Higher-Order Unfolding of Peri/Centric Satellite Heterochromatin is an Early and Consistent Event in Cell Senescence: A Dissertation
Cellular senescence is thought to play an essential role in many biological functions including tumor suppression and organismal aging. Senescent cells, which are permanently removed from the cell cycle, can be found both in vivo in many different tissue types and in vitro within cultures of non-immortalized cells. Despite their inability to proliferate, these cells persist and remain metabolically active for indefinite periods of time. This physiologic process occurs in response to a variety of cellular insults including oxidative stress, shortened telomeres, constitutive oncogene expression, and DNA damage, and can be initiated by upregulation of one of the two known senescent pathways, involving p16/Rb or p53/p21. The senescent cell phenotype is also characterized by changes to cell and nuclear morphology and to the secretory profile of the cell.
Related to changes in nuclear morphology, epigenetic modifications to the packaging of DNA are thought to be key to the initiation and maintenance of the senescence program. While a large number of earlier studies focused on the findings that senescent cells gain regions of condensed heterochromatin, often in the form of Senescent Associated Heterochromatin Foci (SAHF), this thesis work shows that there is a marked loss of heterochromatin in the peri/centromeric regions of the genome. In fact, both α-satellite and satellite II sequences across the genome distend in a striking and unanticipated fashion; this can be readily visualized by fluorescence in situ hybridization (FISH) as their structure changes from a condensed spot to highly elongated and fine thread-like signals. We have termed this exceptional decondensation of constitutive heterochromatin Senescence Associated Distension of Satellites (SADS). Importantly, a series of experiments shows that SADS is both a consistent and an early event in the cell senescence process, which occurs as a result of every senescence induction method examined. We also observed that this distension was characteristic of both human and murine cells and in vivo in human benign Prostatic Intraepithelial Neoplasia (PIN) tissue. Furthermore, unlike SAHF formation, SADS can occur due to the activation of either of the two senescence pathways, p16/Rb or p53/p21.
Additionally, the cytological dimensions of the thread-like satellite signals indicates that SADS represents “unraveling” of DNA on an unprecedented scale. Thus, it was surprising that this event was not facilitated by changes to several canonical histone modifications associated with condensed heterochromatin, namely H3K9Me3, H3K27Me3, or H3K4Me3, nor is it caused by loss of DNA methylation. Consequently, we believe that this marked distension of satellite DNA is due to changes in higher-order folding of the chromatin fiber. This is important for understanding fundamental events in the cell senescence process, but also provides a unique system for study of chromatin packaging that may provide new insights into the organization of DNA well beyond nucleosome packaging and the ten nanometer fiber. In fact, initial super resolution images of SADS suggest that the satellite sequences may be organized into domains or “globules”. Hence, we suggest that the changes to satellite sequence packaging may be facilitated by changes to higher-order nuclear structural proteins, such as LaminB1, which is reduced in senescent cells.
Finally, this work provides analysis of the literature and preliminary experiments to consider the possibility that there are increased levels of cell senescence in Down syndrome (trisomy 21) cells. As individuals with Down syndrome (DS) experience many manifestations of premature aging (including early-onset Alzheimer’s Disease), have a resistance to solid tumor formation, are more susceptible to oxidative stress, and are trisomic for several genes implicated in causing senescence, our analysis provides plausibility for the hypothesis that accelerated rates of senescence may play a significant role in DS physiology. We also provide results of preliminary studies and outline the next steps for experimentation, using DS fibroblasts and a unique genetically engineered DS iPS cell system. As a final note, the quantification of cell senescence in trisomic versus disomic cells for these experiments relies substantially on the new single-cell marker of senescence discovered and established by this theses work, the Senescence-Associated Distension of Satellites.
This chapter examines how clinical investigators ensure the safety of psychiatric research participants while maintaining the integrity of research protocols. It discusses the ethical issues arising from data monitoring, disclosure of interim data, and termination of clinical trials. It outlines unique features of psychiatric research and related cultural issues that may warrant consideration before and during clinical trials. It focuses on the Data Safety Monitoring Boards (DSMBs) overseeing clinical trials their development of detailed plans for monitoring safety and protocol adherence. It looks at the use of statistical programs by DSMBs to document the progression of research studies and make early termination decisions; whether DSMBs actually improve the safety of participants or the integrity of research; how independent DSMBs are; and the factors that DSMBs consider when terminating a trial. Cultural issues involved in clinical trials and challenges that may compromise the neutrality and function of DSMBs are analyzed.
In Selective Allure of Neuroscience and Its Implications for the Courtroom, Shniderman adds to an already long list of reasons for why attorneys and trial consultants should be cautious in using neuroscientific evidence in legal proceedings. Scurich and Shniderman (2014) found that individuals evaluated the scientific validity of neuroscientific evidence based on preexisting beliefs. At first glance, this study might seem like another example of scientists proving a well-known concept that juries and judges bring their individual experiences into the courtroom. In fact, voir dire is premised on identifying individuals with particular types of beliefs that may produce a particular type of verdict. However, on closer examination, the findings from this study highlight a different point – introduction of neuroscientific research may backfire, or in the very least not produce the intended results. And, not knowing how the jury or a judge will interpret a particular type of evidence should be disconcerting to attorneys, legal consultants and experts.
A response to the article: Neuroimagery and the Jury.
An essay about delivering good expert testimony.
The polygraph, an instrument designed to identify deception, first entered the American courtroom more than 90 years ago. In Frye v. United States (1923), the D.C. Circuit Court excluded expert testimony about the findings from a polygraph. The court noted that the “systolic blood pressure deception test, ” the polygraph, had “not yet gained such standing and scientific recognition among physiological and psychological authorities as would justify the courts in admitting expert testimony.…”
Since then, the polygraph and its modern incarnations have continued to incite legal controversy and debate. The public, press and fact finders are no less fascinated with the polygraph now than they were in the beginning of the twentieth century (Keeler, 1930; Myers, Latter, & Abdolahhi-Arena, 2006). Overwhelmingly, courts have banned results of polygraph testing in criminal proceedings (United States v. Scheffer, 1998). The reasoning for this has largely centered on lack of general acceptance in the scientific community and concerns about prejudicial impact of the findings on the jury (Myers et al., 2006). Nevertheless, the polygraph continues to be widely used by law enforcement, in employment screenings, and for specific types of forensic assessments, such as sexual offender evaluations (Grubin, 2010). Accordingly, litigators, corporate counsel, and trial consultants need to have a current understanding of the scientific underpinnings of the polygraph, the improvements to the instrument throughout the decades, and the ongoing controversies regarding the interpretation of results.
High-profile schemes to defraud the elderly of their lifetime savings have headlined top newspapers and tabloids alike. As crime rates -- and vulnerable populations -- increase, the scientific and legal communities must pool our ever-increasing knowledge and resources to protect elderly family members.
Are Measures of Cognitive Effort and Motivation Useful in Differentiating Feigned from Genuine Psychiatric Symptoms?
This study examined the accuracy of two measures of cognitive effort and motivation, the Test of Memory Malingering (TOMM; Tombaugh, 1996) and the Validity Indicator Profile Verbal subtest (VIP-V; Frederick, 2003) using a simulation study design with psychiatric patients (n = 88) and community participants instructed to feign mental illness (n = 29). Little research has evaluated either the TOMM or the VIP in psychiatric patients, a group that may be at an increased risk of misclassification, despite the common use of these measures by forensic evaluators to assess for malingering. Specificity for the TOMM (94.2%) and the VIP-V (71.6%) were somewhat lower than the original validation samples, but Sensitivity rates were mixed: lower for the TOMM (62.1%) but higher for the VIP-V (73.1%). Additionally, VIP-V indicators were examined using Receiver Operating Curve (ROC) and stepwise discriminant analyses. The implications of these results for forensic assessment are discussed.
In United States v. Beatty, 642 F.3d 514 (6th Cir. 2011), the United States Court of Appeals for the Sixth Circuit upheld a decision by the U.S. District Court for the Eastern District of Tennessee to recognize antisocial personality disorder (ASPD) as a mental disease for the purposes of conditional release under the civil commitment statute according to Title 18 United States Code Service (18 U.S.C.S.) § 4243 (hospitalization of a person found not guilty by reason of insanity; 1984).
Gender Differences in Professional Development Among AP-LS Members: Results of the Professional Development of Women Survey
The current survey was designed to examine gender differences in professional development among American Psychology - Law Society (AP-LS) members. The survey was based on the University of California, Irvine NSF ADVANCE survey, and examines issues related to work climate, workload, productivity, job satisfaction, work/life balance, and leadership among AP-LS members.
A partial preview of this chapter is available in Google Books.
This study describes the potential problems and possible solutions to the integration of multiple malingering measures. Multivariate prediction models, using both discriminant function analyses and regression tree approaches, are compared. Study measures, including an abbreviated version of the SIRS (SIRS-A), the MMPI-2, the TOMM and the VIP Verbal subtest, were administered to 29 community members instructed to malinger and 87 psychiatric patients instructed to respond honestly. Predictive accuracy varied substantially across measures and the correlations between tests ranged from .19 to .79. Further, 48% of the psychiatric sample were misclassified as malingering by at least one test and 46% of the malingering sample were classified as honest by at least one test; “unanimous” findings occurred in only half of the cases. Multivariate models identified the SIRS-A as the strongest predictor of malingering, but the MMPI-2, TOMM, and VIP provided significant contributions to these models. The implications of these findings for the problem of multiple, contradictory indicators in general, and the specific problems associated with clinical assessments of malingering in particular, are discussed.
What are we talking about at the annual meetings of ABCT? An analysis of presentations from 1997-2006
The purpose of this article is to bring a descriptive quantitative evaluation of the content of the conferences for the most recent 10-year period, from 1997 through 2006. In this article we focus on areas covered at the conference dealing with psychopathology research and treatment. The annual convention is a forum where the early conceptualizations of psychopathology, and interventions, have been presented and refined. The diversity of problems is impressive: psychotic disorders; health and somatic concerns; depression and related affective disorders; addictions; eating disorders; disorders associated with advanced age; and anxiety disorders, to name just a few. This analysis was intended to be descriptive, and therefore to stimulate additional discussion among members of ABCT. It is our hope that the presentation of this material highlights the current and changing areas of focus at the conference, and therefore in the field of cognitive and behavior therapy (CBT). It is also our hope that it will stimulate discussion about whether we should continue these trends, direct our attention to areas that are not as well represented at the annual conference, or develop a broad range of "tracks" that effectively covers all the various areas of CBT. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
A preview of this chapter is available in Google Books.
Validation of an abbreviated version of the structured interview of reported symptoms in outpatient psychiatric and community settings
This study examined the effectiveness of an abbreviated version of the Structured Interview of Reported Symptoms (SIRS-A) in identifying malingered mental illness. The SIRS-A is comprised of 69 items drawn from the SIRS (R. Rogers et al. 1992, SIRS: Structured Interview of Reported Symptoms: Professional Manual. Odessa, FL: Psychological Assessment Resources, Inc.), substantially reducing the administration time. A simulation design was used with three samples; 87 psychiatric outpatients who responded honestly were compared to 29 community-dwelling adults and 24 psychiatric patients instructed to malinger psychopathology. The SIRS-A generated sensitivity comparable to or exceeding that of the SIRS normative data, but specificity was poorer; many genuinely impaired patients were misclassified as malingering. Although these findings suggest the SIRS-A may be an effective means to assess malingering in psychiatric populations, further research assessing the reasons for the elevated false positive rates is necessary.
Therapeutic misconception (TM)-when clinical research participants fail to adequately grasp the difference between participating in a clinical trial and receiving ordinary clinical care-has long been recognized as a significant problem in consent to clinical trials. We suggest that TM does not primarily reflect inadequate disclosure or participants' incompetence. Instead, TM arises from divergent primary cognitive frames. The researchers' frame places the clinical trial in the context of scientific designs for assessing intervention efficacy. In contrast, most participants have a cognitive frame that is personal and focused primarily on their medical problems. To illustrate this, we draw on interview material from both clinical researchers and participants in clinical trials. We suggest that reducing TM requires encouraging subjects to adjust their frame, not just add information to their existing frame. What is necessary is a scientific reframing of participation in a clinical trial.
Sensing of Endogenous Nucleic Acids by the Innate Immune System during Viral Infection: A Dissertation
Innate sensing of nucleic acids lies at the heart of antiviral host defense. However, aberrant activation of innate sensors by host nucleic acids can also lead to the development of autoimmune diseases. Such host nucleic acids can also be released from stressed, damaged or dying cells into the tissue microenvironment. It however remains unclear how the extracellular nucleic acids impacts the quality of the host immune responses against viral infections. Using a mouse model of influenza A virus (IAV) infection, we uncovered an important immune-regulatory pathway that tempers the intensity of the host-response to infection. We found that host-derived DNA from necrotic cells accumulates in the lung microenvironment during IAV infection, and is sensed by the DNA receptor Absent in Melanoma 2 (AIM2). AIM2-deficiency resulted in severe immune pathology highlighted by enhanced recruitments of immune cells, and excessive systemic inflammation after IAV challenge, which led to increased morbidity and lethality in IAV-infected mice. Interestingly, these effects of AIM2 were largely independent of its ability to mediate IL-1β maturation through inflammasome complexes. Finally, ablation of accumulated DNA in the lung by transgenic expression of DNaseI in vivo had similar effects. Collectively, our results identify a novel mechanism of cross talk between PRR pathways, where sensing of hostderived nucleic acids limits immune mediated damage to virus infected tissues.
Method of administration of PROMIS scales did not significantly impact score level, reliability, or validity
OBJECTIVES: To test the impact of the method of administration (MOA) on score level, reliability, and validity of scales developed in the Patient Reported Outcomes Measurement Information System (PROMIS).
STUDY DESIGN AND SETTING: Two nonoverlapping parallel forms each containing eight items from each of three PROMIS item banks (Physical Function, Fatigue, and Depression) were completed by 923 adults with chronic obstructive pulmonary disease, depression, or rheumatoid arthritis. In a randomized crossover design, subjects answered one form by interactive voice response (IVR) technology, paper questionnaire (PQ), personal digital assistant (PDA), or personal computer (PC) and a second form by PC, in the same administration. Method equivalence was evaluated through analyses of difference scores, intraclass correlations (ICCs), and convergent/discriminant validity.
RESULTS: In difference score analyses, no significant mode differences were found and all confidence intervals were within the prespecified minimal important difference of 0.2 standard deviation. Parallel-forms reliabilities were very high (ICC = 0.85-0.93). Only one across-mode ICC was significantly lower than the same-mode ICC. Tests of validity showed no differential effect by MOA. Participants preferred screen interface over PQ and IVR.
CONCLUSION: We found no statistically or clinically significant differences in score levels or psychometric properties of IVR, PQ, or PDA administration compared with PC.
Can Streamlined Multicriteria Decision Analysis Be Used to Implement Shared Decision Making for Colorectal Cancer Screening
BACKGROUND: Current US colorectal cancer screening guidelines that call for shared decision making regarding the choice among several recommended screening options are difficult to implement. Multicriteria decision analysis (MCDA) is an established method well suited for supporting shared decision making. Our study goal was to determine whether a streamlined form of MCDA using rank-order-based judgments can accurately assess patients' colorectal cancer screening priorities.
METHODS: We converted priorities for 4 decision criteria and 3 subcriteria regarding colorectal cancer screening obtained from 484 average-risk patients using the analytic hierarchy process (AHP) in a prior study into rank-order-based priorities using rank order centroids. We compared the 2 sets of priorities using Spearman rank correlation and nonparametric Bland-Altman limits of agreement analysis. We assessed the differential impact of using the rank-order-based versus the AHP-based priorities on the results of a full MCDA comparing 3 currently recommended colorectal cancer screening strategies. Generalizability of the results was assessed using Monte Carlo simulation.
RESULTS: Correlations between the 2 sets of priorities for the 7 criteria ranged from 0.55 to 0.92. The proportions of differences between rank-order-based and AHP-based priorities that were more than +/-0.15 ranged from 1% to 16%. Differences in the full MCDA results were minimal, and the relative rankings of the 3 screening options were identical more than 88% of the time. The Monte Carlo simulation results were similar.
CONCLUSIONS: Rank-order-based MCDA could be a simple, practical way to guide individual decisions and assess population decision priorities regarding colorectal cancer screening strategies. Additional research is warranted to further explore the use of these methods for promoting shared decision making.