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1.  Testing the Vesicular Morphology to Destruction: Birth and Death of Diblock Copolymer Vesicles Prepared via Polymerization-Induced Self-Assembly 
Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepared by polymerization-induced self-assembly (PISA) using a reversible addition–fragmentation chain transfer (RAFT) aqueous dispersion polymerization formulation. A G55 chain transfer agent is utilized to prepare a series of G55-Hx diblock copolymers, where the mean degree of polymerization (DP) of the membrane-forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200–1000, while SAXS indicates a gradual reduction in mean aggregation number for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diameter between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calculation of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation number. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain constant. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water molecules into the vesicle membrane, as confirmed by SAXS analysis. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphology when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle “death”.
doi:10.1021/ja511423m
PMCID: PMC4333598  PMID: 25526525
2.  Impulsivity, Neural Deficits, and the Addictions: The “Oops” Factor in Relapse 
Journal of addictive diseases  2007;26(0 1):25-39.
SUMMARY
Impulsive behaviors are observed in a wide range of psychiatric disorders, including substance use, bipolar, attention-deficit hyperactivity, antisocial and borderline personality, gambling, and eating disorders. The shared phenotype of impulsivity is thought to significantly contribute to both the etiology and perpetuation of these disorders. In this review, we focus upon the relevance of impulsivity to the addictive disorders, particularly substance use disorders. First, the literature supporting the presence of impulsive behaviors prior to the onset of drug use and addiction is discussed. The relevance of impulsivity to relapse is then presented, with a focus on three distinct neurocognitive constructs: automaticity, response inhibition, and decision making. Automaticity is a quickly occurring relapse process resulting from the learned habits induced by persistent drug use. Addicted persons with response inhibition deficits are unable to suppress these previously reinforced behaviors. Decision-making deficits contribute to relapse through a poorly considered assessment of the consequences of drug use. The brain regions associated with each model of impulsive behavior are described, and relevant neurobiologic disruptions in addicted subjects are discussed in the context of their specific neurocognitive deficit(s). Descriptive confusions in the terminology and confounds inherent in the study of impulsivity are described. Empirical investigations documenting the hypothesized relationship between specific deficits in impulsive behaviors, coupled with their neurobiological correlates, and relapse should be the focus of future studies.
doi:10.1300/J069v26S01_04
PMCID: PMC4321793  PMID: 19283972
Addictive disorders; impulsive behavior; substance use; automaticity
3.  Children and Older Adults Exhibit Distinct Sub-Optimal Cost-Benefit Functions when Preparing to Move Their Eyes and Hands 
PLoS ONE  2015;10(2):e0117783.
Numerous activities require an individual to respond quickly to the correct stimulus. The provision of advance information allows response priming but heightened responses can cause errors (responding too early or reacting to the wrong stimulus). Thus, a balance is required between the online cognitive mechanisms (inhibitory and anticipatory) used to prepare and execute a motor response at the appropriate time. We investigated the use of advance information in 71 participants across four different age groups: (i) children, (ii) young adults, (iii) middle-aged adults, and (iv) older adults. We implemented ‘cued’ and ‘non-cued’ conditions to assess age-related changes in saccadic and touch responses to targets in three movement conditions: (a) Eyes only; (b) Hands only; (c) Eyes and Hand. Children made less saccade errors compared to young adults, but they also exhibited longer response times in cued versus non-cued conditions. In contrast, older adults showed faster responses in cued conditions but exhibited more errors. The results indicate that young adults (18–25 years) achieve an optimal balance between anticipation and execution. In contrast, children show benefits (few errors) and costs (slow responses) of good inhibition when preparing a motor response based on advance information; whilst older adults show the benefits and costs associated with a prospective response strategy (i.e., good anticipation).
doi:10.1371/journal.pone.0117783
PMCID: PMC4320084  PMID: 25659134
4.  Luminal microbes promote monocyte-stem cell interactions across a healthy colonic epithelium 
The intestinal epithelium forms a vital barrier between luminal microbes and the underlying mucosal immune system. Epithelial barrier function is maintained by continuous renewal of the epithelium and is pivotal for gut homeostasis. Breaching of the barrier causes mobilisation of immune cells to promote epithelial restitution. However, it is not known whether microbes at the luminal surface of a healthy epithelial barrier influence immune cell mobilisation to modulate tissue homeostasis. Using a mouse colonic mucosal explant model, we demonstrate that close proximity of luminal microbes to a healthy, intact epithelium results in rapid mucus secretion and movement of Ly6C+7/4+ monocytes closer to epithelial stem cells. These early events are driven by the epithelial MyD88-signalling pathway and result in increased crypt cell proliferation and intestinal stem cell number. Over time stem cell number and monocyte-crypt stem cell juxtapositioning return to homeostatic levels observed in vivo. We also demonstrate that reduced numbers of tissue Ly6C+ monocytes can suppress Lgr5EGFP+ stem cell expression in vivo and abrogate the response to luminal microbes ex vivo. The functional link between monocyte recruitment and increased crypt cell proliferation was further confirmed using a crypt-monocyte co-culture model. This work demonstrates that the healthy gut epithelium mediates communication between luminal bacteria and monocytes, and monocytes can modulate crypt stem cell number and promote crypt cell proliferation to help maintain gut homeostasis.
doi:10.4049/jimmunol.1301497
PMCID: PMC4067517  PMID: 24907348
6.  NCOA5 Haplo-insufficiency Results in Glucose Intolerance and Subsequent Hepatocellular Carcinoma 
Cancer cell  2013;24(6):725-737.
Summary
Type 2 Diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC, exclusively in male mice. Tumor development is preceded by increased IL-6 expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced NCOA5 expression is associated with a fraction of human HCCs and HCCs with comorbid T2D. These findings suggest that NCOA5 is a haplo-insufficient tumor suppressor, and NCOA5 deficiency increases susceptibility to both glucose intolerance and HCC, partially by increasing IL-6 expression. Thus, our findings open additional avenues for developing therapeutic approaches to combat these diseases.
doi:10.1016/j.ccr.2013.11.005
PMCID: PMC3891053  PMID: 24332041
NCOA5/CIA; Hepatocellular carcinoma; Type 2 diabetes; IL-6 signaling; Tumor suppressor
7.  A chancelloriid-like metazoan from the early Cambrian Chengjiang Lagerstätte, China 
Scientific Reports  2014;4:7340.
Nidelric pugio gen. et sp. nov. from the Cambrian Series 2 Heilinpu Formation, Chengjiang Lagerstätte, Yunnan Province, China, is an ovoid, sac-like metazoan that bears single-element spines on its surface. N. pugio shows no trace of a gut, coelom, anterior differentiation, appendages, or internal organs that would suggest a bilateral body plan. Instead, the sac-like morphology invites comparison with the radially symmetrical chancelloriids. However, the single-element spines of N. pugio are atypical of the complex multi-element spine rosettes borne by most chancelloriids and N. pugio may signal the ancestral chancelloriid state, in which the spines had not yet fused. Alternatively, N. pugio may represent a group of radial metazoans that are discrete from chancelloriids. Whatever its precise phylogenetic position, N. pugio expands the known disparity of Cambrian scleritome-bearing animals, and provides a new model for reconstructing scleritomes from isolated microfossils.
doi:10.1038/srep07340
PMCID: PMC4260403  PMID: 25487514
8.  Overcoming Roadblocks: Current and Emerging Reimbursement Strategies for Integrated Mental Health Services in Primary Care 
Journal of General Internal Medicine  2013;28(12):1667-1672.
ABSTRACT
The Chronic Care Model (CCM) has been shown to improve medical and psychiatric outcomes for persons with mental disorders in primary care settings, and has been proposed as a model to integrate mental health care in the patient-centered medical home under healthcare reform. However, the CCM has not been widely implemented in primary care settings, primarily because of a lack of a comprehensive reimbursement strategy to compensate providers for day-to-day provision of its core components, including care management and provider decision support. Drawing upon the existing literature and regulatory guidelines, we provide a critical analysis of challenges and opportunities in reimbursing CCM components under the current fee-for-service system, and describe an emerging financial model involving bundled payments to support core CCM components to integrate mental health treatment into primary care settings. Ultimately, for the CCM to be used and sustained over time to integrate physical and mental health care, effective reimbursement models will need to be negotiated across payers and providers. Such payments should provide sufficient support for primary care providers to implement practice redesigns around core CCM components, including care management, measurement-based care, and mental health specialist consultation.
doi:10.1007/s11606-013-2496-z
PMCID: PMC3832738  PMID: 23733375
chronic care model; health care financing; mental disorders
9.  Feasibility Evaluation of an Interpersonal and Social Rhythm Therapy Group Delivery Model 
Archives of psychiatric nursing  2013;27(6):271-277.
The effectiveness of psychotherapies, such as interpersonal and social rhythm therapy (IPSRT), is supported by randomized controlled trials. These trials provide minimal direction regarding feasibility of psychotherapy delivery models. The study purpose was to identify factors facilitating implementation and sustainability of an IPRST group for patients with bipolar disorder. Qualitative data were assessed by the normalization process model (NPM). The results demonstrate feasibility of implementation with experienced clinicians, program coordination, and leadership support. Sustainability challenges include aftercare groups, space, and clinician time. The NPM provides a useful framework for evaluation of factors influencing the feasibility of psychotherapy delivery models.
doi:10.1016/j.apnu.2013.08.002
PMCID: PMC4020708  PMID: 24238006
10.  Secondary Prevention of Atherosclerotic Cardiovascular Disease in Older Adults: A Scientific Statement From the American Heart Association 
Circulation  2013;128(22):2422-2446.
doi:10.1161/01.cir.0000436752.99896.22
PMCID: PMC4171129  PMID: 24166575
secondary prevention; older age; atherosclerotic cardiovascular disease; coronary heart disease
11.  Autoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1 
PLoS ONE  2014;9(9):e107213.
The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.
doi:10.1371/journal.pone.0107213
PMCID: PMC4178025  PMID: 25259810
12.  Preclinical Characterization of Recombinant Human Tissue Kallikrein-1 as a Novel Treatment for Type 2 Diabetes Mellitus 
PLoS ONE  2014;9(8):e103981.
Modulation of the kallikrein-kinin system (KKS) has been shown to have beneficial effects on glucose homeostasis and several other physiological responses relevant to the progression of type 2 diabetes mellitus (T2D). The importance of bradykinin and its receptors in mediating these responses is well documented, but the role of tissue kallikrein-1, the protease that generates bradykinin in situ, is much less understood. We developed and tested DM199, recombinant human tissue kallikrein-1 protein (rhKLK-1), as a potential novel therapeutic for T2D. Hyperinsulinemic-euglycemic clamp studies suggest that DM199 increases whole body glucose disposal in non-diabetic rats. Single-dose administration of DM199 in obese db/db mice and ZDF rats, showed an acute, dose-dependent improvement in whole-body glucose utilization. Sub-acute dosing for a week in ZDF rats improved glucose utilization, with a concomitant rise in fasting insulin levels and HOMA1-%B scores. After cessation of sub-acute dosing, fasting blood glucose levels were significantly lower in ZDF rats during a drug wash-out period. Our studies show for the first time that DM199 administration results in acute anti-hyperglycemic effects in several preclinical models, and demonstrate the potential for further development of DM199 as a novel therapeutic for T2D.
doi:10.1371/journal.pone.0103981
PMCID: PMC4123992  PMID: 25100328
13.  DNA bridging and looping by HMO1 provides a mechanism for stabilizing nucleosome-free chromatin 
Nucleic Acids Research  2014;42(14):8996-9004.
The regulation of chromatin structure in eukaryotic cells involves abundant architectural factors such as high mobility group B (HMGB) proteins. It is not understood how these factors control the interplay between genome accessibility and compaction. In vivo, HMO1 binds the promoter and coding regions of most ribosomal RNA genes, facilitating transcription and possibly stabilizing chromatin in the absence of histones. To understand how HMO1 performs these functions, we combine single molecule stretching and atomic force microscopy (AFM). By stretching HMO1-bound DNA, we demonstrate a hierarchical organization of interactions, in which HMO1 initially compacts DNA on a timescale of seconds, followed by bridge formation and stabilization of DNA loops on a timescale of minutes. AFM experiments demonstrate DNA bridging between strands as well as looping by HMO1. Our results support a model in which HMO1 maintains the stability of nucleosome-free chromatin regions by forming complex and dynamic DNA structures mediated by protein–protein interactions.
doi:10.1093/nar/gku635
PMCID: PMC4132745  PMID: 25063301
14.  Feasibility, Acceptability and Preliminary Efficacy of an Online Peer-to-Peer Social Support ART Adherence Intervention 
AIDS and behavior  2013;17(6):2031-2044.
This study describes the results of an online social support intervention, called “Thrive With Me” (TWM), to improve antiretroviral therapy (ART) adherence. HIV-positive gay or bisexually-identified men self-reporting imperfect ART adherence in the past month were randomized to receive usual care (n=57) or the eight-week TWM intervention (n=67). Self-reported ART outcome measures (0–100% in the past month) were collected at baseline, post-intervention, and 1-month follow-up. Follow-up assessment completion rate was 90%. Participants rated (1–7 scale) the intervention high in information and system quality and overall satisfaction (Means≥5.0). The intervention showed modest effects for the overall sample. However, among current drug-using participants, the TWM (v. Control) group reported significantly higher overall ART adherence (90.1% v. 57.5% at follow-up; difference=31.1, p=.02) and ART taken correctly with food (81.6% v. 55.7% at follow-up; difference=47.9, p=.01). The TWM intervention appeared feasible to implement, acceptable to users, and demonstrated greatest benefits for current drug users.
doi:10.1007/s10461-013-0469-1
PMCID: PMC3674213  PMID: 23553347
antiretroviral adherence; Internet-based intervention; social support; men who have sex with men
15.  Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid binding protein 
Nature chemistry  2013;6(1):28-33.
The human APOBEC3 proteins are a family of DNA-editing enzymes that play an important role in the innate immune response and have broad activity against retroviruses and retrotransposons. APOBEC3G is a member of this family that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism. Efficient deamination requires rapid binding to and dissociation from ssDNA. However, a relatively slow dissociation rate is required for the proposed deaminase-independent roadblock mechanism in which APOBEC3G binds the viral template strand and blocks reverse transcriptase-catalyzed DNA elongation. Here we show that APOBEC3G initially binds ssDNA with rapid on-off rates and subsequently converts to a slowly dissociating mode. In contrast, an oligomerization-deficient APOBEC3G mutant did not exhibit a slow off rate. We propose that catalytically active monomers or dimers slowly oligomerize on the viral genome and inhibit reverse transcription.
doi:10.1038/nchem.1795
PMCID: PMC3950479  PMID: 24345943
APOBEC; DNA binding; HIV-1; restriction factor; roadblock mechanism; optical tweezers; single molecule force spectroscopy
16.  Effect of femoral neck modularity upon the prosthetic range of motion in total hip arthroplasty 
In total hip arthroplasty, aseptic loosening and dislocation are associated with not being able to achieve the correct prosthetic component orientation. Femoral neck modularity has been proposed as a solution to this problem by allowing the surgeon to alter either the neck-shaft or version angle of the prosthetic femoral component intra-operatively. A single replicate full factorial design was used to evaluate how effective a modular femoral neck cementless stem was in restoring a healthy prosthetic range of motion in comparison with a leading fixed-neck cementless stem with the standard modular parameters. It was found that, if altered to a large enough degree, femoral neck modularity can increase the amount of prosthetic motion as well as alter its position to where it is required physiologically. However, there is a functional limit to the amount that can be corrected and there is a risk with regard to the surgeon having to select the optimum modular neck before any benefit is realised.
Electronic supplementary material
The online version of this article (doi:10.1007/s11517-014-1171-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11517-014-1171-9
PMCID: PMC4102828  PMID: 24969948
Total hip arthroplasty; Femoral neck modularity; Impingement; Range of motion
17.  A controlled vocabulary for pathway entities and events 
Entities involved in pathways and the events they participate in require descriptive and unambiguous names that are often not available in the literature or elsewhere. Reactome is a manually curated open-source resource of human pathways. It is accessible via a website, available as downloads in standard reusable formats and via Representational State Transfer (REST)-ful and Simple Object Access Protocol (SOAP) application programming interfaces (APIs). We have devised a controlled vocabulary (CV) that creates concise, unambiguous and unique names for reactions (pathway events) and all the molecular entities they involve. The CV could be reapplied in any situation where names are used for pathway entities and events. Adoption of this CV would significantly improve naming consistency and readability, with consequent benefits for searching and data mining within and between databases.
Database URL: http://www.reactome.org
doi:10.1093/database/bau060
PMCID: PMC4064568  PMID: 24951798
18.  Luminal Microbes Promote Monocyte–Stem Cell Interactions Across a Healthy Colonic Epithelium 
The intestinal epithelium forms a vital barrier between luminal microbes and the underlying mucosal immune system. Epithelial barrier function is maintained by continuous renewal of the epithelium and is pivotal for gut homeostasis. Breaching of the barrier causes mobilization of immune cells to promote epithelial restitution. However, it is not known whether microbes at the luminal surface of a healthy epithelial barrier influence immune cell mobilization to modulate tissue homeostasis. Using a mouse colonic mucosal explant model, we demonstrate that close proximity of luminal microbes to a healthy, intact epithelium results in rapid mucus secretion and movement of Ly6C+7/4+ monocytes closer to epithelial stem cells. These early events are driven by the epithelial MyD88-signaling pathway and result in increased crypt cell proliferation and intestinal stem cell number. Over time, stem cell number and monocyte–crypt stem cell juxtapositioning return to homeostatic levels observed in vivo. We also demonstrate that reduced numbers of tissue Ly6C+ monocytes can suppress Lgr5EGFP+ stem cell expression in vivo and abrogate the response to luminal microbes ex vivo. The functional link between monocyte recruitment and increased crypt cell proliferation was further confirmed using a crypt–monocyte coculture model. This work demonstrates that the healthy gut epithelium mediates communication between luminal bacteria and monocytes, and monocytes can modulate crypt stem cell number and promote crypt cell proliferation to help maintain gut homeostasis.
doi:10.4049/jimmunol.1301497
PMCID: PMC4067517  PMID: 24907348
19.  Changes in assembly processes in soil bacterial communities following a wildfire disturbance 
The ISME Journal  2013;7(6):1102-1111.
Although recent work has shown that both deterministic and stochastic processes are important in structuring microbial communities, the factors that affect the relative contributions of niche and neutral processes are poorly understood. The macrobiological literature indicates that ecological disturbances can influence assembly processes. Thus, we sampled bacterial communities at 4 and 16 weeks following a wildfire and used null deviation analysis to examine the role that time since disturbance has in community assembly. Fire dramatically altered bacterial community structure and diversity as well as soil chemistry for both time-points. Community structure shifted between 4 and 16 weeks for both burned and unburned communities. Community assembly in burned sites 4 weeks after fire was significantly more stochastic than in unburned sites. After 16 weeks, however, burned communities were significantly less stochastic than unburned communities. Thus, we propose a three-phase model featuring shifts in the relative importance of niche and neutral processes as a function of time since disturbance. Because neutral processes are characterized by a decoupling between environmental parameters and community structure, we hypothesize that a better understanding of community assembly may be important in determining where and when detailed studies of community composition are valuable for predicting ecosystem function.
doi:10.1038/ismej.2013.11
PMCID: PMC3660671  PMID: 23407312
niche vs neutral processes; community assembly; 16S rRNA gene pyrosequencing; Betaproteobacteria; Firmicutes; beta diversity
20.  Venue-based affiliation networks and HIV risk-taking behavior among male sex workers 
Sexually transmitted diseases  2013;40(6):453-458.
Background
This study examined venue-based networks constituted by affiliation with gay bars and street intersections where male sex workers (MSWs) congregate to find their sexual/drug-sharing partners, and network influence on risky sexual behavior (e.g., unprotected anal intercourse [UAI]) and HIV infection.
Methods
Data collected during 2003–2004 in Houston, Texas, consists of 208 MSWs affiliated with 15 gay bars and 51 street intersections. Two-mode network analysis was conducted to examine structural characteristics in affiliation networks, as well as venue-based network influence on UAI and HIV infection.
Results
Centralized affiliation patterns were found where only a few venues were popular among MSWs and these were highly inter-dependent. Distinctive structural patterns of venue-based clustering were associated with UAI and infection. Individuals who shared venue affiliation with MSWs who engage in UAI were less likely to have UAI themselves. This suggests a downhill effect, i.e., individuals compensate for their risk of infection by adjusting their own risk-taking behavior, based on their perceptions of their venue affiliates.
Conclusions
Venue-based HIV/AIDs interventions could be tailored to specific venues so as to target specific clusters that are more likely to engage in risky sexual behavior.
doi:10.1097/OLQ.0b013e31829186e5
PMCID: PMC3675278  PMID: 23677019
social network analysis; risky sexual behavior; HIV diffusion; affiliation networks; male sex workers
21.  Adrenocortical and Pituitary Glucocorticoid Feedback in Abstinent Alcohol-Dependent Women 
Background
The long-term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone.
Methods
Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 μg/kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes.
Results
Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone.
Conclusion
Significant differences in pituitary–adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.
doi:10.1111/j.1530-0277.2010.01164.x
PMCID: PMC4038906  PMID: 20331575
Adrenal Cortex; Alcoholism; Cosyntropin; Dexamethasone; Pituitary-Adrenal System; Gender; Female
22.  The relationship between a child’s postural stability and manual dexterity 
Experimental Brain Research  2014;232(9):2907-2917.
The neural systems responsible for postural control are separate from the neural substrates that underpin control of the hand. Nonetheless, postural control and eye-hand coordination are linked functionally. For example, a stable platform is required for precise manual control tasks (e.g. handwriting) and thus such skills often cannot develop until the child is able to sit or stand upright. This raises the question of the strength of the empirical relationship between measures of postural stability and manual motor control. We recorded objective computerised measures of postural stability in stance and manual control in sitting in a sample of school children (n = 278) aged 3–11 years in order to explore the extent to which measures of manual skill could be predicted by measures of postural stability. A strong correlation was found across the whole sample between separate measures of postural stability and manual control taken on different days. Following correction for age, a significant but modest correlation was found. Regression analysis with age correction revealed that postural stability accounted for between 1 and 10 % of the variance in manual performance, dependent on the specific manual task. These data reflect an interdependent functional relationship between manual control and postural stability development. Nevertheless, the relatively small proportion of the explained variance is consistent with the anatomically distinct neural architecture that exists for ‘gross’ and ‘fine’ motor control. These data justify the approach of motor batteries that provide separate assessments of postural stability and manual dexterity and have implications for therapeutic intervention in developmental disorders.
doi:10.1007/s00221-014-3947-4
PMCID: PMC4131166  PMID: 24825824
Fine and gross motor control; Posture; Manual dexterity; Visuomotor; Kinematic; Motor development
23.  Distinct nucleic acid interaction properties of HIV-1 nucleocapsid protein precursor NCp15 explain reduced viral infectivity 
Nucleic Acids Research  2014;42(11):7145-7159.
During human immunodeficiency virus type 1 (HIV-1) maturation, three different forms of nucleocapsid (NC) protein—NCp15 (p9 + p6), NCp9 (p7 + SP2) and NCp7—appear successively. A mutant virus expressing NCp15 shows greatly reduced infectivity. Mature NCp7 is a chaperone protein that facilitates remodeling of nucleic acids (NAs) during reverse transcription. To understand the strict requirement for NCp15 processing, we compared the chaperone function of the three forms of NC. NCp15 anneals tRNA to the primer-binding site at a similar rate as NCp7, whereas NCp9 is the most efficient annealing protein. Assays to measure NA destabilization show a similar trend. Dynamic light scattering studies reveal that NCp15 forms much smaller aggregates relative to those formed by NCp7 and NCp9. Nuclear magnetic resonance studies suggest that the acidic p6 domain of HIV-1 NCp15 folds back and interacts with the basic zinc fingers. Neutralizing the acidic residues in p6 improves the annealing and aggregation activity of NCp15 to the level of NCp9 and increases the protein–NA aggregate size. Slower NCp15 dissociation kinetics is observed by single-molecule DNA stretching, consistent with the formation of electrostatic inter-protein contacts, which likely contribute to the distinct aggregate morphology, irregular HIV-1 core formation and non-infectious virus.
doi:10.1093/nar/gku335
PMCID: PMC4066767  PMID: 24813443
24.  THE CENTRAL SENSITIZATION INVENTORY (CSI): ESTABLISHING CLINICALLY-SIGNIFICANT VALUES FOR IDENTIFYING CENTRAL SENSITIVITY SYNDROMES IN AN OUTPATIENT CHRONIC PAIN SAMPLE 
Central Sensitization (CS) is a proposed physiological phenomenon in which central nervous system neurons become hyper-excitable, resulting in hypersensitivity to both noxious and non-noxious stimuli. The term Central Sensitivity Syndrome (CSS) describes a group of medically-indistinct (or nonspecific) disorders, such as fibromyalgia, chronic fatigue, and irritable bowel, for which CS may be a common etiology. In a previous study, the Central Sensitization Inventory (CSI) was introduced as a screening instrument for clinicians to help identify patients with a CSS. It was found to have high reliability and validity (test-retest reliability = 0.82; Cronbach’s alpha = 0.88). The present study investigated a cohort of 121 patients who were referred to a multidisciplinary pain center, which specialized in the assessment and treatment of complex pain and psychophysiological disorders, including CSSs. A large percentage of patients (n = 89, 74%) met clinical criteria for one or more CSSs, and CSI scores were positively correlated with the number of diagnosed CSSs. A Receiver Operating Characteristic (ROC) analysis determined that a CSI score of 40 out of 100 best distinguished between the CSS patient group and a non-patient comparison sample (n = 129) (AUC= 0.86, Sensitivity = 81%, Specicifity = 75%).
PERSPECTIVE
The Central Sensitization Inventory (CSI) is a new self-report screening instrument to help identify patients with Central Sensitivity Syndromes, including fibromyalgia. The present study investigated CSI scores in a heterogeneous pain population, with a large percentage of CSSs, and a normative non-clinical sample, to determine a clinically-relevant cutoff value.
doi:10.1016/j.jpain.2012.11.012
PMCID: PMC3644381  PMID: 23490634
Central Sensitization Inventory (CSI); Central Sensitivity Syndrome; fibromyalgia; chronic widespread pain; irritable
25.  Immuno-PET imaging of the hepatocyte growth factor receptor Met using the one-armed antibody Onartuzumab (MetMAb) 
The over-expression and -activation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET imaging agent to assess Met expression would aid in diagnosis and monitoring responses to Met-targeted therapies. In these studies Onartuzumab (MetMAb), the experimental therapeutic one-armed monoclonal antibody, was radiolabeled with 76Br or 89Zr and evaluated as an imaging agent in Met expressing cell lines and mouse xenografts.
Methods
89Zr-df-Onartuzumab was synthesized using a desferrioxamine-Onartuzumab conjugate (df-Onartuzumab); 76Br-Onartuzumab was labeled directly. Met binding studies were performed using the human tumor-derived cell lines MKN-45, SNU-16 and U87-MG, which have relatively high, moderate and low levels of Met, respectively. Biodistribution and microPET imaging studies were performed in MKN-45 and U87-MG xenografts.
Results
76Br-Onartuzumab and 89Zr-df-Onartuzumab exhibited specific, high affinity Met binding (nM) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from non-target tissues with the highest uptakes in tumor, blood, kidney, and lung. 76Br-Onartuzumab MKN-45 tumor uptakes remained relatively constant from 18 h (5%ID/g) to 48 h (3%ID/g) and exhibited tumor:muscle ratios ranging from 4:1 to 6:1. In contrast, 89Zr-df-Onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10%ID/g) to 120 h (23%ID/g), attaining tumor:muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h but after 48 h 89Zr-df-Onartuzumab image quality improved with at least 2 fold greater tumor uptakes compared to non-target tissues. MKN-45 tumor uptakes for both tracers correlated significantly with tumor mass and Met expression, and were not affected by the presence of plasma shed Met.
Conclusions
89Zr-df-Onartuzumab and 76Br-Onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-Onartuzumab achieved higher tumor uptakes and tumor:muscle ratios than 76Br-Onartuzumab at later times suggesting that 89Zr-df-Onartuzumab would be better suited to image Met for diagnostic and prognostic purposes.
doi:10.2967/jnumed.111.102293
PMCID: PMC3982858  PMID: 22917884
Immuno-PET imaging; Met receptor; Onartuzumab; MetMAb

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