Search

KMT2B (MLL2/WBP7) is a member of the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal embryonic development in the mouse. To gain insight into the molecular mechanism underlying KMT2B function, we focused on MagohB, which is controlled by a CpG island promoter. We show that in cells lacking Mll2—the gene encoding KMT2B—the MagohB promoter resides in inaccessible chromatin and is methylated. To dissect the molecular events leading to the establishment of silencing, we performed kinetic studies in Mll2-conditional-knockout embryonic stem cells. KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated. We demonstrate that in the presence of KMT2B, neither transcription elongation nor RNA polymerase II binding is required to maintain H3K4 trimethylation at the MagohB promoter and protect it from DNA methylation. Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter. Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters.

This paper focuses on several issues that arise in Miranda Fricker’s book Epistemic injustice surrounding her claims about our (moral) culpability for perpetrating acts of testimonial injustice. While she makes frequent claims about moral culpability with respect to specific examples, she never addresses the issue in its full generality, and we are left to extrapolate her general view about moral culpability for acts of testimonial injustice from these more restricted and particular claims. Although Fricker never describes testimonial injustice in such terms, I argue that the fundamental wrong done in acts of testimonial injustice is a form of negligence. Once we understand testimonial injustice in this way, it is easier to see when and why we are culpable for perpetrating such injustices. Indeed, explicitly recognizing testimonial injustice as a form of negligence solves several problems for Fricker’s view, which are elucidated briefly along the way. However, construing testimonial injustice as a form of...

Background: The present article reports on recruiting strategies in a 16-week, multi-site trial of osmotic-release methylphenidate combined with cognitive-behavioral therapy in adolescents with co-occurring attention deficit hyperactivity disorder and substance use disorder. Methods: A multifaceted recruiting strategy was employed that targeted multiple referral sources, used incentives, involved numerous staff members, emphasized the therapeutic alliance during prescreening, and utilized data to modify strategies based on results. Overall, 303 adolescents were randomized from 1,333 total referrals across 11 participating sites. Results: Overall, existing treatment program sources, including treatment program staff, social services, the juvenile justice system, and mental health clinics provided a majority of referrals for pre-screening and randomization. Conclusions and Scientific Significance: These results support the feasibility of recruiting dually-diagnosed adolescents utilizing a multifaceted appro...

The objective of this study was to provide agronomic, nematode, and economic analysis of alternative production rotation systems for soybeans (Glycine max L. Merr.) on a silt loam soil association in Arkansas. Monocropped soybeans and soybeans double‐cropped with wheat (Triocum aestivam L.) was included as well as grain sorghum (Sorghum bicolor L. Moench) under dryland conditions in order to reduce soybean cyst nematode (SCN, Heteroderaglycine Ichinohe) populations. A total of seven crop rotations and eleven treatments that included alternative tillage conditions and wheat stubble management practices were analyzed using data from 1980–1984 experiments conducted at the Arkansas Cotton Branch Experiment Station on a silt loam Loring‐Calloway‐Henry Association (Alfisols). Although crop rotation was effective for nematode suppression, yields for double‐cropped soybeans were comparable to soybean yields under monocropped’ continuous management practices. Economic results indicated that average net re...

(1997). The weakness of strong justification. Australasian Journal of Philosophy: Vol. 75, No. 2, pp. 179-189.

Cyclobutane dipyrimidines and less than mean value of 6-4 dipyrimidines are the two major classes of mutagenic DNA photoproducts produced by UV irradiation of cells. We developed a method to map cyclobutane dipyrimidines at the DNA sequence level in mammalian cells. The frequency of this class of photoproducts was determined at every dipyrimidine along the human phosphoglycerate kinase-1 (PGK1) promoter sequence and was compared to the UV-induced frequency distribution of mean value of 6-4 dipyrimidines. After irradiation of living cells containing active or inactive PGK1 genes, enzymatic or chemical cleavage at UV photoproducts, and amplification by ligation-mediated polymerase chain reaction, photofootprints were seen in all regions which bind transcription factors and appear as DNase I footprints. Photoproduct frequency within transcription factor binding sites was suppressed or enhanced relative to inactive genes or naked DNA with enhancements of up to 30-fold. Since photoproducts are mutagenic, this indicates that photoproduct (mutation?) hot spots may be tissue specific in mammals.

The 5' control region and first exon for human X-chromosome-linked phosphoglycerate kinase is contained in a G + C-rich island. We measured methylation at all HpaII sites in this 5' region of leukocyte DNA. By use of a blotting procedure that allows analysis of small DNA fragments, we found that the HpaII sites are entirely methylated when from an inactive X chromosome and entirely unmethylated when from an active one. In contrast, methylation of HpaII sites in more downstream regions of the gene is essentially the same in active and inactive X chromosomes.

ministration and articles concerning the role of the secondary school principal, the writers have emphatically pointed out that the primary concern of the principal should be curriculum improvement. But, as most practicing administrators will agree, his time is more often than not taken up with "administrivia." This neglect of curriculum was brought about, in part, by the tremendous growth in size and complexity of the junior high school over the past 50 years, some of which have reached the 2,500 mark in size. Throughout all this growth, the principal's span of control became greater and in many instances unwieldy. The office of vice (assistant) principal was established, and this helped to shorten the span of control and provided the principal with some time for effecting curriculum change. However, since in most instances the principal was only a curriculum generalist, he obviously needed the assistance of a specialist. Thus, the departmental organization emerged as the dominant pattern for the secondary school. Within recent years the departmental organization has come under increasingly sharp criticism, and many alternatives have been suggested, such as the division plan and the inter-disciplinary approach. While serving as a junior high school principal, I experienced many of the frustrations inherent in a weak organizational pattern (including no assistant principal) and decided to do my doctoral dissertation on this subject. The purpose of the research was to determine the existing organizational patterns used in the intra-school administrative hierarchy. I anticipated that the study would provide information as to the need for internal reorganization of the junior high school and criteria for that organization. On the assumption that instruction was facilitated or hindered by the administrative organization of the school, a sample of schools engaged in administrative innovations was needed in order to obtain an