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The goal of this review was to seek a better understanding of the function and differential expression of circadian clock genes during the reproductive process. Through a discussion of how the circadian clock is involved in these steps, the identification of new clinical targets for sleep disorder-related diseases, such as reproductive failure, will be elucidated. Here, we focus on recent research findings regarding circadian clock regulation within the reproductive system, shedding new light on circadian rhythm-related problems in women. Discussions on the roles that circadian clock plays in these reproductive processes will help identify new clinical targets for such sleep disorder-related diseases.

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer.

Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations—a phenomenon dubbed “oncogene addiction.” Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9—a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.

Short hairpin RNAs (shRNAs) are versatile tools for analyzing loss-of-function phenotypes in vitro and in vivo1. However, their use for studying genes involved in proliferation and survival, which are potential therapeutic targets in cancer and other diseases, is confounded by the strong selective advantage of cells in which shRNA expression is inefficient. We therefore developed a toolkit that combines Tet-regulated miR30-shRNA technology, robust transactivator expression and two fluorescent reporters to track and isolate cells with potent target knockdown. We demonstrated that this system improves the study of essential genes and was sufficiently robust to eradicate aggressive cancer in mice by suppressing a single gene. Further, we applied this system for in vivo negative-selection screening with pooled shRNAs and propose a streamlined, inexpensive workflow that will facilitate the use of RNA interference (RNAi) for the identification and evaluation of essential therapeutic targets.

In the first experiment, schematic outline drawings of upright and inverted faces and house fronts, where nontargets differed from targets by all three features, were flashed to left and right visual fields (LVF and RVF, respectively), in a discriminatory manual RT task. An equally strong LVF superiority occurred for each type of stimulus. There was no evidence in this task of a specialist processor for upright faces in the right hemisphere over and above the latter's general mediation of complex visuospatial stimuli. The second experiment confirmed that a right hemisphere superiority is not an inevitable concommitant of processing face material. Upright faces which previously had been shown to generate a RVF superiority in the context of difficult, analytic, single-feature discriminations, and a LVF superiority in the context of an easy holistic match-mismatch, were combined into a single sequence to determine whether the perceived nature of the total task would change the magnitude or direction...

Ninety-six student subjects were studied in a strictly balanced design contrasting sex, handedness and familial dextrality/sinistrality. WAIS scores were obtained, and two tachistoscopic tasks (RT responses) administered, involving laterally presented verbal stimuli (word/non-word decisions with high frequency, concrete, imageable and low frequency, abstract non-imageable words), and a face discrimination task designed to generate right hemisphere processing. There was a striking WAIS Performance deficit among sinistrals, particularly familial; familial dextrals proved overall fastest; directional asymmetries were weakest for the sinistrals, particularly the non-familial; non-familial dextrals were no less lateralized than familial dextrals; parental handedness was a better predictor of performance than sibling handedness; and no differential pattern of field asymmetries appeared for the two classes of word stimuli. Some theoretical implications of these findings are discussed.

A hierarchically-branching system is recommended for classifying published work in the field of cerebral asymmetry, and its rapid retrieval. It can readily accommodate practically everything published since 1965.

Dextral, familial and nonfamilial sinistral Undergraduates, balanced by sex and all strongly dextral or sinistral, called out laterally presented words and nonwords. Vocal latencies, accuracy and field differences consistently discriminated between the three groups, dextrals performing best and nonfamilial sinistrals the worst. Subjects with a left field superiority had significantly smaller field differences and more errors than the right-superior, and a tendency to a higher birth stress index, which also characterized nonfamilial sinistrals. However sinistrals writing with an inverted hand position did not show greater field superiorities. Familial sinistrals appear closer to dextrals than nonfamilials, and either type of sinistrality, but particularly when non-familial and/or associated with reversed field asymmetries, seems detrimental to reading tachistoscopically-flashed letter strings and words in a student population.

Two measures of adjustment, the Erikson Psychosocial Stage Inventory and the Offer Self-Image Questionnaire, were administered to a sample of 450 working class Anglo-, Greek-, and Italian-Australian adolescents in years 9 and 11 of 9 Melbourne high schools. Anglo- and Greek-Australian adolescents scored similarly and significantly higher than Italian-Australians on a number of subscales, suggesting that culture conflict may be an influential factor in the adjustment of Italian-Australians, but not Greek-Australians. Significant differences between the minority groups, in favor of Greek-Australians, were interpreted as resulting from the relative differences in institutional support for and press toward assimilation of the two groups.

Laterally presented verbal stimuli nowadays frequently include words and letter strings, as well as the more traditional single-character alphanumeric materials. In addition to studying hemisphere differences in word processing in their own right, these studies often use word materials as tools in investigating such factors as sex, handedness, practice, familiarity, and developmental aspects. Doubt has been expressed, partly on the basis of some earlier studies involving unilaterally and bilaterally presented word and letter strings, English, Hebrew, and Yiddish, in normal and mirror-reversed orientation, whether the obtained right-visual-field (RVF) superiorities are a function of cerebral dominance or of left-to-right directional processing or scanning, associated with Western reading habits. More recent and better controlled studies are reviewed which bear upon this issue, including some where words are presented in a vertical organization, together with current theories of word recognition. It is concluded that at least with unilateral presentations, in the absence of any central “fixation” digit, single-syllable words can safely be employed in the knowledge that any resultant field differences are likely to reflect neural organization, and that any directional scanning or processing artifacts make, at the most, a minor contribution.