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1.  Effects of Alcohol and Saccharin Deprivations on Concurrent Ethanol and Saccharin Operant Self-Administration by Alcohol-Preferring (P) Rats 
Alcohol (Fayetteville, N.Y.)  2008;42(4):277-284.
Consumption of sweet solutions has been associated with a reduction in withdrawal symptoms and alcohol craving in humans. The objective of the present study was to determine the effects of EtOH and saccharin (SACC) deprivations on operant oral self-administration. P rats were allowed to lever press concurrently self-administer EtOH (15% v/v) and SACC (0.0125% g/v) for 8 weeks. Rats were then maintained on daily operant access (non-deprived), deprived of both fluids (2 weeks), deprived of SACC and given 2 ml of EtOH daily, or deprived of EtOH and given 2 ml of SACC daily. All groups were then given two weeks of daily operant access to EtOH and SACC, followed by an identical second deprivation period. P rats responded more for EtOH than SACC. All deprived groups increased responding on the EtOH lever, but not on the SACC lever. Daily consumption of 2 ml EtOH decreased the duration of the ADE. Home cage access to 2 ml SACC also decreased the ADE but to a lesser extent than access to EtOH. A second deprivation period further increased and prolonged the expression of an ADE. These results show EtOH is a more salient reinforcer than SACC. With concurrent access to EtOH and SACC, P rats do not display a saccharin deprivation effect. Depriving P rats of both EtOH and SACC had the most pronounced effect on the magnitude and duration of the ADE, suggesting that there may be some interactions between EtOH and SACC in their CNS reinforcing effects.
doi:10.1016/j.alcohol.2008.01.011
PMCID: PMC4280856  PMID: 18400451
Alcohol deprivation effect; operant self-administration; alcohol-preferring P rats; repeated deprivations; Saccharin self-administration
2.  TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice 
eLife  null;3:e03464.
SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.
DOI: http://dx.doi.org/10.7554/eLife.03464.001
eLife digest
In response to an injury or infection, areas of the body can become inflamed as the immune system attempts to repair the damage and/or destroy any microbes or toxins that have entered the body. At the level of individual cells inflammation can involve cells being programmed to die in one of two ways: apoptosis and necroptosis.
Apoptosis is a highly controlled process during which the contents of the cell are safely destroyed in order to prevent damage to surrounding cells. Necroptosis, on the other hand, is not controlled: the cell bursts and releases its contents into the surroundings.
Inflammation is activated by a protein called TNFR1, which is controlled by a complex that includes a protein called SHARPIN. Mice that lack the SHARPIN protein develop inflammation on the skin and internal organs, even in the absence of injury or infection. However, it is not clear how SHARPIN controls TNFR1 to prevent inflammation. Rickard et al. and, independently Kumari et al. have now studied this process in detail.
Rickard et al. cross bred mice that lack SHARPIN with mice lacking other proteins involved in inflammation and cell death. The experiments show that apoptosis is the main form of cell death in skin inflammation, but necroptosis has a bigger role in the inflammation of internal organs.
Mice that lack both the apoptotic and necroptotic cell-death pathways can develop relatively normally, but they die shortly after birth if they also lack SHARPIN. Experiments on these mice could help us to understand how SHARPIN works.
DOI: http://dx.doi.org/10.7554/eLife.03464.002
doi:10.7554/eLife.03464
PMCID: PMC4270099  PMID: 25443632
apoptosis; TNF signaling; inflammation; dermatitis; LUBAC; ubiquitin; mouse
3.  Radioactive Seed Localization Compared to Wire Localization in Breast-Conserving Surgery: Initial 6-Month Experience 
Annals of surgical oncology  2013;20(13):4121-4127.
Introduction
Wire localization (WL) of non-palpable breast cancers on the day of surgery is uncomfortable for patients and impacts OR efficiency. Radioactive seed localization (RSL) before the day of surgery avoids these disadvantages. In this study we compare outcomes of our initial 6-month experience with RSL to those with WL in the preceding 6 months.
Methods
Lumpectomies for invasive or intraductal cancers localized with a single 125iodine seed (January-June 2012) were compared to those using 1 wire (July-December 2011). Surgeons and radiologists did not change. Positive and close margins were defined as tumor on ink and tumor ≤1mm from ink, respectively. Demographic and clinical characteristics and outcomes were compared between RSL and WL patients.
Results
There were 431 RSL and 256 WL lumpectomies performed. Clinicopathologic characteristics did not differ between groups. Most seeds (90%) were placed before the day of surgery. Positive margins were present in 7.7% of RSL versus 5.5% of WL patients, and 16.9% of RSL versus 19.9% of WL had close margins (p=0.38). The median operative time was longer for lumpectomy and sentinel lymph node biopsy (SLNB) in the RSL group (55 versus 48 minutes, p<0.0001). There was no significant difference in the volume of tissue excised between groups.
Conclusions
In the first 6 months of RSL, operative scheduling was simplified, while rates of positive and close margins were similar to those seen after many years of experience with WL. Operative time was slightly longer for RSL lumpectomy and SLNB; we anticipate this will decrease with experience.
doi:10.1245/s10434-013-3166-4
PMCID: PMC4003499  PMID: 23943024
breast-conserving surgery; radioactive seed localization; wire localization
4.  Protective Behavioral Strategies, Social Norms, and Alcohol-Related Outcomes 
Addiction research & theory  2014;22(4):279-285.
The present study examined the unique contributions of protective behavioral strategies and social norms in predicting alcohol-related outcomes. Participants were 363 students from a large public university in the Midwest who reported at least one binge-drinking episode (5+/4+ drinks for men/women in one sitting) in the past 30 days. Data were collected 1/2010–3/2011. We used SEM to test models where protective behavioral strategies (PBS) and social norms were predictors of both alcohol use and alcohol-related problems, after controlling for the effects of gender. Both PBS and descriptive norms had relationships with alcohol use. PBS also had a relationship with alcohol-related problems. Overall, the findings suggest that PBS and social norms have unique associations with distinct alcohol-related outcomes.
doi:10.3109/16066359.2013.838226
PMCID: PMC4237203  PMID: 25419202
Alcohol; Protective Behavioral Strategies; Social Norms
5.  Methyltransferases acquired by lactococcal 936-type phage provide protection against restriction endonuclease activity 
BMC Genomics  2014;15(1):831.
Background
So-called 936-type phages are among the most frequently isolated phages in dairy facilities utilising Lactococcus lactis starter cultures. Despite extensive efforts to control phage proliferation and decades of research, these phages continue to negatively impact cheese production in terms of the final product quality and consequently, monetary return.
Results
Whole genome sequencing and in silico analysis of three 936-type phage genomes identified several putative (orphan) methyltransferase (MTase)-encoding genes located within the packaging and replication regions of the genome. Utilising SMRT sequencing, methylome analysis was performed on all three phages, allowing the identification of adenine modifications consistent with N-6 methyladenine sequence methylation, which in some cases could be attributed to these phage-encoded MTases. Heterologous gene expression revealed that M.Phi145I/M.Phi93I and M.Phi93DAM, encoded by genes located within the packaging module, provide protection against the restriction enzymes HphI and DpnII, respectively, representing the first functional MTases identified in members of 936-type phages.
Conclusions
SMRT sequencing technology enabled the identification of the target motifs of MTases encoded by the genomes of three lytic 936-type phages and these MTases represent the first functional MTases identified in this species of phage. The presence of these MTase-encoding genes on 936-type phage genomes is assumed to represent an adaptive response to circumvent host encoded restriction-modification systems thereby increasing the fitness of the phages in a dynamic dairy environment.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-831) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-831
PMCID: PMC4190342  PMID: 25269955
Lactococcus lactis; Bacteriophage; Methylome; Restriction-modification; SMRT sequencing
6.  Age Disparity in Palliative Radiotherapy Among Elderly Patients with Advanced Cancer 
Objective:
Radiotherapy (RT) is often utilized in cancer care with palliative intent. The purpose of this study was to verify that differences exist in rates of palliative radiotherapy relating to the age of the patient that go beyond the expected survival differences in older people.
Methods:
Using the Surveillance, Epidemiology, and End Results (SEER) - Medicare Linked Database, 56,519 patients were identified with Stage IV breast, lung, prostate, or colorectal cancer diagnosed between 2000 and 2007. Multivariate logistic regression was performed with Statistical Analysis System (SAS, 1976) to determine rates of palliative radiotherapy accounting for known confounding factors.
Results:
Thirty-four percent of the study population received palliative radiotherapy with a disease distribution of lung (65%), colorectal (20%), prostate (8%), and breast (6%) cancer. Upon multivariate analysis, it was revealed that older patients (P <.001) and patients with higher Charlson comorbidity scores (P <.001) were less likely to receive palliative RT. Black patients (P <.001) and married patients (P <.001) were also correlated with reduced likelihood of receiving palliative RT.
Conclusion:
An age disparity exists among older patients, who are less likely to receive palliative radiotherapy, even when controlling for the length of survival. This suggests that a physician and/or patient bias exists against the elderly. Identifying the cause for these discrepancies in the receipt of palliative RT is important, so that we may improve access to quality palliative RT.
PMCID: PMC4175928
7.  Deployment Risk Factors and Postdeployment Health Profiles Associated With Traumatic Brain Injury in Heavy Drinking Veterans 
Military medicine  2012;177(7):789-796.
Along with post-traumatic stress disorder (PTSD), mild traumatic brain injury (mTBI) is considered one of the “signature wounds” of combat operations in Iraq (Operation Iraqi Freedom [OIF]) and Afghanistan (Operation Enduring Freedom [OEF]), but the role of mTBI in the clinical profiles of Veterans with other comorbid forms of postdeployment psychopathology is poorly understood. The current study explored the deployment risk and postdeployment health profiles of heavy drinking OIF and OEF Veterans as a function of mTBI. Sixty-nine heavy-drinking OIF/OEF Veterans were recruited through a Veterans’ Affairs Medical Center and completed questionnaires and structured interviews assessing war-zone experiences, postdeployment drinking patterns, and PTSD symptoms. Veterans with positive mTBI screens and confirmed mTBI diagnoses endorsed higher rates of combat experiences, including direct and indirect killing, and met criteria for PTSD at a higher rate than Veterans without a history of mTBI. Both PTSD and combat experiences independently predicted screening positive for mTBI, whereas only combat experiences predicted receiving a confirmed mTBI diagnosis. mTBI was not associated with any dimension of alcohol use. These results support a growing body of literature linking mTBI with PTSD.
PMCID: PMC4136652  PMID: 22808885
8.  Approaches for the design of reduced toxicant emission cigarettes 
SpringerPlus  2014;3:374.
Cigarette smoking causes serious diseases through frequent and prolonged exposure to toxicants. Technologies are being developed to reduce smokers’ toxicant exposure, including filter adsorbents, tobacco treatments and substitutes. This study examined the effect of modifications to filter ventilation, variations in cigarette circumference and active charcoal filter length and loading, as well as combinations of these features in a reduced-toxicant prototype (RTP) cigarette, on the yields of toxicants in cigarette smoke. An air-dilution mechanism, called split-tipping, was developed in which a band of porous paper in the centre of the filter tipping functions to minimise the loss of effective filter ventilation that occurs at the high flow rates encountered during human-smoking, and to facilitate the diffusional loss of volatile toxicants. As compared with conventional filter ventilation cigarettes, split-tipping reduced tar and volatile smoke constituent emissions under high flow rate machine-smoking conditions, most notably for products with a 1-mg ISO tar yield. Furthermore, mouth level exposure (MLE) to tar and nicotine was reduced among smokers of 1-mg ISO tar cigarettes in comparison to smokers of cigarettes with traditional filter ventilation. For higher ISO tar level cigarettes, however, there were no significant reductions in MLE. Smaller cigarette circumferences reduced sidestream toxicant yields and modified the balance of mainstream smoke chemistry with reduced levels of aromatic amines and benzo[a]pyrene but increased yields of formaldehyde. Smaller circumference cigarettes also had lower mainstream yields of volatile toxicants. Longer cigarette filters containing increased levels of high-activity carbon (HAC) showed reduced machine-smoking yields of volatile toxicants: with up to 97% removal for some volatile toxicants at higher HAC loadings. Split-tipping was combined with optimal filter length and cigarette circumference in an RTP cigarette that gave significantly lower mainstream (up to ~90%) and sidestream (predominately 20%–60%) smoke yields of numerous toxicants as compared with a commercial comparator cigarette under machine-smoking conditions. Significantly lower mainstream and sidestream smoke toxicant yields were observed for an RTP cigarette comprising several toxicant reducing technologies; these observations warrant further evaluation in clinical studies where real-world relevance can be tested using biomarkers of exposure and physiological effect.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-3-374) contains supplementary material, which is available to authorized users.
doi:10.1186/2193-1801-3-374
PMCID: PMC4125608  PMID: 25110628
9.  Biphasic Effects of Alcohol on Delay and Probability Discounting 
Delay discounting and probability discounting are behavioral economic indices of impulsive and risky decision making that have been associated with addictive behavior, but the acute biphasic effects of alcohol on these decision-making processes are not well understood. This study sought to investigate the biphasic effects of alcohol on delay and probability discounting across the ascending and descending limbs of the breath alcohol concentration (BAC) curve, which are respectively characterized by the stimulant and sedative effects of alcohol. Delay and probability discounting were measured at four time points (Baseline, Ascending, Descending, and Endpoint) across the BAC curve at two target alcohol doses (40 mg/dl and 80 mg/dl) in healthy adults (N = 23 and 27, for both doses, respectively). There was no significant effect of alcohol on delay discounting at either dose. Alcohol significantly affected probability discounting, such that reduced discounting for uncertain rewards was evident during the descending limb of the BAC curve at the lower dose (p<.05) and during both the ascending and descending limb of the BAC curve at the higher dose (p<.05). Thus, alcohol resulted in increased risky decision making, particularly during the descending limb which is primarily characterized by the sedative effects of alcohol. These findings suggest that the biphasic effects of alcohol across the ascending and descending limbs of the BAC have differential effects on behavior related to decision-making for probabilistic, but not delayed, rewards. Parallels to and distinctions from previous findings are discussed.
doi:10.1037/a0032284
PMCID: PMC4050433  PMID: 23750692
delay discounting; probability discounting; impulsivity; alcohol use; behavioral economics
10.  The Impact of Elevated Posttraumatic Stress on the Efficacy of Brief Alcohol Interventions for Heavy Drinking College Students 
Addictive behaviors  2012;38(3):1719-1725.
Brief alcohol interventions (BAIs) have been widely adopted for use with college students and are associated with significant reductions in drinking and problems. However, many students do not respond to these approaches and little is known about risk factors for poor response. The current study investigated one possible risk factor by examining the impact of posttraumatic stress (PTS) symptoms on BAI efficacy. This study presents pooled data from two randomized clinical trials that examined the efficacy of counselor-administered BAIs compared with computerized interventions. Participants were 207 college students (53.1% women, 68.1% White/Caucasian, 16.9% with elevated post-traumatic stress) who reported past-month heavy episodic drinking. Follow-up assessments were completed six months post-intervention. Analyses testing differences in frequency of past-month heavy episodic drinking revealed a significant post-traumatic stress by time interaction (F(1,165) = 8.27, p = .005) such that individuals screening positive for PTS showed larger reductions in heavy episodic drinking at follow-up. A significant three-way interaction between time, PTS, and intervention condition (F(2,167) = 5.76, p = .004) was found for alcohol related consequences. Specifically, among individuals screening positive for PTS, only those that received the counselor-administered BAI showed a significant reduction in consequences at follow-up. These results suggest that overall college students with PTS may respond well to BAIs and that counselor-delivered BAIs may be more efficacious than computer-delivered interventions for reducing alcohol problems for these high-risk students.
doi:10.1016/j.addbeh.2012.09.004
PMCID: PMC4050664  PMID: 23261489
Alcohol; Brief intervention; college students; mental health; PTSD
11.  Bacteriophage Orphan DNA Methyltransferases: Insights from Their Bacterial Origin, Function, and Occurrence 
Applied and Environmental Microbiology  2013;79(24):7547-7555.
Type II DNA methyltransferases (MTases) are enzymes found ubiquitously in the prokaryotic world, where they play important roles in several cellular processes, such as host protection and epigenetic regulation. Three classes of type II MTases have been identified thus far in bacteria which function in transferring a methyl group from S-adenosyl-l-methionine (SAM) to a target nucleotide base, forming N-6-methyladenine (class I), N-4-methylcytosine (class II), or C-5-methylcytosine (class III). Often, these MTases are associated with a cognate restriction endonuclease (REase) to form a restriction-modification (R-M) system protecting bacterial cells from invasion by foreign DNA. When MTases exist alone, which are then termed orphan MTases, they are believed to be mainly involved in regulatory activities in the bacterial cell. Genomes of various lytic and lysogenic phages have been shown to encode multi- and mono-specific orphan MTases that have the ability to confer protection from restriction endonucleases of their bacterial host(s). The ability of a phage to overcome R-M and other phage-targeting resistance systems can be detrimental to particular biotechnological processes such as dairy fermentations. Conversely, as phages may also be beneficial in certain areas such as phage therapy, phages with additional resistance to host defenses may prolong the effectiveness of the therapy. This minireview will focus on bacteriophage-encoded MTases, their prevalence and diversity, as well as their potential origin and function.
doi:10.1128/AEM.02229-13
PMCID: PMC3837797  PMID: 24123737
12.  A Protective Lipidomic Biosignature Associated with a Balanced Omega-6/Omega-3 Ratio in fat-1 Transgenic Mice 
PLoS ONE  2014;9(4):e96221.
A balanced omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio has been linked to health benefits and the prevention of many chronic diseases. Current dietary intervention studies with different sources of omega-3 fatty acids (omega-3) lack appropriate control diets and carry many other confounding factors derived from genetic and environmental variability. In our study, we used the fat-1 transgenic mouse model as a proxy for long-term omega-3 supplementation to determine, in a well-controlled manner, the molecular phenotype associated with a balanced omega-6/omega-3 ratio. The fat-1 mouse can convert omega-6 to omega-3 PUFAs, which protect against a wide variety of diseases including chronic inflammatory diseases and cancer. Both wild-type (WT) and fat-1 mice were subjected to an identical diet containing 10% corn oil, which has a high omega-6 content similar to that of the Western diet, for a six-month duration. We used a multi-platform lipidomic approach to compare the plasma lipidome between fat-1 and WT mice. In fat-1 mice, an unbiased profiling showed a significant increase in the levels of unesterified eicosapentaenoic acid (EPA), EPA-containing cholesteryl ester, and omega-3 lysophosphospholipids. The increase in omega-3 lipids is accompanied by a significant reduction in omega-6 unesterified docosapentaenoic acid (omega-6 DPA) and DPA-containing cholesteryl ester as well as omega-6 phospholipids and triacylglycerides. Targeted lipidomics profiling highlighted a remarkable increase in EPA-derived diols and epoxides formed via the cytochrome P450 (CYP450) pathway in the plasma of fat-1 mice compared with WT mice. Integration of the results of untargeted and targeted analyses has identified a lipidomic biosignature that may underlie the healthful phenotype associated with a balanced omega-6/omega-3 ratio, and can potentially be used as a circulating biomarker for monitoring the health status and the efficacy of omega-3 intervention in humans.
doi:10.1371/journal.pone.0096221
PMCID: PMC3997567  PMID: 24760204
13.  Examining a curvilinear model of readiness to change and alcohol consumption 
Addiction research & theory  2013;21(6):507-515.
Research examining the relationship between readiness to change and alcohol consumption among college students is inconsistent. The purpose of the present study was to extend these findings, using two different measures of readiness to change. We hypothesized a curvilinear effect would occur such that the relationship between readiness to change and alcohol use would be relatively low for students low and high on readiness to change, whereas the relationship would be relatively high for those with moderate levels of readiness to change. Data were collected from two studies: Study 1 consisted of 263 undergraduate students and Study 2 consisted of 245 undergraduates participating in either intercollegiate or recreational athletics at three US universities. In Study 1, we examined the association between both linear and quadratic scores on a readiness to change measure and alcohol use. In Study 2, we examined the relationship between scores on a stage of change measure that included subscales indicative of different levels of readiness to change and alcohol use. The pattern of relationships supported the existence of an effect where the highest levels of alcohol use occurred among those with scores representing moderate levels of readiness to change.
doi:10.3109/16066359.2012.754884
PMCID: PMC3970817  PMID: 24696671
Readiness to change; alcohol; college students
14.  Intensity-modulated stereotactic radiosurgery for arteriovenous malformations: guidance for treatment planning 
Background
Stereotactic Radiosurgery (SRS) is a common tool used to treat Arteriovenous Malformations (AVMs) in anatomical locations associated with a risk of surgical complications. Despite high rates of clinical effectiveness, SRS carries a risk of toxicity as a result of radiation injury to brain tissue. The use of intensity-modulated radiotherapy (IMRT) has increased because it may lead to improved PTV conformity and better Normal Tissue (NT) sparing compared to 3D Conformal Radiotherapy (3DCRT). The aim of this study was twofold: 1) to develop simple patient stratification rules for the recommendation of IMRT planning strategies over 3DCRT in the treatment of AVMs with SRS; and 2) to estimate the impact of IMRT in terms of toxicity reduction using retrospectively reported data for symptomatic radiation injury following SRS.
Methods
Thirty-one AVM patients previously treated with 3DCRT were replanned in a commercial treatment planning system using 3DCRT and static gantry IMRT with identical beam arrangements. The radiotherapy planning metrics analyzed included AVM volume, diameter, and volume to surface area ratio. The dosimetric endpoints analyzed included conformity index improvements and NT sparing measured by the maximum NT dose, and the volume of surrounding tissue that received 7Gy and 12Gy.
Results
Our analysis revealed stratified subsets of patients for IMRT that were associated with improved conformity, and those that were associated with decreased doses to normal tissue. The stratified patients experienced an improvement in conformity index by −6-68%, a reduction in the maximum NT dose by −0.5-12.3%, a reduction in the volume of NT receiving 7Gy by 1-8 cc, and a reduction in the volume of NT receiving 12Gy by 0–3.7 cc. The reduction in NT receiving 12Gy translated to a theoretical decrease in the probability of symptomatic injury by 0–9.3%.
Conclusions
This work indicates the potential for significant patient improvements when treating AVMs and provides rules to predict which patients are likely to benefit from IMRT.
doi:10.1186/1748-717X-9-73
PMCID: PMC3995862  PMID: 24612667
Stereotactic radiosurgery; Intensity modulated radiotherapy (IMRT); Arteriovenous malformation (AVM); Treatment planning; Patient stratification
15.  Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus 
FEBS letters  2012;587(3):272-277.
Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2.
doi:10.1016/j.febslet.2012.12.011
PMCID: PMC3558538  PMID: 23266514
Protein-protein interaction; Signal transduction; Cerebral cavernous malformation; X-ray crystallography; harmonin-homology domain
16.  Continuous Objective Monitoring of Alcohol Use: 21st Century Measurement using Transdermal Sensors 
Transdermal alcohol sensors continuously collect reliable and valid data on alcohol consumption in vivo over the course of hours to weeks. Transdermal alcohol readings are highly correlated with breath alcohol measurements, but transdermal alcohol levels lag behind breath alcohol levels by one or more hours due to the longer time required for alcohol to be expelled through perspiration. By providing objective information about alcohol consumption, transdermal alcohol sensors can validate self-report and provide important information not previously available. In this article we describe the development and evaluation of currently available transdermal alcohol sensors, present the strengths and limitations of the technology, and give examples of recent research using the sensors.
doi:10.1111/j.1530-0277.2012.01869.x
PMCID: PMC3623856  PMID: 22823467
17.  Investigation of the Relationship between Lactococcal Host Cell Wall Polysaccharide Genotype and 936 Phage Receptor Binding Protein Phylogeny 
Applied and Environmental Microbiology  2013;79(14):4385-4392.
Comparative genomics of 11 lactococcal 936-type phages combined with host range analysis allowed subgrouping of these phage genomes, particularly with respect to their encoded receptor binding proteins. The so-called pellicle or cell wall polysaccharide of Lactococcus lactis, which has been implicated as a host receptor of (certain) 936-type phages, is specified by a large gene cluster, which, among different lactococcal strains, contains highly conserved regions as well as regions of diversity. The regions of diversity within this cluster on the genomes of lactococcal strains MG1363, SK11, IL1403, KF147, CV56, and UC509.9 were used for the development of a multiplex PCR system to identify the pellicle genotype of lactococcal strains used in this study. The resulting comparative analysis revealed an apparent correlation between the pellicle genotype of a given host strain and the host range of tested 936-type phages. Such a correlation would allow prediction of the intrinsic 936-type phage sensitivity of a particular lactococcal strain and substantiates the notion that the lactococcal pellicle polysaccharide represents the receptor for (certain) 936-type phages while also partially explaining the molecular reasons behind the observed narrow host range of such phages.
doi:10.1128/AEM.00653-13
PMCID: PMC3697520  PMID: 23666332
18.  Symptoms of Depression and PTSD are Associated with Elevated Alcohol Demand 
Drug and alcohol dependence  2012;127(0):129-136.
BACKGROUND
Behavioral economic demand curves measure individual differences in motivation for alcohol and have been associated with problematic patterns of alcohol use, but little is known about the variables that may contribute to elevated demand. Negative visceral states have been theorized to increase demand for alcohol and to contribute to excessive drinking patterns, but little empirical research has evaluated this possibility. The present study tested the hypothesis that symptoms of depression and PTSD would be uniquely associated with elevated alcohol demand even after taking into account differences in typical drinking levels.
METHOD
An Alcohol Purchase Task (APT) was used to generate a demand curve measure of alcohol reinforcement in a sample of 133 college students (50.4% male, 64.4% Caucasian, 29.5% African-American) who reported at least one heavy drinking episode (5/4 or more drinks in one occasion for a man/woman) in the past month. Participants also completed standard measures of alcohol consumption and symptoms of depression and PTSD.
RESULTS
Regression analyses indicated that symptoms of depression were associated with higher demand intensity (alcohol consumption when price = 0; ΔR2 = .05, p = .002) and lower elasticity (ΔR2 = .04, p = .03), and that PTSD symptoms were associated with all five demand curve metrics (ΔR2 = .04 – .07, ps < .05).
CONCLUSIONS
These findings provide support for behavioral economic models of addiction that highlight the role of aversive visceral states in increasing the reward value of alcohol and provide an additional theoretical model to explain the association between negative affect and problematic drinking patterns.
doi:10.1016/j.drugalcdep.2012.06.022
PMCID: PMC3775331  PMID: 22809894
behavioral economics; alcohol abuse; reinforcement; demand curve; comorbidity
19.  High-resolution Behavioral Economic Analysis of Cigarette Demand to Inform Tax Policy 
Addiction (Abingdon, England)  2012;107(12):2191-2200.
Aims
Novel methods in behavioral economics permit the systematic assessment of the relationship between cigarette consumption and price. Toward informing tax policy, the goals of this study were to conduct a high-resolution analysis of cigarette demand in a large sample of adult smokers and to use the data to estimate the effects of tax increases in ten U.S. States.
Design
In-person descriptive survey assessment.
Setting
Academic departments at three universities.
Participants
Adult daily smokers (i.e., 5+ cigarettes/day; 18+ years old; ≥8th grade education); N = 1056.
Measurements
Estimated cigarette demand, demographics, expired carbon monoxide.
Findings
The cigarette demand curve exhibited highly variable levels of price sensitivity, especially in the form of ‘left-digit effects’ (i.e., very high price sensitivity as pack prices transitioned from one whole number to the next; e.g., $5.80-$6/pack). A $1 tax increase in the ten states was projected to reduce the economic burden of smoking by an average of $531M (range: $93.6M-$976.5M) and increase gross tax revenue by an average of 162% (range: 114%- 247%).
Conclusions
Tobacco price sensitivity is nonlinear across the demand curve and in particular for pack-level left-digit price transitions. Tax increases in U.S. states with similar price and tax rates to the sample are projected to result in substantial decreases in smoking-related costs and substantial increases in tax revenues.
doi:10.1111/j.1360-0443.2012.03991.x
PMCID: PMC3504189  PMID: 22845784
Nicotine Dependence; Cigarette Demand; Behavioral Economics; Tax Policy
20.  Latent factor structure of a behavioral economic cigarette demand curve in adolescent smokers 
Addictive behaviors  2012;37(11):1257-1263.
Behavioral economic demand curves, or quantitative representations of drug consumption across a range of prices, have been used to assess motivation for a variety of drugs. Such curves generate multiple measures of drug demand that are associated with cigarette consumption and nicotine dependence. However, little is known about the relationships among these facets of demand. The aim of the study was to quantify these relationships in adolescent smokers by using exploratory factor analysis to examine the underlying structure of the facets of nicotine incentive value generated from a demand curve measure. Participants were 138 adolescent smokers who completed a hypothetical cigarette purchase task, which assessed estimated cigarette consumption at escalating levels of price/cigarette. Demand curves and five facets of demand were generated from the measure: Elasticity (i.e., 1/α or proportionate price sensitivity); Intensity (i.e., consumption at zero price); Omax (i.e., maximum financial expenditure on cigarettes); Pmax (i.e., price at which expenditure is maximized); and Breakpoint (i.e., the price that suppresses consumption to zero). Principal components analysis was used to examine the latent structure among the variables. The results revealed a two-factor solution, which were interpreted as “Persistence,” reflecting insensitivity to escalating price, and “Amplitude,” reflecting the absolute levels of consumption and price. These findings suggest a two factor structure of nicotine incentive value as measured via a demand curve. If supported, these findings have implications for understanding the relationships among individual demand indices in future behavioral economic studies and may further contribute to understanding of the nature of cigarette reinforcement.
doi:10.1016/j.addbeh.2012.06.009
PMCID: PMC3597467  PMID: 22727784
tobacco; smoking; adolescents; behavioral economics; reinforcement; demand curve; nicotine dependence; motivation
21.  A Randomized Controlled Trial of a Behavioral Economic Supplement to Brief Motivational Interventions for College Drinking 
Objective
Behavioral economic theory suggests that a reduction in substance use is most likely when there is an increase in rewarding substance-free activities. The goal of this randomized controlled clinical trial was to evaluate the incremental efficacy of a novel behavioral economic supplement (Substance-Free Activity Session, SFAS) to a standard alcohol brief motivational interviewing (BMI) session for heavy drinking college students.
Method
Participants were 82 first-year college students (50% female, 81.7% White/European American, Mean age = 18.5 years, SD = .71) who reported two or more past-month heavy drinking episodes. After completing a baseline assessment and an individual alcohol-focused BMI, participants were randomized to either the SFAS or to a Relaxation Training (RT) control session. The SFAS was delivered in an MI style and attempted to increase the salience of delayed academic and career rewards and the patterns of behavior leading to those rewards.
Results
The combination of an alcohol BMI plus the SFAS was associated with significantly greater reductions in alcohol problems compared to an alcohol BMI plus RT at the 1-month and 6-month follow-up assessments (p = .015, ηp2 = .07), an effect that was partially mediated by increases in protective behavioral strategies. BMI + SFAS was also associated with greater reductions in heavy drinking among participants who at baseline reported low levels of substance-free reinforcement or symptoms of depression.
Conclusion
These results are consistent with behavioral economic theory and suggest that a single session focused on increasing engagement in alternatives to drinking can enhance the effects of brief alcohol interventions.
doi:10.1037/a0028763
PMCID: PMC3435453  PMID: 22663899
alcohol; behavioral economics; binge drinking; college; motivational interventions; substance-free reinforcement
22.  SOCS3 binds specific receptor–JAK complexes to control cytokine signaling by direct kinase inhibition 
The inhibitory protein SOCS3 plays a key role in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus Kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between murine SOCS3, JAK2 (kinase domain) and a fragment of the IL-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. Whilst the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phospho-independent manner to a non-canonical surface. The kinase inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2 and biochemical studies show it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action.
doi:10.1038/nsmb.2519
PMCID: PMC3618588  PMID: 23454976
23.  Regulation of Janus Kinases by SOCS proteins 
Biochemical Society transactions  2013;41(4):1042-1047.
Janus Kinases (JAKs) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines. However, aberrant and/or prolonged JAK- induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies. For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels. Primarily this is achieved by: (1) Ensuring the catalytic domain is “switched off” under basal conditions and (2) Inhibiting the activity of JAK after it has been switched on. Whilst the first mode of inhibition is mediated by JAK’s own pseudokinase domain (JH2 domain) as well as the action of phosphatases, the second is achieved by the action of the SOCS (Suppressor of Cytokine Signalling) proteins, negative feedback inhibitors of JAK-mediated signalling. This review focuses on the mode of action of SOCS1 and SOCS3, the two most potent JAK inhibitors.
doi:10.1042/BST20130077
PMCID: PMC3773493  PMID: 23863176
Janus Kinases; SOCS; cytokine signalling; JAK/STAT
24.  A behavioral economic supplement to brief motivational interventions for college drinking 
Addiction research & theory  2012;20(6):456-465.
Basic behavioral and neurobiological research has demonstrated that deficiencies in naturally occurring substance-free rewards are both a cause and a consequence of substance abuse that are due in part to the systematic discounting of delayed substance-free rewards. Existing brief motivational interventions (BMIs) for alcohol abuse do not target this mechanism of change. The goal of this uncontrolled pilot study was to evaluate a behavioral economic Substance-Free Activity Session (SFAS) to traditional alcohol BMIs. Participants were 13 college freshmen who reported two or more heavy drinking episodes (>5/4 drinks in an occasion for men/ women) in the past month. All participants completed a baseline assessment and a BMI that addressed alcohol use. In addition, participants received the SFAS, a 50-min individual session that attempts to increase engagement in constructive alternatives to drinking by enhancing the salience of delayed rewards (academic and career success) and the patterns of behavior (academic and extracurricular engagement) leading to these outcomes. At the 1-month follow-up assessment, participants reported significant reductions in heavy drinking, and moderate to large effect size reductions in weekly drinking and peak blood alcohol levels. The results of this pilot study provide preliminary support for the efficacy of this behavioral economic intervention session as a supplement to traditional alcohol BMIs.
doi:10.3109/16066359.2012.665965
PMCID: PMC3770470  PMID: 24039620
Alcohol; behavioral economics; binge drinking; college; motivational interventions; substance-free reinforcement
25.  A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation 
COPD  2012;9(2):151-159.
The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring
Methods
Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were fifty-eight observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements.
Results
Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively.
Conclusions
Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.
doi:10.3109/15412555.2012.654923
PMCID: PMC3752926  PMID: 22429093

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