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1.  Peptide neuroregulators: the opioid system as a model. 
Aaron Lerner's work provides a stunning set of examples of substances that help to transmit information in the brain and body. His characterization of alpha-MSH and melatonin and his sparking of interest in the further discovery of previously unknown substances have been of inestimable value for the field of neurobiology. Efforts such as those that Lerner undertook so successfully in the field of investigative dermatology now constitute a major research thrust in the field of behavioral neurochemistry and are directly related to advances in psychiatry and neurology. This review considers aspects of research on the neuropeptides, with particular attention to the endogenous opioid (morphine-like) peptides that are active on neural tissue. Neuropeptide research can be categorized broadly as efforts to discover and characterize new families and classes of active agents, investigations of their genetic and molecular processing, and studies of their relationships to behavior in animals and human beings. This review selectively considers some key research questions and strategies that arise from such research.
PMCID: PMC2589971  PMID: 2938344
2.  Studies on the Cloudman melanoma cell line as a model for the action of MSH. 
A review of the studies done at Yale on the role of MSH in regulating pigmentation and growth of Cloudman (S91) melanoma cells is presented. The areas covered include the isolation and analyses of mutant cell lines unresponsive to MSH; the role of cyclic AMP, cyclic AMP-dependent protein kinases, and protein phosphorylation reactions in the response of MSH; new regulators of the melanogenesis pathway; the cytotoxicity of melanin precursors; the development of methodology for synthesizing 125I-beta-MSH; the use of this ligand to study receptors for MSH; and the chemical and biological properties of phosphorylated isomers of L-dopa, a new class of compounds exhibiting potent bio-activity toward melanocytes. All of the experiments described were carried out in the Department of Dermatology at the Yale University School of Medicine during the tenure of Dr. Aaron B. Lerner as chairman.
PMCID: PMC2589958  PMID: 3008451
3.  Judgments of the lucky across development and culture 
For millennia human beings have believed that it is morally wrong to judge others by the fortuitous or unfortunate events that befall them or by the actions of another person. Rather, an individual’s own intended, deliberate actions should be the basis of his/her evaluation, reward and punishment. In a series of studies we investigate whether such rules guide the judgments of children. The first three studies demonstrate that children view lucky others as more likely than unlucky others to perform intentional good actions. Children similarly assess the siblings of lucky others as more likely to perform intentional good actions than the siblings of unlucky others. The next three studies demonstrate that children as young as 3 years believe that lucky people are nicer than unlucky people. The final two studies find that Japanese children also demonstrate a robust preference for the lucky and their associates. These findings are discussed in relation to Lerner’s just world theory and Piaget’s immanent justice research and in relation to the development of intergroup attitudes.
doi:10.1037/0022-3514.94.5.757
PMCID: PMC2745195  PMID: 18444737
preference for the lucky; immanent justice; evaluative contagion; social cognitive development; cross-cultural psychology
4.  ARE HONORS RECEIVED DURING SURGERY CLERKSHIPS USEFUL IN THE SELECTION OF INCOMING ORTHOPAEDIC RESIDENTS? 
The purpose of this study was to review institutional statistics provided in dean's letters and determine the percentage of honors awarded by institution and clerkship specialty.
Institutional and clerkship aggregate data were compiled from a review of dean's letters from 80 United States medical schools. The percentage of honors awarded during 3rd year clerkships during 2005 were collected for analysis. Across clerkship specialties, there were no statistically significant differences between the mean percentage of honors given by the medical schools examined with Internal Medicine (27.6%) the low and Psychiatry (33.5%) the high. However, inter-institutional variability observed within each clerkship was high, with surgery clerkship percentage of honors ranging from 2% to 75% of the students. This suggests some schools may be more lenient and other more stringent in awarding honors to their students. This inter-institutional variability makes it difficult to compare honors received by students from different medical schools and weakens the receipt of honors as a primary tool for evaluating potential incoming residents.
PMCID: PMC2723699  PMID: 19742092
5.  Mind, Machine, and Creativity: An Artist's Perspective 
The Journal of Creative Behavior  2013;48(2):136-151.
Harold Cohen is a renowned painter who has developed a computer program, AARON, to create art. While AARON has been hailed as one of the most creative AI programs, Cohen consistently rejects the claims of machine creativity. Questioning the possibility for AI to model human creativity, Cohen suggests in so many words that the human mind takes a different route to creativity, a route that privileges the relational, rather than the computational, dimension of cognition. This unique perspective on the tangled web of mind, machine, and creativity is explored by an application of three relational models of the mind to an analysis of Cohen's talks and writings, which are available on his website: www.aaronshome.com.
doi:10.1002/jocb.44
PMCID: PMC4265294  PMID: 25541564
Harold Cohen; Machine creativity; the extended mind hypothesis; anthropomorphism; Charles Sanders Peirce; Cyborg
6.  Could shame and honor save cooperation? 
Shame and honor are mechanisms that expose behavior that falls outside the social norm. With recent six-player public goods experiments, we demonstrated that the threat of shame or the promise of honor led to increased cooperation. Participants were told in advance that after ten rounds two participants would be asked to come forward and write their names on the board in front of the fellow group members. In the shame treatment, the least cooperative players were exposed and wrote their names under the sentence “I donated least” while the honored participants wrote their name under “I donated most.” In both the shame and honor treatments, participants contributed approximately 50% more to the public good, as compared with the control treatment in which all players retained their anonymity. Here, we also discuss how shame and honor differ from full transparency, and some of the challenges to understanding how anonymity and exposure modify behavior.
doi:10.4161/cib.19016
PMCID: PMC3376067  PMID: 22808336
cooperation; honor; public goods game; shame; tragedy of the commons
7.  Forging Faculty Student Relationships at the College Level Using a Freshman Research Experience 
Journal of chemical education  2008;85(12):1696-1698.
Coupling the scholarly activities of the chemistry research faculty with that of the freshman Honors general chemistry class has resulted in a rise of productivity within the Department. For seven years, freshman Honors students enrolled in the Honors general chemistry laboratory sections have been assigned to work in the labs of the research active faculty within the Department of Chemistry. Approximately a quarter of those enrolled in the Honors general chemistry laboratory sections elect to continue their research experience. The continued and sustained research experience has resulted in a research journal paper for six participants. For the past four years, four papers have been accepted for publication because of the research activities conducted as freshman stemming from this program. Each paper has had at least one co-author as an undergraduate at the sophomore or freshman level.
PMCID: PMC2691711  PMID: 19503760
Curriculum; Inquiry-Based / Discovery Learning; Problem Solving / Decision Making; Undergraduate Research
8.  Student-written Simulation Scenarios: A Novel Cognitive Assessment Method In a Trauma Curriculum 
Hawaii Medical Journal  2011;70(8):172-175.
Introduction
Global cognitive and psychomotor assessment in simulation based curricula is complex. We describe assessment of novices' cognitive skills in a trauma curriculum using a simulation aligned facilitated discovery method.
Methods
Third-year medical students in a surgery clerkship completed two student-written simulation scenarios (SWSS) as an assessment method in a trauma curriculum employing high fidelity human patient simulators (manikins). SWSS consisted of written physiologic parameters, intervention responses, a performance evaluation form, and a critical interventions checklist.
Results
Seventy-one students participated. SWSS scores were compared to multiple choice test (MCQ), checklist-graded solo performance in a trauma scenario (STS), and clerkship summative evaluation grades. The SWSS appeared to be slightly better than STS in discriminating between Honors and non-Honors students, although the mean scores of Honors and non-Honors students on SWSS, STS, or MCQ were not significantly different. SWSS exhibited good equivalent form reliability (r=0.88), and higher interrater reliability versus STS (r=0.93 vs r=0.79).
Conclusion
SWSS is a promising assessment method for simulation based curricula.
PMCID: PMC3158380  PMID: 21886310
9.  Reflective Writing in the Competency-Based Curriculum at the Cleveland Clinic Lerner College of Medicine 
The Permanente Journal  2008;12(2):82-88.
The Cleveland Clinic Lerner College of Medicine of Case Western Reserve University is a five-year medical school where the major emphasis is to train physician investigators. In this article we describe our experience with reflective writing in our competency-based medical school, which has reflective practice as one of the nine core competencies. We outline how we use reflective writing as a way to help students develop their reflective practice skills. Reflective writing opportunities, excerpts of student pieces, and faculty and student perspectives are included. We have experienced the value of reflective writing in medical school education and believe elements of our program can be adapted to other training environments.
PMCID: PMC3042298  PMID: 21364819
10.  Anatomists Provide the Foundation for Learning Pathophysiology 
Anatomical Sciences Education  2012;5(2):122-124.
The need for interdisciplinary graduate training programs which prepare students to conceptualize the application of their research in clinical settings continues to grow. Though several programs have been cultivated to address this need, demand still outweighs supply. The following describes a curriculum developed with the intent of incorporating medical knowledge into a PhD graduate training program. Development of this Molecular Medicine program by the Cleveland Clinic Lerner College of Medicine in collaboration with Case Western Reserve University was funded by the Howard Hughes Medical Institute “Med into Grad” initiative. The core curriculum of this program begins with a foundation in Human Physiology and Disease course in which anatomy faculty introduce students to a basic overview of gross anatomy structure and function. This course is followed by five fundamental basic science courses, a composite course focusing on principles of clinical and translation research, a course on laboratory techniques and three, 12-week research rotations. In the second year of the program, students begin their dissertation research, complete their qualifying examination, and partake in an individually-tailored Clinical Experience course. Interdisciplinary graduate programs like this provide another venue for faculty in anatomical sciences to help aspiring translational scientists relate basic science knowledge to human pathophysiology and health.
doi:10.1002/ase.1257
PMCID: PMC3397717  PMID: 22232086
gross anatomy education; anatomy teaching; pathophysiology education; graduate education; curriculum; basic science faculty; integration; translational research
11.  Making the Grade in a Portfolio-Based System: Student Performance and the Student Perspective 
Assessment is such an integral part of the educational system that we rarely reflect on its value and impact. Portfolios have gained in popularity, but much attention has emphasized the end-user and portfolio assessment. Here we focus on the portfolio creator (the student) and examine whether their educational needs are met with such an assessment method. This study aims to investigate how assessment practices influence classroom performance and the learning experience of the student in a graduate education setting. Studied were 33 medical students at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, a program utilizing a portfolio-based system. The students may elect to simultaneously enroll in a Masters program; however, these programs employ traditional letter grades. Thus creating a unique opportunity to assess 25 portfolio only (P) students and 8 portfolio and grade (PG) students concurrently taking a course that counts for both programs. Classroom performance was measured via a comprehensive evaluation where the PG students scored modestly better (median total scores, 72% P vs. 76% PG). Additionally, a survey was conducted to gain insight into student’s perspective on how assessment method impacts the learning experience. The students in the PG group (those receiving a grade) reported increased stress but greater affirmation and self-assurance regarding their knowledge and skill mastery. Incorporation of such affirmation remains a challenge for portfolio-based systems and an area for investigation and improvement.
doi:10.3389/fpsyg.2013.00155
PMCID: PMC3613592  PMID: 23565103
assessment; portfolio; grading; student performance; student perspective
12.  Multiple Sponsor Support for Core Facilities: Effective Communication and Collaboration 
The Lerner Research Institute's core services support all investigators at Cleveland Clinic, including a group of nearly 200 research faculty and their teams, as well as clinical research groups who need access to our centralized technologies. We offer approximately 20 different types of services and instruments ranging from preparation of media and cell lines to genomics and proteomics resources. Services are also available to the greater Cleveland scientific community, with selected cores open to “external” (i.e. non-Cleveland) users as long as capacity permits. Beyond the expected technical and scientific expertise, LRI researchers rely on the cores heavily for education and advice on emerging methodologies and research trends. Core structure is kept flexible by design; annual evaluations of the demand, cost-effectiveness, staffing, and customer satisfaction for each core guide decisions about continued operation or restructuring. The LRI cores are supported in part by the Cleveland Translational Science Collaborative, by the Case Comprehensive Cancer Center, and by multiple PPGs to individual investigators. Resolution of differences in objectives, policies, direction, reporting, and allowable practices among funding sources requires constant, highly effective communication. To this end, we have found that a seemingly pedestrian approach – frequent meetings, scrupulous meeting attendance and insightful, diplomatic selection of meeting participants and agendas – when used consistently and inclusively, has proven effective in resolving most conflicts and generating compromises. In the best of cases, this enlightened cooperativity can result in development of services beyond the standard core fare, such as the development of a service to distribute highly purified, elutriated human peripheral blood cells, made possible by the Clinical Research Unit Core Laboratory in collaboration with 2 PPGs and with the TTR component of the CTSC. Management of ongoing challenges that result from changes in enthusiasm, funding, or direction, requires flexibility and strong institutional support.
PMCID: PMC3635448
13.  Declines in psychiatric care in inpatient settings in Israel mirror global trend 
Levinson and Lerner provide compelling evidence that reforms to the mental health system in Israel led to significant declines in institutional-based care. These declines are similar to those found in other high income countries over the same time period. Additional evidence on concurrent changes to the amount and quality of care in community settings is an important area for future research.
doi:10.1186/2045-4015-2-30
PMCID: PMC3751511  PMID: 23947563
14.  Misery is not Miserly: Sad and Self-Focused Individuals Spend More 
Psychological science  2008;19(6):525-530.
Misery is not miserly: sadness increases the amount of money decision makers give up to acquire a commodity (Lerner, Small, & Loewenstein, 2004). The present research investigated when and why the “misery-is-not-miserly” effect occurs. Drawing on William James’s (1890) concept of the material self, we tested a model specifying relationships among sadness, self-focus, and the amount of money decision makers spend. Consistent with our Jamesian hypothesis, results revealed that self-focus both moderates and mediates the effect of sadness on spending. Results were consistent across males and females. Because the study used real commodities and real money, results hold implications for everyday decisions. They also hold implications for theoretical development. Economic theories of spending may benefit from incorporating psychological theories – specifically theories of emotion and the self.
doi:10.1111/j.1467-9280.2008.02118.x
PMCID: PMC4142804  PMID: 18578840
emotion; sadness; self; self-focus; decision making; choice; behavioral economics
15.  Examining Sexual Dysfunction in Non-Muscle-Invasive Bladder Cancer: Results of Cross-Sectional Mixed-Methods Research 
Sexual Medicine  2014;2(3):141-151.
Introduction
More than 70,000 new cases of bladder cancer are diagnosed in the United States annually; with 75% being non-muscle-invasive (NMIBC). Research examining sexual dysfunction in bladder cancer survivors is limited, and previous studies have focused on cystectomy patients.
Aims
To evaluate the impact of sexual dysfunction on NMIBC survivors.
Methods
Mixed-methods data collection integrated a quantitative survey (Study 1; n = 117) and semi-structured qualitative interviews (Study 2; n = 26) from a non-overlapping sample of NMIBC survivors. We performed descriptive and classification and regression tree (CART) analyses of survey data and qualitative analysis of interviews.
Main Outcome Measures
Self-reported sexual activity, interest in sex, and physiologic symptoms (e.g., male erectile/ejaculatory difficulties, female vaginal dryness) over the previous 4 weeks; partner communication about sexuality; contamination concerns; illness intrusiveness.
Results
Participants in these studies averaged 65 years of age (mean and median) and were male (77%), white (91%), and married (75%). Survey (Study 1) results linked NMIBC treatment to sexual symptoms and relationship issues. Many participants reported sexual inactivity (38.8%). Sexually active participants reported erectile difficulties (60.0%), vaginal dryness (62.5%), and worry about contaminating partner with treatment agents (23.2%). While almost one-half reported the usefulness of talking with partners about sexual function, only one-fifth of participants reported sharing all concerns with their partners. CART analysis supported the importance of communication.
One-half of interviewees (Study 2) reported sexual dysfunction. Two-thirds reported negative impacts on their relationships, including perceived loss of intimacy and divorce; over one-third were sexually inactive for fear of contaminating their partner or spreading NMIBC.
Conclusions
Survivors' sexual symptoms may result from NMIBC, comorbidities, or both. These results inform literature and practice by raising awareness about the frequency of symptoms and the impact on NMIBC survivors' intimate relationships. Further work is needed to design symptom management education programs to dispel misinformation about contamination post-treatment and improve quality of life. Kowalkowski MA, Chandrashekar A, Amiel GE, Lerner SP, Wittmann DA, Latini DM, and Goltz HH. Examining sexual dysfunction in non-muscle-invasive bladder cancer: Results of cross-sectional mixed-methods research. Sex Med 2014;2:141–151.
doi:10.1002/sm2.24
PMCID: PMC4184494  PMID: 25356311
Urinary Bladder Cancer; Sexual Dysfunction; Cancer Survivorship; Partner Communication; Calmette-Guerin Bacillus
16.  Purification and characterization of a simple ribonucleoprotein particle containing small nucleoplasmic RNAs (snRNP) as a subset of RNP containing heterogenous nuclear RNA (hnRNP) from HeLa cells. 
Nucleic Acids Research  1981;9(4):815-830.
A ribonucleoprotein complex whose RNA complement consists exclusively of small nuclear RNA species (snRNA) has been purified from particles containing heterogenous nuclear RNA (hnRNP) from HeLa cells. This was accomplished by taking advantage of their ability to band at a density of about 1.43 g/cm3 in plain cesium chloride as well as in cesium chloride gradients containing 0.5% sarkosyl without prior aldehyde fixation. After these two steps of equilibrium density centrifugation, these snRNPs were still largely contaminated by free proteins (and especially phosphoproteins). A final step of purification by velocity sedimentation in a sucrose gradient containing 0.5 M cesium chloride and 0.5% sarkosyl was efficient in completely eliminating all free proteins. U1, U2, U4, U5 and U6 species according to the nomenclature of Lerner et al. (Nature, (1980) 283, 220-224) were found in these purified snRNPs, while a significant part of U6 and a small amount of U2 were found in the bottom fraction. 5S species behaved entirely as free RNA and is presumably a contaminant of cytoplasmic origin. Electrophoresis of proteins from snRNP labeled in vivo with (35S) methionine, revealed four bands with migrations corresponding to molecular weights ranging between 10,000 and 14,000 daltons.
Images
PMCID: PMC326714  PMID: 6164981
17.  Interaction of snRNAs with rapidly sedimenting nuclear sub-structures (hnRNPs) from HeLa cells. 
Nucleic Acids Research  1983;11(19):6631-6646.
We have shown previously (Liautard et al., 1982, J. Mol. Biol., 162, 623-643) that digestion with micrococcal nuclease under drastic conditions of a pure U1 snRNP, as well as a mixture containing U2, U1, U4, U5 and U6 snRNPs, gives rise to resistant RNA fragments derived from all but U6 snRNAs. As an attempt to elucidate the way in which snRNPs are attached to their native structure, the same approach was applied to hnRNP which are known to contain snRNP (Guimont-Ducamp et al., 1977, Biochimie, 59, 755-758). Micrococcal nuclease digestion of hnRNPs yielded a population of 15-50 nucleotides long resistant fragments of snRNAs. Sequence analyses showed that all fragments previously identified in core snRNPs were also present. Only U2 and U5 snRNAs were further protected as a result of their association with the hnRNP complex (from the cap to nucleotide 32 for U2 and from nucleotide 22 to nucleotide 70 for U5). No additional protected fragment derived from U1, U4 and U6 snRNAs was found. This finding confirms that the 5' terminal region of U1 snRNP remains available for base-pairing interaction with the premessenger RNA, as predicted by the model of Lerner et al. (Nature, 1980, 283, 220-224).
Images
PMCID: PMC326404  PMID: 6195594
18.  Thirty-five years of progress in the study of MSH. 
In this paper, initial work on MSH at Dr. Lerner's laboratory in Portland, Oregon, from 1952 to 1954 is presented. The development of an in vitro bioassay method enabled us to show increased urinary excretion of MSH in Addison's disease. The ability of MSH to increase skin pigmentation in man was also demonstrated. Subsequent work on MSH during the past thirty years is reviewed, such as characterization of alpha- and beta-MSH and their precursors in the pituitary gland and localization of MSH-like peptides in various regions of the brain. Finally there are presented the characterization of gamma-MSH, the hypothermic effect of intracisternal administration of gamma-MSH, the effect of corticortropin releasing factor on increased secretion of alpha-MSH from rat pituitary, and the effect of arginine vasopressin on secretion of alpha-MSH from pituitary adenoma.
PMCID: PMC2589974  PMID: 3008450
19.  Teicoplanin-resistant Staphylococcus aureus expresses a novel membrane protein and increases expression of penicillin-binding protein 2 complex. 
Antimicrobial Agents and Chemotherapy  1993;37(11):2432-2437.
In the recent clinical trials of teicoplanin therapy of endocarditis caused by Staphylococcus aureus, at least one instance of the emergence of teicoplanin-resistant strains during therapy has been reported (G.W. Kaatz, S. M. Seo, N. J. Dorman, and S. A. Lerner, J. Infect. Dis 162:103-108, 1990). We have confirmed, using conventional electrophoresis of EcoRI-digested chromosomal DNA and pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA, that the resistant strain (12873) (MIC, 16 micrograms/ml) is genetically very similar to the susceptible parent (12871) (MIC, 4 micrograms/ml). Kaatz et al. were able to select spontaneous teicoplanin-resistant mutants (10(-9)), suggesting that a single gene might be involved. We have shown that the mutation is highly stable during growth in the absence of teicoplanin. Using Tn551, we have selected insertion mutants of 12873 that become teicoplanin susceptible. We have examined a number of aspects of cell wall physiology in strains 12871 and 12873 and the teicoplanin-susceptible Tn551 mutants of 12873. 12873 was more susceptible to lysostaphin lysis than 12871 and the susceptible Tn551 derivatives of 12873. Autolysis in phosphate buffer (pH 7.5) and cell wall turnover rates were similar in 12871 and 12873. An analysis of membrane proteins revealed the expression of a ca. 35-kDa protein and increased expression of both polypeptides of penicillin-binding protein (PBP) 2 (PBP2) in 12873 relative to 12871 and the Tn551 mutants of 12873. This increased expression was not related to PBP2', since both strains were susceptible to oxacillin in 2% NaCl (MIC, < or = 0.25 microgram/ml) and cellular DNA from neither strain hybridized with a specific mec gene probe. Two independent Tn551 inserts have been mapped to a ca. 117-kb SmaI fragment of the chromosome. These data suggest the possibility that the mutation resulting in resistance to teicoplanin involves the regulation of expression of both polypeptides of PBP2 and a 35-kDa membrane protein.
Images
PMCID: PMC192404  PMID: 8285629
20.  Rash Associated with Coxsackie A9 Infection 
Coxsackie A9 virus was identified by the authors during the fall of 1965 in Montreal in six children with fever and exanthem. Three of the six children were siblings. The exanthem was centrally distributed as described by Lerner et al. and consisted of discrete maculopapules 3 to 4 mm. in diameter. The viral agent was recovered and identified in tissue culture in five cases, while in the sixth Coxsackie type-A lesions were produced in suckling mice. Serological confirmation was obtained in two patients from whom sera were available. In contrast, no exanthem was observed in three older patients with a diagnosis of aseptic meningitis associated with Coxsackie A9 virus. In only one of 16 patients with Coxsackie B virus infection was an exanthem observed during the same period.
The true incidence of Coxsackie A9-associated exanthems is difficult to determine because of the benign nature of the disease.
PMCID: PMC1936635  PMID: 5943201
21.  Proteasome-Independent Activation of Nuclear Factor κB in Cytoplasmic Extracts from Human Endothelial Cells by Rickettsia rickettsii 
Infection and Immunity  1998;66(5):1827-1833.
Interaction of many infectious agents with eukaryotic host cells is known to cause activation of the ubiquitous transcription factor nuclear factor κB (NF-κB) (U. Siebenlist, G. Franzoso, and K. Brown, Annu. Rev. Cell Biol. 10:405–455, 1994). Recently, we reported a biphasic pattern of NF-κB activation in cultured human umbilical vein endothelial cells consequent to infection with Rickettsia rickettsii, an obligate intracellular gram-negative bacterium and the etiologic agent of Rocky Mountain spotted fever (L. A. Sporn, S. K. Sahni, N. B. Lerner, V. J. Marder, D. J. Silverman, L. C. Turpin, and A. L. Schwab, Infect. Immun. 65:2786–2791, 1997). In the present study, we describe activation of NF-κB in a cell-free system, accomplished by addition of partially purified R. rickettsii to endothelial cell cytoplasmic extracts. This activation was rapid, reaching maximal levels at 60 min, and was dependent on the number of R. rickettsii organisms added. Antibody supershift assays using monospecific antisera against NF-κB subunits (p50 and p65) confirmed the authenticity of the gel-shifted complexes and identified both p50-p50 homodimers and p50-p65 heterodimers as constituents of the activated NF-κB pool. Activation occurred independently of the presence of endothelial cell membranes and was not inhibited by removal of the endothelial cell proteasome. Lack of involvement of the proteasome was further confirmed in assays using the peptide-aldehyde proteasome inhibitor MG 132. Activation was not ATP dependent since no change in activation resulted from addition of an excess of the unhydrolyzable ATP analog ATPγS, supplementation with exogenous ATP, or hydrolysis of endogenous ATP with ATPase. Furthermore, Western blot analysis before and after in vitro activation failed to demonstrate phosphorylation of serine 32 or degradation of the cytoplasmic pool of IκBα. This lack of IκBα involvement was supported by the finding that R. rickettsii can induce NF-κB activation in cytoplasmic extracts prepared from T24 bladder carcinoma cells and human embryo fibroblasts stably transfected with a superrepressor phosphorylation mutant of IκBα, rendering NF-κB inactivatable by many known signals. Thus, evidence is provided for a potentially novel NF-κB activation pathway wherein R. rickettsii may interact with and activate host cell transcriptional machinery independently of the involvement of the proteasome or known signal transduction pathways.
PMCID: PMC108131  PMID: 9573057
22.  Partial nucleotide sequence of Rous sarcoma virus-29 provides evidence that the original Rous sarcoma virus was replication defective. 
Journal of Virology  1985;55(3):728-735.
Rous sarcoma virus-29 (RSV-29) is the strain of RSV that has the least number of passages beyond its isolation from chicken tumor no. 1 among all current strains of RSV. Biological characterization indicated that it was replication defective. RNA analysis of nonproducer clones of RSV-29-infected chicken embryonic fibroblasts showed the presence of a subgenomic message of 2.6 kilobases containing src and a genomic RNA of 7.7 kilobases that contains gag, pol, and src, but not env. The src-containing EcoRI fragment of RSV-29 proviral DNA was molecularly cloned. Sequence analysis of the regions flanking src revealed that the env gene was completely deleted in RSV-29 and that the sequence across the deletion was exactly the same as the Bryan high-titer strain of RSV. The sequence immediately 3' to src in RSV-29 was closely related to that of the Prague strain of RSV. The fact that the strain of RSV which has the minimal number of passages beyond its isolation is replication defective supports the hypothesis of Lerner and Hanafusa (J. Virol. 49:549-556, 1984) that the original RSV is a defective transforming virus. This defective transforming virus is postulated to be the precursor to other defective RSVs like the Bryan high-titer strain and to nondefective RSVs like the Prague strain. The particular clone of RSV-29 that we studied also had a short stretch of sequence duplication at the 3' end of the pol gene, which was presumably created by an error of reverse transcription.
Images
PMCID: PMC255056  PMID: 2991593
23.  Characterization of equine infectious anemia virus dUTPase: growth properties of a dUTPase-deficient mutant. 
Journal of Virology  1993;67(5):2592-2600.
The putative dUTPase domain was deleted from the polymerase (pol) gene of equine infectious anemia virus (EIAV) to produce a recombinant delta DUpol Escherichia coli expression cassette and a delta DU proviral clone. Expression of the recombinant delta DUpol polyprotein yielded a properly processed and enzymatically active reverse transcriptase, as determined by immunoblot analysis and DNA polymerase activity gels. Transfection of delta DU provirus into feline (FEA) cells resulted in production of virus that replicated to wild-type levels in both FEA cells and fetal equine kidney cells. In contrast, the delta DU virus replicated poorly (less than 1% of wild-type levels) in primary equine macrophage cultures, as measured by reverse transcriptase assays. Preparations of delta DU virus contained negligible dUTPase activity, which confirms that virion-associated dUTPase is encoded in the pol gene region between the RNase H domain and integrase, as has been demonstrated previously for feline immunodeficiency virus (J. H. Elder, D. L. Lerner, C. S. Hasselkus-Light, D. J. Fontenot, E. Hunter, P. A. Luciw, R. C. Montelaro, and T. R. Phillips, J. Virol. 66:1791-1794, 1992). Our results suggest that virus-encoded dUTPase is dispensable for virus replication in dividing cells in vitro but may be required for efficient replication of EIAV in nondividing equine macrophages, the natural host cells for this virus.
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PMCID: PMC237580  PMID: 8386267
24.  The herpes simplex virus 1 gene for ICP34.5, which maps in inverted repeats, is conserved in several limited-passage isolates but not in strain 17syn+. 
Journal of Virology  1990;64(3):1014-1020.
In a previous study, it was reported that herpes simplex virus 1 (HSV-1) strain F contains a transcribed open reading frame situated in the inverted repeats of the L component between the terminal a sequence and the open reading frame that encodes the alpha 0 gene (J. Chou and B. Roizman, J. Virol. 57: 629-637, 1986). By means of an antibody to repeats of the trimer Ala-Thr-Pro predicted to be specified by the open reading frame, it was shown that the open reading frame specifies a protein (M. Ackermann, J. Chou, M. Sarmiento, R. A. Lerner, and B. Roizman, J. Virol. 58: 843-850, 1986). This open reading frame is absent from the reported sequence of HSV-1(17)syn+ (D. J. McGeoch, M. A. Dalrymple, A. J. Davison, A. Dolan, M. C. Frame, D. McNab, L. J. Perry, J. E. Scott, and P. Taylor, J. Gen. Virol. 69: 1531-1574, 1988; L. J. Perry and D. J. McGeoch, J. Gen. Virol. 69: 2831-2846, 1988). To define the extent of variability in this open reading frame, we compared the sequences of the ICP34.5-encoding open reading frames of the genomes of three strains characterized by limited passage in cell culture with that of the HSV-1(17)syn+ strain. Furthermore, to establish unambiguously that the antibody to the Ala-Thr-Pro repeats reacts with the product of this open reading frame, we inserted a short sequence that encodes a known epitope in frame at the 5' terminus of the coding domain. Our results indicate that with minor variations, the open reading frame is conserved in the three HSV-1 genomes analyzed but not in HSV-1(17)syn+. Thus, two strains contain an inserted amino acid and one strain, isolated from a case of human encephalitis, lacks a seven-amino-acid sequence. The recombinant virus carrying the foreign epitope expressed a slightly slower-migrating protein which reacted with both the rabbit polyclonal antibody to the Ala-Thr-Pro trimer repeats and the monoclonal antibody to the inserted epitope. The implications of the results are discussed.
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PMCID: PMC249211  PMID: 2154589
25.  Satisfaction with Counseling among Black Males in Transition from the Foster Care System 
Using the Multidimensional Adolescent Satisfaction Scale (Garland, Saltzman, & Aarons, 2000), satisfaction with counseling and associated variables were examined among Black males (n = 47) transitioning from the foster care system. Potential associated variables assessed were foster care custody status, counseling status, diagnosis of major depression and disruptive behavior disorder based DSM-IV criteria, history of placement in congregate care settings, attitudes toward mental health services, stigma beliefs, and masculine norms. Results from simultaneous multiple regression analysis showed that attitudes toward mental health services contributed significantly to satisfaction with counseling. Specifically, Black males who expressed more positive attitudes toward mental health services in terms of confidence in mental health professionals and the therapeutic process reported greater satisfaction. Implications and future research directions are discussed.
doi:10.1016/j.childyouth.2008.07.008
PMCID: PMC2637618  PMID: 20046996
Black males; foster care; client satisfaction; counseling; attitudes toward mental health services

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