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1.  Heward Bell 
BMJ : British Medical Journal  2003;326(7389):603.
PMCID: PMC1125496
At last, the field of applied behavior analysis has a beautifully crafted, true textbook that can proudly stand cover to cover and spine to spine beside any of the expensive, imposing, and ornately designed textbooks used by college instructors who teach courses in conventional areas of education or psychology. In this review, I fully laud this development, credit Cooper, Heron, and Heward for making it happen, argue that it signifies a checkered flag for students and professors, and recommend the book for classes in applied behavior analysis everywhere. Subsequently, I review its chapters, each of which could easily stand alone as publications in their own right. Finally, I supply a cautionary note, a yellow flag to accompany the well-earned checkered flag, by pointing out that, as is true with all general textbooks on applied behavior analysis, a major portion of the references involves research on persons who occupy only a tail of the normal distribution. To attain the mainstream role Skinner envisioned and most (if not all) behavior analysts desire, the field will have to increase its focus on persons who reside under the dome of that distribution.
PMCID: PMC2831449
textbooks; applied behavior analysis
3.  In Memoriam Mila Rainof, MD 
Since 1839, Yale medical students have been writing theses as part of their professional training. It is an introduction to the practice of original research, a demanding and sometimes exhausting pursuit. The thesis project promotes a tenacity well suited for the practice of medicine. The thesis advisor has a challenging role as well — one that can only be filled by an individual whose dedication to research is matched with a patience for mentoring students.
In a dedicated commentary included in this issue of the journal, Margaret Drickamer, MD, Associate Professor of Medicine at Yale University, shares her account of one advisor’s relationship to a maturing clinician-scholar. Mila Rainof, MD, was a member of the Yale School of Medicine 2008 graduating class. She died tragically in April 2008, just months prior to beginning an emergency medicine residency in Oakland, California.
By including Drickamer’s commentary with Rainof’s thesis abstract, the Yale Journal of Biology and Medicine honors Rainof’s memory and also celebrates the professional work and scholarly life that took form during her relationship with her thesis advisor.
The Yale School of Medicine has established the Mila Rainof, MD, Memorial Fund in her honor.
PMCID: PMC2496696
4.  In Memoriam 
Human Vaccines & Immunotherapeutics  2012;8(9):1321-1322.
Dr H. Fred Clark, a colleague and friend, passed away on April 28, 2012. Drs Frederick Murphy, Stanley Plotkin, and Paul Offit, who knew Fred at different stages of his career, recall his life.
PMCID: PMC3579916  PMID: 22906941
H. Fred Clark; Stanley Plotkin; vaccines; Paul Offit; rotavirus; Frederick Murphy
5.  Improvement in Psychotic Symptoms After a Gluten-Free Diet in a Boy With Complex Autoimmune Illness 
The American journal of psychiatry  2015;172(3):219-221.
At age 8, “Chris,” a Caucasian boy, experienced intermittent auditory and visual hallucinations, but without bizarre behaviors or much deterioration in functioning. At age 15, he developed a depressed mood, started talking to himself, and became socially withdrawn, and his academic performance declined. He was hospitalized and diagnosed as having major depressive disorder with psychotic features. MRI and EEG showed no abnormalities. Treatment with escitalopram (10 mg/day) and aripiprazole (5 mg/day) had little effect. Several weeks after discharge, he was admitted for a second time with the same diagnosis; a third admission, again with the same diagnosis, occurred several months after that. At age 16, Chris developed visual and auditory hallucinations with homicidal ideations. He cut himself superficially following the command of voice hallucinations, and he was hospitalized again, with the diagnosis changed to schizophrenia, paranoid type.
During this inpatient stay, he was treated with venlafaxine (150 mg/day) and risperidone (1.5 mg/day). During the same admission, a blood test showed the presence of antinuclear antibodies (ANAs), but the patient had no symptoms of any autoimmune disease. In the meantime, he was also receiving clindamycin/benzoyl peroxide and adapaline gels and minocycline for acne and fluticasone nasal spray and albuterol for asthma. An allergy to gluten was demonstrated by an assay (Accessa Labs) that showed only IgE antigluten antibodies. Chris’sparents reported that he developed anallergy to peanuts and soy at about the same time. Gluten was removed from his diet at the suggestion of the mother, a licensed dietitian. After the dietary change, the intensity of Chris’s auditory hallucinations declined dramatically and the violent element diminished, and he was discharged after 9 weeks.
During the next 2 years, Chris remained on a gluten-free diet, which he and his family associated with the disappearance of his psychotic symptoms. Sensitivity to gluten was demonstrated by an assay (Metametrix Clinical Laboratory) of a stool sample that yielded a value of 10.6 mg/dL of IgA antigliadin antibodies, in the top quintile of the reference range. The dosage of risperidone was tapered to 0.5 mg/day, and no auditory or visual hallucinations occurred, although when the dosage was lowered to 0.25 mg/day, Chris reported feeling anxious, and the dosage was returned to 0.5 mg/day for a time. Eventually the risperidone was discontinued completely. Chris was able to return to school, where his academic performance was normal and he joined several athletic teams.
At age 16, after his hospital stay, Chris lost his hearing suddenly and was fitted with a hearing aid. His ANA level was high, and the diagnosis of autoimmune inner ear disease was made. He was treated with prednisone and then methotrexate over a 2-month period. Despite his hearing loss, he has maintained a high level of functioning, including learning to read lips, and he has continued to play competitive sports.
Both of Chris’s parents have a history of seasonal affective disorder, and two grandparents had experienced bouts of depression. The father had hypothyroidism, and the father’s aunt had Crohn’s disease. The mother’s brother had hearing loss with ANAs, and the mother’s cousin had systemic lupus erythematosus. The parents were 32 years old when Chris was born, and the pregnancy and birth were unremarkable, with no complications. He is the second son. Starting in infancy, he had recurrent bouts of otitis media, which were treated with tympanoplasty and continued until age 12. At 3 months, he was diagnosed with eosinophilic gastritis.
PMCID: PMC4477691  PMID: 25727533
6.  Differential Management of the Replication Terminus Regions of the Two Vibrio cholerae Chromosomes during Cell Division 
PLoS Genetics  2014;10(9):e1004557.
The replication terminus region (Ter) of the unique chromosome of most bacteria locates at mid-cell at the time of cell division. In several species, this localization participates in the necessary coordination between chromosome segregation and cell division, notably for the selection of the division site, the licensing of the division machinery assembly and the correct alignment of chromosome dimer resolution sites. The genome of Vibrio cholerae, the agent of the deadly human disease cholera, is divided into two chromosomes, chrI and chrII. Previous fluorescent microscopy observations suggested that although the Ter regions of chrI and chrII replicate at the same time, chrII sister termini separated before cell division whereas chrI sister termini were maintained together at mid-cell, which raised questions on the management of the two chromosomes during cell division. Here, we simultaneously visualized the location of the dimer resolution locus of each of the two chromosomes. Our results confirm the late and early separation of chrI and chrII Ter sisters, respectively. They further suggest that the MatP/matS macrodomain organization system specifically delays chrI Ter sister separation. However, TerI loci remain in the vicinity of the cell centre in the absence of MatP and a genetic assay specifically designed to monitor the relative frequency of sister chromatid contacts during constriction suggest that they keep colliding together until the very end of cell division. In contrast, we found that even though it is not able to impede the separation of chrII Ter sisters before septation, the MatP/matS macrodomain organization system restricts their movement within the cell and permits their frequent interaction during septum constriction.
Author Summary
The genome of Vibrio cholerae is divided into two circular chromosomes, chrI and chrII. ChrII is derived from a horizontally acquired mega-plasmid, which raised questions on the necessary coordination of the processes that ensure its segregation with the cell division cycle. Here, we show that the MatP/matS macrodomain organization system impedes the separation of sister copies of the terminus region of chrI before the initiation of septum constriction. In its absence, however, chrI sister termini remain sufficiently close to mid-cell to be processed by the FtsK cell division translocase. In contrast, we show that MatP cannot impede the separation of chrII sister termini before constriction. However, it restricts their movements within the cell, which allows for their processing by FtsK at the time of cell division. These results suggest that multiple redundant factors, including MatP in the enterobacteriaceae and the Vibrios, ensure that sister copies of the terminus region of bacterial chromosomes remain sufficiently close to mid-cell to be processed by FtsK.
PMCID: PMC4177673  PMID: 25255436
7.  A Human Protein Interaction Network Shows Conservation of Aging Processes between Human and Invertebrate Species 
PLoS Genetics  2009;5(3):e1000414.
We have mapped a protein interaction network of human homologs of proteins that modify longevity in invertebrate species. This network is derived from a proteome-scale human protein interaction Core Network generated through unbiased high-throughput yeast two-hybrid searches. The longevity network is composed of 175 human homologs of proteins known to confer increased longevity through loss of function in yeast, nematode, or fly, and 2,163 additional human proteins that interact with these homologs. Overall, the network consists of 3,271 binary interactions among 2,338 unique proteins. A comparison of the average node degree of the human longevity homologs with random sets of proteins in the Core Network indicates that human homologs of longevity proteins are highly connected hubs with a mean node degree of 18.8 partners. Shortest path length analysis shows that proteins in this network are significantly more connected than would be expected by chance. To examine the relationship of this network to human aging phenotypes, we compared the genes encoding longevity network proteins to genes known to be changed transcriptionally during aging in human muscle. In the case of both the longevity protein homologs and their interactors, we observed enrichments for differentially expressed genes in the network. To determine whether homologs of human longevity interacting proteins can modulate life span in invertebrates, homologs of 18 human FRAP1 interacting proteins showing significant changes in human aging muscle were tested for effects on nematode life span using RNAi. Of 18 genes tested, 33% extended life span when knocked-down in Caenorhabditis elegans. These observations indicate that a broad class of longevity genes identified in invertebrate models of aging have relevance to human aging. They also indicate that the longevity protein interaction network presented here is enriched for novel conserved longevity proteins.
Author Summary
Studies of longevity in model organisms such as baker's yeast, roundworm, and fruit fly have clearly demonstrated that a diverse array of genetic mutations can result in increased life span. In fact, large-scale genetic screens have identified hundreds of genes that when mutated, knocked down, or deleted will significantly enhance longevity in these organisms. Despite great progress in understanding genetic and genomic determinants of life span in model organisms, the general relevance of invertebrate longevity genes to human aging and longevity has yet to be fully established. In this study, we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue. We also show that human genes encoding proteins that interact with human longevity homolog proteins are also changed in expression during human aging. These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity. We also present a collection of novel candidate genes and proteins that may influence human life span.
PMCID: PMC2657003  PMID: 19293945
8.  Segregation of the Replication Terminus of the Two Vibrio cholerae Chromosomes 
Journal of Bacteriology  2006;188(3):1060-1070.
Genome duplication and segregation normally are completed before cell division in all organisms. The temporal relation of duplication and segregation, however, can vary in bacteria. Chromosomal regions can segregate towards opposite poles as they are replicated or can stay cohered for a considerable period before segregation. The bacterium Vibrio cholerae has two differently sized circular chromosomes, chromosome I (chrI) and chrII, of about 3 and 1 Mbp, respectively. The two chromosomes initiate replication synchronously, and the shorter chrII is expected to complete replication earlier than the longer chrI. A question arises as to whether the segregation of chrII also is completed before that of chrI. We fluorescently labeled the terminus regions of chrI and chrII and followed their movements during the bacterial cell cycle. The chrI terminus behaved similarly to that of the Escherichia coli chromosome in that it segregated at the very end of the cell division cycle: cells showed a single fluorescent focus even when the division septum was nearly complete. In contrast, the single focus representing the chrII terminus could divide at the midcell position well before cell septation was conspicuous. There were also cells where the single focus for chrII lingered at midcell until the end of a division cycle, like the terminus of chrI. The single focus in these cells overlapped with the terminus focus for chrI in all cases. It appears that there could be coordination between the two chromosomes through the replication and/or segregation of the terminus region to ensure their segregation to daughter cells.
PMCID: PMC1347332  PMID: 16428410
9.  Distinct Centromere-Like parS Sites on the Two Chromosomes of Vibrio spp.▿  
Journal of Bacteriology  2007;189(14):5314-5324.
Vibrio cholerae, the cause of cholera, has two circular chromosomes. The parAB genes on each V. cholerae chromosome act to control chromosome segregation in a replicon-specific fashion. The chromosome I (ChrI) parAB genes (parAB1) govern the localization of the origin region of ChrI, while the chromosome II (ChrII) parAB genes (parAB2) control the segregation of ChrII. In addition to ParA and ParB proteins, Par systems require ParB binding sites (parS). Here we identified the parS sites on both V. cholerae chromosomes. We found three clustered origin-proximal ParB1 binding parS1 sites on ChrI. Deletion of these three parS1 sites abrogated yellow fluorescent protein (YFP)-ParB1 focus formation in vivo and resulted in mislocalization of the ChrI origin region. However, as observed in a parA1 mutant, mislocalization of the ChrI origin region in the parS1 mutant did not compromise V. cholerae growth, suggesting that additional (non-Par-related) mechanisms may mediate the partitioning of ChrI. We also identified 10 ParB2 binding parS2 sites, which differed in sequence from parS1. Fluorescent derivatives of ParB1 and ParB2 formed foci only with the cognate parS sequence. parABS2 appears to form a functional partitioning system, as we found that parABS2 was sufficient to stabilize an ordinarily unstable plasmid in Escherichia coli. Most parS2 sites were located within 70 kb of the ChrII origin of replication, but one parS2 site was found in the terminus region of ChrI. In contrast, in other sequenced vibrio species, the distribution of parS1 and parS2 sites was entirely chromosome specific.
PMCID: PMC1951861  PMID: 17496089
10.  High fives motivate: the effects of gestural and ambiguous verbal praise on motivation 
The type of praise children receive influences whether children choose to persist after failure. One mechanism through which praise affects motivation is through the causal attributions inferred from language. For example, telling a child “You got an A on the test because you’re smart,” provides an explicit link between possessing a trait and an outcome, specifically that intelligence causes success. Nonetheless, most praise given to children is ambiguous, or lacks explicit attributions (e.g., “yea” or a thumbs up). To investigate the effects of ambiguous praise on motivation, we randomly assigned 95 5–6-year-old children to a praise condition (verbal trait; verbal effort; verbal ambiguous; or gestural) and measured motivation using task persistence, self-evaluations, and eye fixations on errors. Ambiguous praise, similar to verbal effort praise, produced higher persistence and self-evaluations, and fewer fixations on error after failure compared to verbal trait praise. Interestingly, gestures produced the highest self-evaluations. Thus, praise without explicit attributions motivated as well or better than praise explicitly focused on effort, which may suggest that children interpret ambiguous praise in the most beneficial manner.
PMCID: PMC4145712  PMID: 25221532
praise; gesture; motivation; attribution; development
11.  Insensitivity of Chromosome I and the Cell Cycle to Blockage of Replication and Segregation of Vibrio cholerae Chromosome II 
mBio  2012;3(3):e00067-12.
Vibrio cholerae has two chromosomes (chrI and chrII) whose replication and segregation are under different genetic controls. The region covering the replication origin of chrI resembles that of the Escherichia coli chromosome, and both origins are under control of the highly conserved initiator, DnaA. The origin region of chrII resembles that of plasmids that have iterated initiator-binding sites (iterons) and is under control of the chrII-specific initiator, RctB. Both chrI and chrII encode chromosome-specific orthologs of plasmid partitioning proteins, ParA and ParB. Here, we have interfered with chrII replication, segregation, or both, using extra copies of sites that titrate RctB or ParB. Under these conditions, replication and segregation of chrI remain unaffected for at least 1 cell cycle. In this respect, chrI behaves similarly to the E. coli chromosome when plasmid maintenance is disturbed in the same cell. Apparently, no checkpoint exists to block cell division before the crippled chromosome is lost by a failure to replicate or to segregate. Whether blocking chrI replication can affect chrII replication remains to be tested.
Chromosome replication, chromosome segregation, and cell division are the three main events of the cell cycle. They occur in an orderly fashion once per cell cycle. How the sequence of events is controlled is only beginning to be answered in bacteria. The finding of bacteria that possess more than one chromosome raises the important question: how are different chromosomes coordinated in their replication and segregation? It appears that in the evolution of the two-chromosome genome of V. cholerae, either the secondary chromosome adapted to the main chromosome to ensure its maintenance or it is maintained independently, as are bacterial plasmids. An understanding of chromosome coordination is expected to bear on the evolutionary process of chromosome acquisition and on the efficacy of possible strategies for selective elimination of a pathogen by targeting a specific chromosome.
PMCID: PMC3350373  PMID: 22570276
12.  Chromosome I Controls Chromosome II Replication in Vibrio cholerae 
PLoS Genetics  2014;10(2):e1004184.
Control of chromosome replication involves a common set of regulators in eukaryotes, whereas bacteria with divided genomes use chromosome-specific regulators. How bacterial chromosomes might communicate for replication is not known. In Vibrio cholerae, which has two chromosomes (chrI and chrII), replication initiation is controlled by DnaA in chrI and by RctB in chrII. DnaA has binding sites at the chrI origin of replication as well as outside the origin. RctB likewise binds at the chrII origin and, as shown here, to external sites. The binding to the external sites in chrII inhibits chrII replication. A new kind of site was found in chrI that enhances chrII replication. Consistent with its enhancing activity, the chrI site increased RctB binding to those chrII origin sites that stimulate replication and decreased binding to other sites that inhibit replication. The differential effect on binding suggests that the new site remodels RctB. The chaperone-like activity of the site is supported by the finding that it could relieve the dependence of chrII replication on chaperone proteins DnaJ and DnaK. The presence of a site in chrI that specifically controls chrII replication suggests a mechanism for communication between the two chromosomes for replication.
Author Summary
Genome maintenance in dividing cells requires that the chromosomes replicate reliably once per cell cycle, and that this replication be timed to allow for proper segregation of the daughter chromosomes before cell division. In organisms with divided genomes, eukaryotes and a significant class of bacteria, the chromosomes must avoid interference with one another. They exhibit disciplined chromosome choreography, involving several regulators and control circuits that, even in the simplest organisms, are poorly understood. Here we examine the regulatory processes involved in maintaining the two chromosomes of the well-studied and medically important pathogen Vibrio cholerae. We provide evidence that a site in chromosome I can control the frequency and timing of replication of chromosome II. The mechanism involves a DNA-mediated remodeling of the chromosome II-specific initiator of replication by the chromosome I site. The site enhances the activity of the protein by differentially affecting its affinity for inhibitory and stimulatory sites on chromosome II. Our results provide the groundwork for determining whether coordination of replication might be a conserved feature that maintains chromosomes in proliferating cells of higher organisms.
PMCID: PMC3937223  PMID: 24586205
13.  Prosocial Family Processes and the Quality of Life of Persons With Schizophrenia 
Research on the family’s contribution to the quality of life of persons with serious mental illness has largely focused on negative family interactions associated with poorer client outcomes. The purpose of this naturalistic study of aging mothers and adults with schizophrenia was to investigate prosocial family processes that potentially enhance, rather than detract from, the life satisfaction of persons with serious mental illness.
The data were drawn from a longitudinal study of aging parents caring for a son or daughter with schizophrenia. This report is based on 122 mother–adult child dyads who participated in the third wave of the study. Mothers completed an in-home interview and questionnaire that included measures of the quality of the relationship between the mother and adult child, maternal warmth, and maternal praise of the adult child. The adult with schizophrenia completed a life satisfaction questionnaire.
The adults with schizophrenia had higher life satisfaction when their mothers expressed greater warmth and praise of their son or daughter with schizophrenia and when their mothers reported the quality of their relationship as being close and mutually supportive.
Past research has emphasized changing families, most typically by lowering expressed emotion, with little emphasis on the families’ strengths, in particular, prosocial family processes that may enhance the life satisfaction of their loved one. As a recovery orientation focuses on the strengths of adults with mental illness, it also should focus equally on the supportive presence of families in the lives of clients.
PMCID: PMC2396525  PMID: 17158493
14.  Genome increase as a clock for the origin and evolution of life 
Biology Direct  2006;1:17.
The size of non-redundant functional genome can be an indicator of biological complexity of living organisms. Several positive feedback mechanisms including gene cooperation and duplication with subsequent specialization may result in the exponential growth of biological complexity in macro-evolution.
I propose a hypothesis that biological complexity increased exponentially during evolution. Regression of the logarithm of functional non-redundant genome size versus time of origin in major groups of organisms showed a 7.8-fold increase per 1 billion years, and hence the increase of complexity can be viewed as a clock of macro-evolution. A strong version of the exponential hypothesis is that the rate of complexity increase in early (pre-prokaryotic) evolution of life was at most the same (or even slower) than observed in the evolution of prokaryotes and eukaryotes.
The increase of functional non-redundant genome size in macro-evolution was consistent with the exponential hypothesis. If the strong exponential hypothesis is true, then the origin of life should be dated 10 billion years ago. Thus, the possibility of panspermia as a source of life on earth should be discussed on equal basis with alternative hypotheses of de-novo life origin. Panspermia may be proven if bacteria similar to terrestrial ones are found on other planets or satellites in the solar system.
This article was reviewed by Eugene V. Koonin, Chris Adami and Arcady Mushegian.
PMCID: PMC1526419  PMID: 16768805
15.  Predictors of Exceptional Longevity: Effects of Early-Life Childhood Conditions, Midlife Environment and Parental Characteristics 
Living to 100 monograph  2014;2014:1-18.
Knowledge of strong predictors of mortality and longevity is very important for actuarial science and practice. Earlier studies found that parental characteristics as well as early-life conditions and midlife environment play a significant role in survival to advanced ages. However, little is known about the simultaneous effects of these three factors on longevity. This ongoing study attempts to fill this gap by comparing centenarians born in the United States in 1890–91 with peers born in the same years who died at age 65. The records for centenarians and controls were taken from computerized family histories, which were then linked to 1900 and 1930 U.S. censuses. As a result of this linkage procedure, 765 records of confirmed centenarians and 783 records of controls were obtained.
Analysis with multivariate logistic regression found that parental longevity and some midlife characteristics proved to be significant predictors of longevity while the role of childhood conditions was less important. More centenarians were born in the second half of the year compared to controls, suggesting early origins of longevity. We found the existence of both general and gender-specific predictors of human longevity. General predictors common for men and women are paternal and maternal longevity. Gender-specific predictors of male longevity are the farmer occupation at age 40, Northeastern region of birth in the United States and birth in the second half of year. A gender-specific predictor of female longevity is surprisingly the availability of radio in the household according to the 1930 U.S. census.
Given the importance of familial longevity as an independent predictor of survival to advanced ages, we conducted a comparative study of biological and nonbiological relatives of centenarians using a larger sample of 1,945 validated U.S. centenarians born in 1880–95. We found that male gender of centenarian has significant positive effect on survival of adult male relatives (brothers and fathers) but not female blood relatives. Life span of centenarian siblings-in-law is lower compared to life span of centenarian siblings and does not depend on centenarian gender. Wives of male centenarians (who share lifestyle and living conditions) have a significantly better survival compared to wives of centenarians' brothers. This finding demonstrates an important role of shared familial environment and lifestyle in human longevity.
The results of this study suggest that familial background, early-life conditions and midlife characteristics play an important role in longevity.
PMCID: PMC4318523  PMID: 25664346
16.  Buffering Mechanisms in Aging: A Systems Approach Toward Uncovering the Genetic Component of Aging 
PLoS Computational Biology  2007;3(8):e170.
An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the “oldest old” Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.
Author Summary
Previous research showed that the frequency of deleterious genotype of some age-related disease decreases its prevalence as the population ages, as expected, since subjects with deleterious genotype are weeded out due to mortality. There exists, however, a set of age-related genes whose deleterious genotype indeed decreases up to ages 80–85, but subsequently increases monotonically, until by age 100 its prevalence is similar to that at age ∼60. Why is a known harmful genotype so prevalent among centenarians? Most likely because this genotype is protected by longevity genes. We corroborated this hypothesis by studying gene–gene interactions between age-related disease genotypes and longevity genotypes. Our findings suggest that individuals with the favorable longevity genotype can have just as many deleterious aging genotypes as the rest of the population because their longevity genotype protects them from the harmful effects of the other. We identify genes contributing to extreme lifespan as well as their counterpart, age-related disease genes. Our findings provide a proof of concept for the utility of high-throughput methods, and for elucidating mechanisms by which longevity genes buffer the effects of disease genes. Our approach gives hope for developing new medications that will protect against several age-related diseases.
PMCID: PMC1963511  PMID: 17784782
17.  Effects of an audio cueing system on the rate of teacher praise1 
The effects of automated cueing on teacher praise rate was investigated in one special, one fourth-, and one seventh-grade classroom. After establishing baseline praise rates in each of the three classrooms, two methods for increasing teacher praise rate were introduced according to a multiple-baseline design. During the first phase, two teachers were instructed to count and graph their praise rate during each session. All teachers received auditory cues to prompt praising during another phase. In all cases, introduction of cues markedly increased teacher praise rates, but self-recording was relatively ineffective. An analysis of teacher-praise distributions showed that cues closely controlled teacher praise for two of the three teachers.
PMCID: PMC1311838  PMID: 16795494
cueing; prompting; praise; classroom; response rate; children
18.  The effects of experimenter's instructions, feedback, and praise on teacher praise and student attending behavior1 
Systematic use of experimenter's instructions, feedback, and feedback plus social praise was used to increase teacher praise for student attending behavior of three elementary school teachers. Experimenter's verbal interactions with teachers, teacher's verbal praise for student behaviors, and pupil attending behavior were recorded during baseline conditions. As the three successive experimental conditions were introduced first with Teacher A, then with Teacher B, in a multiple baseline design, behaviors of the experimenter, the two teachers, and eight students were measured and recorded. In the cases of Teachers A and B, experimental condition one (Instructions) and experimental condition two (Feedback) produced inconclusive results. Experimental condition three (Feedback Plus Social Praise) produced more teacher praise for student attending behavior. The entire “Package” of Experimenter's Instructions, Feedback, and Feedback Plus Social Praise was introduced to Teacher C in a single experimental condition. As in the cases of Teachers A and B, behaviors measured were: (1) the experimenter's verbal interactions, (2) the teacher's praise of students, and (3) the student's attending behavior. Introduction of the “Package” also produced more teacher praise for student attending behavior.
PMCID: PMC1310810  PMID: 16795399
19.  Social Rewards Enhance Offline Improvements in Motor Skill 
PLoS ONE  2012;7(11):e48174.
Motor skill memory is first encoded online in a fragile form during practice and then converted into a stable form by offline consolidation, which is the behavioral stage critical for successful learning. Praise, a social reward, is thought to boost motor skill learning by increasing motivation, which leads to increased practice. However, the effect of praise on consolidation is unknown. Here, we tested the hypothesis that praise following motor training directly facilitates skill consolidation. Forty-eight healthy participants were trained on a sequential finger-tapping task. Immediately after training, participants were divided into three groups according to whether they received praise for their own training performance, praise for another participant's performance, or no praise. Participants who received praise for their own performance showed a significantly higher rate of offline improvement relative to other participants when performing a surprise recall test of the learned sequence. On the other hand, the average performance of the novel sequence and randomly-ordered tapping did not differ between the three experimental groups. These results are the first to indicate that praise-related improvements in motor skill memory are not due to a feedback-incentive mechanism, but instead involve direct effects on the offline consolidation process.
PMCID: PMC3492334  PMID: 23144855
20.  Evolution of DNA polymerases: an inactivated polymerase-exonuclease module in Pol ε and a chimeric origin of eukaryotic polymerases from two classes of archaeal ancestors 
Biology Direct  2009;4:11.
Evolution of DNA polymerases, the key enzymes of DNA replication and repair, is central to any reconstruction of the history of cellular life. However, the details of the evolutionary relationships between DNA polymerases of archaea and eukaryotes remain unresolved.
We performed a comparative analysis of archaeal, eukaryotic, and bacterial B-family DNA polymerases, which are the main replicative polymerases in archaea and eukaryotes, combined with an analysis of domain architectures. Surprisingly, we found that eukaryotic Polymerase ε consists of two tandem exonuclease-polymerase modules, the active N-terminal module and a C-terminal module in which both enzymatic domains are inactivated. The two modules are only distantly related to each other, an observation that suggests the possibility that Pol ε evolved as a result of insertion and subsequent inactivation of a distinct polymerase, possibly, of bacterial descent, upstream of the C-terminal Zn-fingers, rather than by tandem duplication. The presence of an inactivated exonuclease-polymerase module in Pol ε parallels a similar inactivation of both enzymatic domains in a distinct family of archaeal B-family polymerases. The results of phylogenetic analysis indicate that eukaryotic B-family polymerases, most likely, originate from two distantly related archaeal B-family polymerases, one form giving rise to Pol ε, and the other one to the common ancestor of Pol α, Pol δ, and Pol ζ. The C-terminal Zn-fingers that are present in all eukaryotic B-family polymerases, unexpectedly, are homologous to the Zn-finger of archaeal D-family DNA polymerases that are otherwise unrelated to the B family. The Zn-finger of Polε shows a markedly greater similarity to the counterpart in archaeal PolD than the Zn-fingers of other eukaryotic B-family polymerases.
Evolution of eukaryotic DNA polymerases seems to have involved previously unnoticed complex events. We hypothesize that the archaeal ancestor of eukaryotes encoded three DNA polymerases, namely, two distinct B-family polymerases and a D-family polymerase all of which contributed to the evolution of the eukaryotic replication machinery. The Zn-finger might have been acquired from PolD by the B-family form that gave rise to Pol ε prior to or in the course of eukaryogenesis, and subsequently, was captured by the ancestor of the other B-family eukaryotic polymerases. The inactivated polymerase-exonuclease module of Pol ε might have evolved by fusion with a distinct polymerase, rather than by duplication of the active module of Pol ε, and is likely to play an important role in the assembly of eukaryotic replication and repair complexes.
This article was reviewed by Patrick Forterre, Arcady Mushegian, and Chris Ponting. For the full reviews, please go to the Reviewers' Reports section.
PMCID: PMC2669801  PMID: 19296856
21.  Health-Related Quality of Life (HRQL) in Children with Sickle Cell Disease and Thalassemia Following Hematopoietic Stem Cell Transplant (HSCT) 
Pediatric blood & cancer  2011;59(4):725-731.
Little is known regarding the health-related quality of life (HRQL) trajectory of children with sickle cell disease or thalassemia (“hemoglobinopathies”) following hematopoietic stem cell transplantation (HSCT).
We serially evaluated the HRQL of 13 children with hemoglobinopathies who received HSCT during two prospective multi-center studies using the Child Health Ratings Inventories (CHRIs). The HRQL scores among children with hemoglobinopathies, as reported separately by the children and their parents were compared using repeated measures models to scores of a comparison group of children receiving HSCT for malignancies or severe aplastic anemia.
The sample included 13 children with hemoglobinopathies (median age: 8 years, range 5–18) and 268 children in the comparison group (median age: 11 years, range 5–18). There were similar rates of early infection, chronic GVHD and all-cause mortality between the two groups. There was no significant difference in recovery to baseline scores for physical, emotional, and role functioning by three months for either group. Children with hemoglobinopathies had higher HRQL scores for physical (beta=12, se=5.5, p=0.01) and baseline emotional functioning (beta=11.6, se=5.5, p=0.03) than the comparison group. For all domains for both groups, parent reports demonstrated a nadir at 45 days with recovery to baseline by three months following transplant. Children’s ratings were higher than those of their parents in both diagnostic groups.
Children with hemoglobinopathies had higher physical and emotional functioning scores prior to HSCT and experienced a similar pattern of recovery to their baseline functioning by three months post-HSCT when compared to children receiving HSCT for acquired conditions.
PMCID: PMC3319491  PMID: 22183952
sickle cell disease; thalassemia; hematopoietic stem cell transplant; health-related quality of life
22.  Transforming and Sustaining the Care Environment 
Global Advances in Health and Medicine  2014;3(Suppl 1):BPA11.
Caring Science Theory and Practices have been part of the Kaiser Permanente's Strategic Priority for Kaiser Permanente Northern Region since 2010. Their goal is to ensure the continued spread across the medical center of practices guided by the Caring Sciences framework that fosters caring-healing environments and that reinforce helping-trusting relationships between caregivers and between caregivers and patients.
Gaining senior-level leader sponsorship is an essential element to integrate and sustain a program in our culture and obtain successful outcomes. The senior level leader sponsorship for HeartMath consists of Chris Boyd, senior vice-president/area manager; Sue G. Murphy, chief operating officer; Anne M. Goldfisher, chief nursing officer; and Barbara Hounslow, care experience leader. Effectively selecting the HeartMath Trainers was essential in helping ensure that the program outcomes were obtained. The four key elements determined in the trainer selection process were (1) trainers selected in contextual alignment with our strategic goals; (2) leveraged key leader/RN staff relationships in trainer selection; (3) trainers committed to advance culture of Caring Science with HeartMath; the chief nursing officer becoming a trainer, emphasizing consistent leadership support.
In planning and implementing the training program, an infrastructure was set up to focus on specific units and service lines. This included developing a “pull” message addressing the aspects of staffing realities and the training process. As lessons were learned, adjustments were made in process to suit the culture. A plan was constructed to support the staff on the units to sustain their practice after the training.
During a 12-month period, more than 400 nurses, leaders, and other support staff trained. The response was overwhelmingly positive. The participant perceptions at program completion are described in the Results section. Other benefits included improved relationships between nursing staff and leaders. The trainers reported being deeply impacted on both professional and personal levels.
Of the 400 participants trained from June 2011 to June 2012, 263 completed both the pre and post surveys. Eight of the 14 metrics showed statistically significant changes. They were work attitude, goal clarity, communication effectiveness, time pressure, intention to quit, strategic understanding, and productivity. Improvements were also noted in well-being, quality of life, impacts on patient satisfaction, safety, and reduction of absenteeism.
PMCID: PMC3923288
Caring Science; absenteeism; stress reduction; HeartMath; biofeedback
23.  Parental Emotional Functioning Declines with Occurrence of Clinical Complications in Pediatric Hematopoietic Stem Cell Transplant 
Parents’ stress levels are high prior to their child's hematopoietic stem cell transplant (HSCT) and during transplant hospitalization, usually abating after discharge. Nevertheless, a subgroup of parents continues to experience frequent anxiety and mood disruption, the causes of which are not well understood. The purpose of this study was to assess whether clinical complications of HSCT could explain variation in parents’ recovery of emotional functioning.
Pediatric HSCT recipients (n=165) aged 5 to 18 and their parents were followed over the first year post-transplant. Health-related quality of life (HRQL) assessments and medical chart reviews were performed at each time period (baseline, 45 days, 3, 6, and 12 months). We tested the association between clinical complications (acute and chronic graft versus host disease - aGVHD and cGVHD, organ toxicity, and infection) and longitudinally measured parental emotional functioning, as assessed by the Child Health-Ratings Inventories (CHRIs). The models used maximum likelihood estimation with repeated measures.
In adjusted analyses covering the early time period (45 days and 3 months), aGVHD grade ≥ 2, intermediate or poor organ toxicity, and systemic infection were associated with decreases in mean parental emotional functioning of 5.2 (p=0.086), 5.8 (p=0.052), and 5.1 (p=0.023) points, respectively. In the later time period (6 and 12 months) systemic infection was associated with a decrease of 20 points (p<0.0001). cGVHD was not significantly associated.
When children experience clinical complications after HSCT, parental emotional functioning can be impacted. Intervening at critical junctures could mitigate potential negative consequences for parents and their children.
PMCID: PMC3540150  PMID: 22936494
Pediatric hematopoietic stem cell transplant; Parental emotional functioning; Parental distress; Transplant-related toxicity
24.  Early severe HIV disease precedes early antiretroviral therapy in infants: Are we too late? 
To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa.
This was a programmatic cohort study.
Electronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t-test and Kaplan–Meier methods.
A total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2–9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4% <25% or absolute CD4<1500 cells/mm3 or WHO clinical Stage 3 or 4). Median age at ART initiation by site was 10.3 (IQR: 8.2–11.9) weeks in Cape Town and 8.6 (IQR: 7.7–10.0) weeks in Soweto infants (p<0.0001). In Cape Town, 73 infants (83%) had advanced HIV disease at ART initiation, compared to 177 infants (56%) in Soweto (p<0.0001). On logistic regression, each month increase in age at ART initiation lowered the odds of initiating ART in an optimal state (OR: 0.56, CI: 0.36–0.94) and increased the odds of advanced HIV disease at ART initiation (OR: 1.69, CI: 1.05–2.71).
ART initiation by three months of age may not adequately prevent disease progression. New emphasis on early diagnosis and rapid initiation of ART in the first weeks of life are essential to further reduce infant mortality.
PMCID: PMC4056161  PMID: 24925044
infant HIV; antiretroviral therapy; South Africa; early infant diagnosis; programmatic cohort
25.  MS/MS-based networking and peptidogenomics guided genome mining revealed the stenothricin gene cluster in Streptomyces roseosporus 
The Journal of antibiotics  2013;67(1):99-104.
Most (75%) of the anti-infectives that save countless lives and enormously improve quality of life originate from microbes found in nature. Herein, we described a global visualization of the detectable molecules produced from a single microorganism, which we define as the ‘molecular network’ of that organism, followed by studies to characterize the cellular effects of antibacterial molecules. We demonstrate that Streptomyces roseosporus produces at least four non-ribosomal peptide synthetase-derived molecular families and their gene subnetworks (daptomycin, arylomycin, napsamycin and stenothricin) were identified with different modes of action. A number of previously unreported analogs involving truncation, glycosylation, hydrolysis and biosynthetic intermediates and/or shunt products were also captured and visualized by creation of a map through MS/MS networking. The diversity of antibacterial compounds produced by S. roseosporus highlights the importance of developing new approaches to characterize the molecular capacity of an organism in a more global manner. This allows one to more deeply interrogate the biosynthetic capacities of microorganisms with the goal to streamline the discovery pipeline for biotechnological applications in agriculture and medicine. This is a contribution to a special issue to honor Chris Walsh’s amazing career.
PMCID: PMC3919142  PMID: 24149839
BioMAP; biosynthesis; cyclic peptides; cytological profiling; mass spectrometry; metabolic exchange

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