The Role of ZMYND8 in Immunoglobulin Class Switch Recombination

Class switch Recombination (CSR) also known as Immunoglobulin (Ig) Class switching is a genomic recombination/deletion reaction that diversifies the effector component of the antibody response but preserves antigen specificity. CSR is initiated by the enzyme activation induced cytidine deaminase (AID), which produces nucleotide mismatches in actively transcribed immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3’ Regulatory Region (3’RR), a prototypical super-enhancer located at the 3’ of the Igh locus, is essential for acceptor switch region transcription, but the mechanism by which it regulates this process is not well defined. After targeting by AID, nearby mismatches in the donor switch region are processed into DNA double strand breaks (DSBs), translocated to DSBs in the acceptor switch region, and ligated through the DNA Damage Repair (DDR) pathway, non-homologous end-joining (NHEJ). Critical components of CSR are 53BP1 and its effector RIF1 because they inhibit end resection to promote NHEJ and oppose competing pathways in DDR. However, the mechanism by which RIF1 effects end-protection in CSR and binds to 53BP1 is still unknown In these studies, I identified a novel component of the RIF1 interactome, ZMYND8, a chromatin reader and transcriptional repressor that binds to RIF1 and facilitates effective CSR. Unexpectedly, ZMYND8 promotes CSR independently of RIF1. In B cells, ZMYND8 binds active promoters and super-enhancers, including the Igh enhancer the 3’RR. ZMYND8 controls 3’RR activity by regulating polymerase loading. In its absence there is increased 3’ RR polymerase loading and decreased acceptor region transcription and CSR. Thus, ZMYND8 controls CSR by regulating the activity of the 3’ Igh super enhancer

ALPHA-SYNUCLEIN MULTIMERIZATION IS DEPENDENT ON STRUCTURAL CHARACTERISTICS OF REPEATED KTKEGV REGIONS

Parkinson’s disease (PD) is the most common movement disorder and is characterized by neuronal loss and the presence of Lewy bodies in dopaminergic neurons of the substantia nigra pars compacta. PD is a chronic, progressive, and irreversible neurodegenerative disorder associated with the selective loss of dopaminergic neurons. Initially described in an Ayurvedic medical treatise and Galen’s writings, and later by James Parkinson in 1817, the most common symptoms of PD are resting tremors, abnormal posture and gait, and muscle rigidity. Approximately 1 million people are living with PD in the United States and worldwide estimates are between 7 and 10 million. Approximately 5-10% of PD cases are genetic, while the vast majority are sporadic and idiopathic. Mutations in genes such as SNCA, GBA, PRKN, PINK1, DJ-1 and LRRK2 along with environmental factors such as pesticides, gut-bacteria and metal toxicity have been associated with PD. The vast array of possible causes paired with the variance of appearance and rate of progression make the disease difficult to diagnose and study both at a clinical and molecular level. Perhaps the most studied protein in the field of PD is alpha-synuclein (a-syn). Indeed, the interest in the protein was sparked in 1997 by the finding that an alanine to threonine substitution (A53T) in a-syn co-segregated with PD subjects. Both genetic lesions in a-syn and the intrinsic accumulation of the protein in neurons are associated with early- and late-onset PD. A neuropathological hallmark of PD is the presence of insoluble intra-neuronal protein aggregates called Lewy Bodies (LB) which are highly enriched in a-syn. A-syn is an intrinsically disordered and natively unfolded protein with a theoretical size of 14 kDa, which has the propensity to form higher order multimers. Although the genetics of SNCA/a-syn are well known, the physiological function of a-syn is largely unknown as is its ability to influence neurodegeneration and cell death in PD. It has been suggested that a-syn may represent a prime target for future diagnostic and therapeutic intervention strategies. However, to further this notion, it will be important to understand the aggregation dynamics of a-syn and how intermediate a-syn multimers may indeed positively and/or negatively impact the death of neurons in PD

Maternal Monitoring and Maternal Psychological Well-Being: Important Components in Treating Conduct Disorder

Conduct disorder is characterized by behaviors that take a large toll on the individuals, families, and communities afflicted. Thus, improving treatment effectiveness should be a high priority. Currently, common intervention programs do not address parental depression, even though it has been linked to adolescent conduct disorder behaviors in some studies. The current study assessed whether the relation between maternal depression and adolescent conduct disorder behaviors is mediated by another factor which has been linked to conduct disorder behaviors, maternal monitoring. Results did not support the hypothesized mediated association, but did show significant individual associations for both maternal depression and maternal monitoring with adolescent conduct disorder behaviors. Secondary analyses showed that adolescent age and household income were significantly related to maternal monitoring and maternal depression, respectively. Findings also suggested that child disclosure may drive the association between maternal monitoring and adolescent conduct disorder behaviors. Implications for intervention are discussed

Longitudinal Relations between Emotional Awareness and Aggression in Early Adolescence: The Mediating Role of Emotion Dysregulation

High prevalence rates exist for physical (i.e., threatened or actual physical force) and relational (i.e., actions meant to harm another’s social relationships) aggression within early adolescence, and these behaviors lead to detrimental social, physical, and mental health outcomes. Thus, there is a need to identify risk and protective processes related to these subtypes of aggression, especially those that can inform violence prevention efforts. Prior studies including early adolescents have shown emotion dysregulation to be a risk factor for aggression. However, few studies have incorporated the emotional competence process of poor emotional awareness, which may be a risk factor for emotion dysregulation and, in turn, for aggression. Furthermore, little research has assessed relations between subtypes of emotion dysregulation (i.e., anger and sadness) and physical and relational aggression. The current study examined longitudinal relations between poor emotional awareness and these subtypes of emotion dysregulation and aggression, as well as concurrent pathways between the emotion dysregulation and aggression variables. Exploratory tests for gender differences were also conducted. Rating scales were collected from 528 sixth graders (51% girls, 49% boys; missing data n = 8) and their teachers over a six month period in the fall and spring of the school year. Across the full sample, 65% of students identified as African-American, 19% European-American, 2%, Hispanic Latino, 11% Multiracial, and 3% as “Other”(missing data n = 8). Results indicated no significant differences by gender in the strength of relations between study variables. Poor emotional awareness was not directly related to changes in subsequent frequency of physical or relational aggression. However, poor emotional awareness at Time 1 was associated with later rates of anger and sadness dysregulation. Furthermore, an indirect effect was found for poor emotional awareness on both physical and relational aggression via anger dysregulation, and this was true for student- and teacher-rated outcomes. Sadness dysregulation showed a negative concurrent association with teacher-rated physical aggression; and there was an indirect effect of poor emotional awareness on teacher-rated physical aggression via sadness dysregulation. Study findings have important implications for theoretical treatises, youth violence prevention programs, and future directions for research, which are all discussed

Modeling tax evasion with genetic algorithms

The U.S. tax gap is estimated to exceed $450 billion, most of which arises from non-compliance on the part of individual taxpayers (GAO 2012; IRS 2006). Much is hidden in innovative tax shelters combining multiple business structures such as partnerships, trusts, and S-corporations into complex transaction networks designed to reduce and obscure the true tax liabilities of their individual shareholders. One known gambit employed by these shelters is to offset real gains in one part of a portfolio by creating artificial capital losses elsewhere through the mechanism of “inflated basis” (TaxAnalysts 2005), a process made easier by the relatively flexible set of rules surrounding “pass-through” entities such as partnerships (IRS 2009). The ability to anticipate the likely forms of emerging evasion schemes would help auditors develop more efficient methods of reducing the tax gap. To this end, we have developed a prototype evolutionary algorithm designed to generate potential schemes of the inflated basis type described above. The algorithm takes as inputs a collection of asset types and tax entities, together with a rule-set governing asset exchanges between these entities. The schemes produced by the algorithm consist of sequences of transactions within an ownership network of tax entities. Schemes are ranked according to a “fitness function” (Goldberg in Genetic algorithms in search, optimization, and machine learning. Addison-Wesley, Boston, 1989); the very best schemes are those that afford the highest reduction in tax liability while incurring the lowest expected penalty.Mitre Corporation (Innovation Program

The impact of a high‐definition multileaf collimator for spine SBRT

PurposeAdvanced radiotherapy delivery systems designed for high‐dose, high‐precision treatments often come equipped with high‐definition multi‐leaf collimators (HD‐MLC) aimed at more finely shaping radiation dose to the target. In this work, we study the effect of a high definition MLC on spine stereotactic body radiation therapy (SBRT) treatment plan quality and plan deliverability.Methods and MaterialsSeventeen spine SBRT cases were planned with VMAT using a standard definition MLC (M120), HD‐MLC, and HD‐MLC with an added objective to reduce monitor units (MU). M120 plans were converted into plans deliverable on an HD‐MLC using in‐house software. Plan quality and plan deliverability as measured by portal dosimetry were compared among the three types of plans.ResultsOnly minor differences were noted in plan quality between the M120 and HD‐MLC plans. Plans generated with the HD‐MLC tended to have better spinal cord sparing (3% reduction in maximum cord dose). HD‐MLC plans on average had 12% more MU and 55% greater modulation complexity as defined by an in‐house metric. HD‐MLC plans also had significantly degraded deliverability. Of the VMAT arcs measured, 94% had lower gamma passing metrics when using the HD‐MLC.ConclusionModest improvements in plan quality were noted when switching from M120 to HD‐MLC at the expense of significantly less accurate deliverability in some cases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139989/1/acm212197.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139989/2/acm212197_am.pd