HIV Treatment as Prevention: Principles of Good HIV Epidemiology Modelling for Public Health Decision-Making in All Modes of Prevention and Evaluation 
PLoS Medicine  2012;9(7):e1001239.
Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection “Investigating the Impact of Treatment on New HIV Infections”—which focuses on the contribution of modelling to current issues in HIV prevention—we present here principles of “best practice” for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.
doi:10.1371/journal.pmed.1001239
PMCID: PMC3393657  PMID: 22802729
3.  Evolving the future: Toward a science of intentional change 
The Behavioral and brain sciences  2014;37(4):395-416.
Humans possess great capacity for behavioral and cultural change, but our ability to manage change is still limited. This article has two major objectives: first, to sketch a basic science of intentional change centered on evolution; second, to provide examples of intentional behavioral and cultural change from the applied behavioral sciences, which are largely unknown to the basic sciences community.
All species have evolved mechanisms of phenotypic plasticity that enable them to respond adaptively to their environments. Some mechanisms of phenotypic plasticity count as evolutionary processes in their own right. The human capacity for symbolic thought provides an inheritance system having the same kind of combinatorial diversity as does genetic recombination and antibody formation. Taking these propositions seriously allows an integration of major traditions within the basic behavioral sciences, such as behaviorism, social constructivism, social psychology, cognitive psychology, and evolutionary psychology, which are often isolated and even conceptualized as opposed to one another.
The applied behavioral sciences include well-validated examples of successfully managing behavioral and cultural change at scales ranging from individuals to small groups to large populations. However, these examples are largely unknown beyond their disciplinary boundaries, for lack of a unifying theoretical framework. Viewed from an evolutionary perspective, they are examples of managing evolved mechanisms of phenotypic plasticity, including open-ended processes of variation and selection.
Once the many branches of the basic and applied behavioral sciences become conceptually unified, we are closer to a science of intentional change than one might think.
doi:10.1017/S0140525X13001593
PMCID: PMC4331065  PMID: 24826907
acceptance and commitment therapy; applied behavioral sciences; cultural evolution; evolution; evolutionary psychology; prevention science; standard social science model
4.  Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo 
NeuroImage  2014;102(0 2):809-816.
Dystrophin, the main component of the dystrophin–glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood–brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38± 0.30 × 10−4mm2/s) and 10-month-old (6.93 ± 0.53 × 10−4 mm2/s) mdx mice as compared to WT (8.49±0.24×10−4, 8.24±0.25× 10−4mm2/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.
doi:10.1016/j.neuroimage.2014.08.053
PMCID: PMC4320943  PMID: 25213753
dystrophin; perfusion; diffusion; cryoimaging
5.  Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival 
The Journal of Experimental Medicine  2014;211(8):1525-1531.
Gata6 regulates differentiation, metabolism and survival of peritoneal macrophages.
The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6flox/flox mice to tackle this issue. In Lyz2-Cre x Gata6flox/flox mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages.
doi:10.1084/jem.20140570
PMCID: PMC4113942  PMID: 25024137
6.  Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta†‡ 
Biochemistry  2006;45(13):4045-4057.
Juvenile hormone (JH) is an insect hormone containing an α,β unsaturated ester consisting of a small alcohol and long, hydrophobic acid. JH degradation is required for proper insect development. One pathway of this degradation is through juvenile hormone esterase (JHE), which cleaves the JH ester bond to produce methanol and JH acid. JHE is a member of the functionally divergent α/β-hydrolase family of enzymes, and is a highly efficient enzyme that cleaves JH at very low in vivo concentrations. We present here a 2.7 Å crystal structure of JHE from the tobacco hornworm Manduca sexta (MsJHE) in complex with the transition state analog inhibitor 3-octylthio-1,1,1-trifluoropropan-2-one (OTFP) covalently bound to the active site. This crystal structure, the first JHE structure reported, contains a long, hydrophobic binding pocket with the solvent inaccessible catalytic triad located at the end. The structure explains many of the interactions observed between JHE and its substrates and inhibitors, such as the preference for small alcohol groups and long hydrophobic backbones. The most potent JHE inhibitors identified to date contain a trifluoromethyl ketone (TFK) moiety and have a sulfur atom beta to the ketone. In this study, sulfur-aromatic interactions were observed between the sulfur atom of OTFP and a conserved aromatic residue in the crystal structure. Mutational analysis supported the hypothesis that these interactions contribute to the potency of sulfur-containing TFK inhibitors. Together these results clarify the binding mechanism of JHE inhibitors and provide useful observations for the development of additional enzyme inhibitors for a variety of enzymes.
doi:10.1021/bi0521644
PMCID: PMC4275126  PMID: 16566578
carboxylesterase; juvenile hormone esterase; trifluoromethyl ketone; crystal structure; inhibitor
7.  CSB interacts with SNM1A and promotes DNA interstrand crosslink processing 
Nucleic Acids Research  2014;43(1):247-258.
Cockayne syndrome (CS) is a premature aging disorder characterized by photosensitivity, impaired development and multisystem progressive degeneration, and consists of two strict complementation groups, A and B. Using a yeast two-hybrid approach, we identified the 5′-3′ exonuclease SNM1A as one of four strong interacting partners of CSB. This direct interaction was confirmed using purified recombinant proteins—with CSB able to modulate the exonuclease activity of SNM1A on oligonucleotide substrates in vitro—and the two proteins were shown to exist in a common complex in human cell extracts. CSB and SNM1A were also found, using fluorescently tagged proteins in combination with confocal microscopy and laser microirradiation, to be recruited to localized trioxsalen-induced ICL damage in human cells, with accumulation being suppressed by transcription inhibition. Moreover, SNM1A recruitment was significantly reduced in CSB-deficient cells, suggesting coordination between the two proteins in vivo. CSB-deficient neural cells exhibited increased sensitivity to DNA crosslinking agents, particularly, in a non-cycling, differentiated state, as well as delayed ICL processing as revealed by a modified Comet assay and γ-H2AX foci persistence. The results indicate that CSB coordinates the resolution of ICLs, possibly in a transcription-associated repair mechanism involving SNM1A, and that defects in the process could contribute to the post-mitotic degenerative pathologies associated with CS.
doi:10.1093/nar/gku1279
PMCID: PMC4288174  PMID: 25505141
8.  Intradural vertebral endarterectomy with nonautologous patch angioplasty for refractory vertebrobasilar ischemia: Case report and literature review 
Background:
The natural history of patients with symptomatic vertebrobasilar ischemic symptoms due to chronic bilateral vertebral artery occlusive disease is progressive, and poses significant challenges when refractory to medical therapy. Surgical treatment options depend largely on location and characteristics of the atheroma (s), and generally include percutaneous transluminal angioplasty (PTA) with or without stent placement, posterior circulation revascularization (bypass), extracranial vertebral artery reconstruction, or vertebral artery endarterectomy.
Case Description:
We present the case of a 56-year-old male with progressive vertebrobasilar ischemia due to tandem lesions in the right vertebral artery at the origin and intracranially in the V4 segment. The contralateral vertebral artery was occluded to the level of posterior inferior cerebellar artery (PICA) and posterior communicating arteries were absent. Following PTA and stent placement at the right vertebral artery origin, the patient was successfully treated with intradural vertebral artery endarterectomy (V4EA) and patch angioplasty via the far lateral approach. Distal endovascular intervention at the V4 segment proved not technically feasible after multiple attempts.
Conclusions:
V4EA is an uncommonly performed procedure, but may be considered for carefully selected patients. The authors’ techniques and indications are discussed. Historical outcomes, relevant anatomic considerations, and lessons learned are reviewed from the literature.
doi:10.4103/2152-7806.145927
PMCID: PMC4278098  PMID: 25558424
Endarterectomy; patch angioplasty; vertebral stenosis; vertebrobasilar ischemia
9.  Embracing different approaches to estimating HIV incidence, prevalence and mortality 
AIDS (London, England)  2014;28(4):S523-S532.
Background:
Joint United Nations Programme on HIV/AIDS (UNAIDS) and Murray et al. have both produced sets of estimates for worldwide HIV incidence, prevalence and mortality. Understanding differences in these estimates can strengthen the interpretation of each.
Methods:
We describe differences in the two sets of estimates. Where possible, we have drawn on additional published data to which estimates can be compared.
Findings:
UNAIDS estimates that there were 6 million more people living with HIV (PLHIV) in 2013 (35 million) compared with the Murray et al. estimates (29 million). Murray et al. estimate that new infections and AIDS deaths have declined more gradually than does UNAIDS. Just under one third of the difference in PLHIV is in Africa, where Murray et al. have relied more on estimates of adult mortality trends than on data on survival times. Another third of the difference is in North America, Europe, Central Asia and Australasia. Here Murray et al. estimates of new infections are substantially lower than the number of new HIV/AIDS diagnoses reported by countries, whereas published UNAIDS estimate tend to be greater. The remaining differences are in Latin America and Asia where the data upon which the UNAIDS methods currently rely are more sparse, whereas the mortality data leveraged by Murray et al. may be stronger. In this region, however, anomalies appear to exist between the both sets of estimates and other data.
Interpretation:
Both estimates indicate that approximately 30 million PLHIV and that antiretroviral therapy has driven large reductions in mortality. Both estimates are useful but show instructive discrepancies with additional data sources. We find little evidence to suggest that either set of estimates can be considered systematically more accurate. Further work should seek to build estimates on as wide a base of data as possible.
doi:10.1097/QAD.0000000000000488
PMCID: PMC4247269  PMID: 25406755
HIV estimates; incidence prevalence; mortality UNAIDS
10.  Diagnosis and management of venereal campylobacteriosis in beef cattle 
BMC Veterinary Research  2014;10(1):280.
Background
Bovine venereal campylobacteriosis is caused by Campylobacter fetus subsp. venerealis and its glycerine-tolerant variant Campylobacter fetus subsp. venerealis biovars intermedius. The disease can be economically important when present in cattle herds, causing poor reproductive performance, embryo mortality and abortion. Sensitive and specific diagnostic tests are required in the diagnosis of infection and to inform and monitor disease control. Current tests include bacterial culture and fluorescent antibody testing of preputial sheath washings and an enzyme-linked immunosorbent assay and an agglutination test on vaginal mucus, although the predictive values of these tests can be inadequate in field investigations.
Artificial insemination is often considered as a simple control method for bovine venereal campylobacteriosis, but is impractical for many beef suckler herds where breeding takes place at pasture. Commercial vaccines are unavailable in the UK, while the efficacy of autogenous vaccines using a bacterial isolate from infected animals on a specific farm is at best unproven. Hence, for some infected herds, the development of an alternative control strategy based on segregation of potentially infected and uninfected animals in combination with culling or treatment would be desirable. This approach requires meticulous records and herd health management.
Case presentation
In this paper we highlight difficulties in diagnosing bovine venereal campylobacteriosis and demonstrate the benefits of good record keeping when investigating poor reproductive performance in a beef suckler herd and establishing a herd-specific approach to bio-containment of the infectious cause.
Conclusions
Bovine venereal campylobacteriosis is an economically important disease that should be considered in investigations of suckler herd subfertility problems. Control of the disease based on segregation of potentially infected and uninfected animals in combination with extensive culling can be achieved without the use of artificial insemination or vaccination, but requires meticulous records and strict adherence to herd biosecurity practices.
doi:10.1186/s12917-014-0280-x
PMCID: PMC4255422  PMID: 25428802
Beef cattle; Campylobacteriosis; Venereal; Bull; Reproduction
11.  The intermediate filament protein vimentin is a regulator of NOD2 activity 
Gut  2012;62(5):695-707.
Objective
Mutations in nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) remain the strongest genetic determinants for Crohn’s disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, we aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim to CD susceptibility.
Design
Co-immunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or NOD2-frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor Withaferin-A (WFA) to assess effects on NOD2 function using nuclear factor-kappaB (NF-κB) reporter gene, GFP-LC3-based autophagy, and bacterial gentamicin protection assays. International GWAS meta-analysis data were used to test for association of SNPs in Vim to CD susceptibility.
Results
The leucine rich repeat (LRR) domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin co-localised at the cell plasma membrane and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation, MDP-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive strain E.coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim.
Conclusion
Vimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. Additionally, Vim is a candidate susceptibility gene for CD, supporting the functional data.
doi:10.1136/gutjnl-2011-301775
PMCID: PMC4225453  PMID: 22684479
inflammatory bowel disease; Crohn’s disease; NOD2; vimentin; E.coli; autophagy; genetic association studies
13.  Dodecafluoropentane Emulsion Elicits Cardiac Protection Against Myocardial Infarction Through an ATP-Sensitive K+ Channel Dependent Mechanism 
Purpose
Dodecafluoropentane emulsion (DDFPe) is a perfluorocarbon with high oxygen dissolving, transport, and delivery capacity that may offer the potential to limit ischemic injury prior to clinical reperfusion. Here we investigated the cardiac protective potential of DDFPe in a mouse model of myocardial infarction.
Methods
Myocardial infarction was initiated by permanent ligation of the left anterior descending (LAD) coronary artery. Mice were administered vehicle or 5-hydroxydecanoate (5-HD) intravenously 10 min before LAD occlusion followed by a single intravenous administration of vehicle or DDFPe immediately after occlusion. Heart tissue and serum samples were collected 24 after LAD occlusion for measurement of infarct size and cardiac troponin I (cTnI) levels, respectively.
Results
DDFPe treatment reduced infarct size by approximately 72 % (36.9 ± 4.2 % for vehicle vs 10.4 ± 2.3 % for DDFPe; p < 0.01; n = 6–8) at 24 h. Serum cTnI levels were similarly reduced by DDFPe (35.0 ± 4.6 ng/ml for vehicle vs 15.8 ± 1.6 ng/ml for DDFPe; p < 0.01; n = 6–8). Pretreatment with 5-HD, a mitochondrial ATP-sensitive potassium channel (mitoKATP) inhibitor, blocked the reduction in infarct size (29.2 ± 4.4 % for 5-HD vs 35.4 ± 7.4 % for 5-HD+DDFPe; p = 0.48; n = 6–8) and serum cTnI levels (27.4 ± 5.1 ng/ml for 5-HD vs 34.6 ± 5.3 ng/ml for 5-HD+DDFPe; p = 0.86; n = 6–8) by DDFPe.
Conclusion
Our data indicate a cardiac protective role of DDFPe that persists beyond its retention time in the body and is dependent on mitoKATP, an important mediator of ischemic preconditioning induced cardiac protection.
doi:10.1007/s10557-014-6557-2
PMCID: PMC4260113  PMID: 25319313
Myocardial infarction; Perfluorocarbons; Dodecafluoropentane
14.  CSF and Plasma Amyloid-β Temporal Profiles and Relationships with Neurological Status and Mortality after Severe Traumatic Brain Injury 
Scientific Reports  2014;4:6446.
The role of amyloid-β (Aβ) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-β1-42 (Aβ42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Aβ42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma Aβ42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma Aβ42 levels strongly correlated with mortality. A positive correlation between changes in CSF Aβ42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Aβ42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury.
doi:10.1038/srep06446
PMCID: PMC4192636  PMID: 25300247
15.  IgG4 Immunostaining and Its Implications in Orbital Inflammatory Disease 
PLoS ONE  2014;9(10):e109847.
Objective
IgG4-related disease is an emerging clinical entity which frequently involves tissue within the orbit. In order to appreciate the implications of IgG4 immunostaining, we analyzed gene expression and the prevalence of IgG4- immunostaining among subjects with orbital inflammatory diseases.
Methods
We organized an international consortium to collect orbital biopsies from 108 subjects including 22 with no known orbital disease, 42 with nonspecific orbital inflammatory disease (NSOI), 26 with thyroid eye disease (TED), 12 with sarcoidosis, and 6 with granulomatosis with polyangiitis (GPA). Lacrimal gland and orbital adipose tissue biopsies were immunostained for IgG4 or IgG secreting plasma cells. RNA transcripts were quantified by Affymetrix arrays.
Results
None of the healthy controls or subjects with TED had substantial IgG4 staining. Among the 63 others, the prevalence of significant IgG4-immunostaining ranged from 11 to 39% depending on the definition for significant. IgG4 staining was detectable in the majority of tissues from subjects with GPA and less commonly in tissue from subjects with sarcoidosis or NSOI. The detection of IgG4+ cells correlated with inflammation in the lacrimal gland based on histology. IgG4 staining tissue expressed an increase in transcripts associated with inflammation, especially B cell-related genes. Functional annotation analysis confirmed this.
Conclusion
IgG4+ plasma cells are common in orbital tissue from patients with sarcoidosis, GPA, or NSOI. Even using the low threshold of 10 IgG4+ cells/high powered field, IgG4 staining correlates with increased inflammation in the lacrimal gland based on histology and gene expression.
doi:10.1371/journal.pone.0109847
PMCID: PMC4193851  PMID: 25303270
16.  Base Excision Repair in the Mammalian Brain: Implication for Age related Neurodegeneration 
Mechanisms of ageing and development  2013;134(10):10.1016/j.mad.2013.04.005.
The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base Excision Repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase β in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer’s.
doi:10.1016/j.mad.2013.04.005
PMCID: PMC3834072  PMID: 23643943
BER; Neurodegeneration; DNA repair; Aging
17.  A two-parameter kinetic model based on a time-dependent activity coefficient accurately describes enzymatic cellulose digestion 
Biochemistry  2013;52(33):5656-5664.
Lignocellulosic biomass is a potential source of renewable, low-carbon-footprint liquid fuels. Biomass recalcitrance and enzyme cost are key challenges associated with the large-scale production of cellulosic fuel. Kinetic modeling of enzymatic cellulose digestion has been complicated by the heterogeneous nature of the substrate and by the fact that a true steady state cannot be attained. We present a two-parameter kinetic model based on the Michaelis-Menten scheme (Michaelis L and Menten ML. (1913) Biochem Z 49:333–369), but with a time-dependent activity coefficient analogous to fractal-like kinetics formulated by Kopelman (Kopelman R. (1988) Science 241:1620–1626). We provide a mathematical derivation and experimental support to show that one of the parameters is a total activity coefficient and the other is an intrinsic constant that reflects the ability of the cellulases to overcome substrate recalcitrance. The model is applicable to individual cellulases and their mixtures at low-to-medium enzyme loads. Using biomass degrading enzymes from a cellulolytic bacterium Thermobifida fusca we show that the model can be used for mechanistic studies of enzymatic cellulose digestion. We also demonstrate that it applies to the crude supernatant of the widely studied cellulolytic fungus Trichoderma reesei and can thus be used to compare cellulases from different organisms. The two parameters may serve a similar role to Vmax, KM, and kcat in classical kinetics. A similar approach may be applicable to other enzymes with heterogeneous substrates and where a steady state is not achievable.
doi:10.1021/bi400358v
PMCID: PMC4089187  PMID: 23837567
18.  Impact of Male Circumcision on the HIV Epidemic in Papua New Guinea: A Country with Extensive Foreskin Cutting Practices 
PLoS ONE  2014;9(8):e104531.
The degree to which adult medical male circumcision (MC) programs can reduce new HIV infections in a moderate HIV prevalence country like Papua New Guinea (PNG) are uncertain especially given the widespread prevalence of longitudinal foreskin cuts among adult males. We estimated the likely impact of a medical MC intervention in PNG using a mathematical model of HIV transmission. The model was age-structured and incorporated separate components for sex, rural/urban, men who have sex with men and female sex workers. Country-specific data of the prevalence of foreskin cuts, sexually transmitted infections, condom usage, and the acceptability of MC were obtained by our group through related studies. If longitudinal foreskin cutting has a protective efficacy of 20% compared to 60% for MC, then providing MC to 20% of uncut males from 2012 would require 376,000 procedures, avert 7,900 HIV infections by 2032, and require 143 MC per averted infection. Targeting uncut urban youths would achieve the most cost effective returns of 54 MC per HIV infection averted. These numbers of MC required to avert an HIV infection change little even with coverage up to 80% of men. The greater the protective efficacy of longitudinal foreskin cuts against HIV acquisition, the less impact MC interventions will have. Dependent on this efficacy, increasing condom use could have a much greater impact with a 10 percentage point increase averting 18,400 infections over this same period. MC programs could be effective in reducing HIV infections in PNG, particularly in high prevalence populations. However the overall impact is highly dependent on the protective efficacy of existing longitudinal foreskin cutting in preventing HIV.
doi:10.1371/journal.pone.0104531
PMCID: PMC4128698  PMID: 25111058
19.  Access to antiretroviral therapy and survival in eastern Europe and central Asia: a case study in Armenia 
Introduction
Antiretroviral therapy (ART) substantially improves the health of people living with HIV and contributes to preventing new infections. While HIV incidence is decreasing in most regions, the epidemic in eastern Europe continues to rise, as new infections currently outnumber the rate of ART initiation. In this study, we assess ART use in Armenia and its impact on the number of AIDS diagnoses and mortality.
Methods
National surveillance data were obtained from the National Centre for AIDS Prevention, Armenia. Cox-proportional hazard models were used to determine the effect of demographic and clinical risk factors, including access to ART, on AIDS and mortality.
Results
Among people diagnosed with HIV since 2005, approximately 40% per year were diagnosed with CD4<200 cells per mL. Overall, 232 people (57.1%) with AIDS or a low CD4 count had not received ART by the end of 2010. Mortality was 34.1% among people living with HIV who did not initiate ART, and 0.3% among people who received ART. Among people diagnosed with HIV from 1996 to 2010, age at diagnosis, no use of ART, likely mode of transmission, likely place of transmission, low baseline CD4 count and no STI diagnosis at last contact are significantly associated with death.
Discussion
In Armenia, HIV is frequently diagnosed at a late stage of disease, indicating low testing rates. Of people diagnosed with HIV and in need of ART, a large proportion (approximately 60%) either do not provide consent for treatment, or are who migrants who cannot be located.
Conclusions
Globally, the scale-up of ART has resulted in substantial reductions in mortality among individuals initiating therapy. However, in an era of momentum for treatment as prevention, treatment levels are not at adequate levels for preventing morbidities and mortality in some settings. Particular focus should be placed on key at-risk subgroups.
doi:10.7448/IAS.17.1.18795
PMCID: PMC4122815  PMID: 25095830
AIDS; survival; treatment; Europe
20.  DNA repair mechanisms in dividing and non-dividing cells 
DNA repair  2013;12(8):620-636.
DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye towards how these pathways may regulate the development of neurological disease.
doi:10.1016/j.dnarep.2013.04.015
PMCID: PMC3720834  PMID: 23684800
DNA repair; Neural cells; Neurological disorder; Dividing and non-dividing; Endogenous DNA damage
21.  Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors – association to carcinoma aggressiveness 
Pathology, research and practice  2013;209(8):503-509.
Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples. Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR.
Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome.
We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHAas a tumor suppressor in humans.
doi:10.1016/j.prp.2013.06.002
PMCID: PMC3777642  PMID: 23866946
adenoma; carcinoma; inhibin; signaling pathway; transcription factor
22.  Validation of a blood protein signature for non-small cell lung cancer 
Clinical Proteomics  2014;11(1):32.
Background
CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations.
Results
Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation.
Conclusions
Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
doi:10.1186/1559-0275-11-32
PMCID: PMC4123246  PMID: 25114662
Lung cancer; Biomarker; SOMAmer; Proteomic; Squamous cell carcinoma; Diagnosis; Preanalytic variability; Sample bias
23.  Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins 
Molecular Biology of the Cell  2014;25(10):1641-1652.
NPM1 is a novel modulator of the BER pathway. NPM1 depletion results in BER protein up-regulation; NPM1 has a stimulatory effect on BER capacity and promotes accumulation of BER proteins within nucleoli. Cisplatin leads to redistribution of NPM1 and BER proteins from nucleoli.
Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis.
doi:10.1091/mbc.E13-12-0717
PMCID: PMC4019495  PMID: 24648491
24.  Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models 
The lancet global health  2013;2(1):23-34.
Background
New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly.
Methods
We used multiple independent mathematical models in four settings—South Africa, Zambia, India, and Vietnam—to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered ‘very cost-effective’ if the $/DALY was less than the country’s per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and ‘cost-effective’ if $/DALY was less than three times per capita GDP.
Findings
In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective.
Interpretation
Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets.
Funding
The Bill and Melinda Gates Foundation and World Health Organization
doi:10.1016/S2214-109X(13)70172-4
PMCID: PMC4114402  PMID: 25083415
25.  Cellulase Processivity 
There are two types of processive cellulases, exocellulases and processive endoglucanases. There are also two classes of exocellulases, ones that attack the reducing ends of cellulose chains and ones that attack the nonreducing ends. There are a number of ways of assaying processivity but none of them are ideal. It appears that exocellulases, all of which have their active sites in a tunnel, couple movement along a cellulose chain with cleavage of cellobiose from the end of the cellulose molecule. There are two sets of structures that suggest how an exocellulase might move along a cellulose chain. For family 48 exocellulases there are two different ways that a chain can be bound in the active site while for family 6 exocellulases there are several different ligand-bound structures. Site-directed mutagenesis of Thermobifida fusca exocellulases Cel48A and Cel6B and the processive endoglucanase Cel9A have identified some mutations that increase processivity and some that decrease processivity. In addition a mutation in Cel6B was identified that appears to allow the mutant enzyme to move along a cellulose chain in the absence of cleavage.
doi:10.1007/978-1-61779-956-3_9
PMCID: PMC4086159  PMID: 22843392
Cellulose; Cellulase processivity; Exocellulases; Processive endoglucanases; Thermobifida fusca

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