Many aspects of transcriptional regulation in eukaryotic cells involve reversible phosphorylation events; these include phosphorylation of both general and gene-specific transcription factors (20, 21). Examples of both positive and negative effects of protein phosphorylation have been reported (for reviews, see references 20 and 21). One such example of transcriptional control mediated by phosphorylation is the global repression of nuclear transcription that occurs when cells enter mitosis (22,36). Over the years, numerous hypotheses have been put forward to explain mitotic repression of transcription (for reviews, see references 12, 16, and 32), including condensation of interphase chromatin into mitotic chromosomes, dissociation of transcription factors or RNA polymerase from the chromatin template, and inactivation of the basal transcription machinery by protein phosphorylation (13,40,50). For the genes transcribed by RNA polymerase III (pol III) (such as 5S rRNA and tRNA genes), previous studies have documented that the activity of the general class III transcription factor TFIIIB is greatly diminished in extracts from synchronized mitotic cells (49) or by the conversion of an interphase Xenopus egg extract to the mitotic state by the addition of recombinant cyclin B1 protein (13,16,50). In the latter experiments, the recombinant cyclin formed a complex with the p34 cdc2 kinase subunit present in the extract and, after a series of specific phosphorylation and dephosphorylation events, the active form of the cdc2/cyclin B kinase (maturation-mitosis promoting factor) was generated (45,46). Inhibition of transcription has been shown to be due to the enzymatic action of this kinase on a TFIIIB subunit (or a repressor protein that binds to and inactivates TFIIIB) (13, 16).Similar to class III gene transcription, transcription of mRNA-coding genes by RNA polymerase II (pol II) is also repressed at mitosis. We have shown that purified cdc2/cyclin B kinase is sufficient to inhibit transcription by pol II in a reconstituted transcription system (27). Recently, Segil et al. (40) reported that the general pol II transcription factor TFIID isolated from mitotic cells is multiply phosphorylated and inactive in supporting activator-dependent transcription. TFIID is composed of the TATA-binding protein (TBP) and TBPassociated factors (TAFs), and the TAFs have been shown to be involved in activator-dependent transcription (for reviews, see references 17 and 33). The activity of mitotic TFIID can be restored by dephosphorylation, showing that a protein phosphorylation event regulates TFIID during mitosis. Thus, for both activated pol II transcription (40) and pol III transcription (13, 49), a TBP-associated factor is inactivated at mitosis. In the work of Segil et al. (40), only TFIID was purified from mitotic cells; thus, it is not clear whether other targets of mitotic regulation exist in the pol II transcription machinery. Indeed, mitotic TFIID was found to be defective in only activator-dependent transcription, suggest...

Multisystemic, eosinophilic, epitheliotropic disease and intestinal lymphosarcoma were diagnosed in a Paso Fino mare that presented with anorexia and weight loss. The stomach, ileum, cecum, colon, pancreas, and lungs were infiltrated by large numbers of eosinophils forming prominent eosinophilic granulomas, as well as lymphocytes and plasma cells. Two jejunal masses composed of solid sheets of neoplastic lymphocytes were present. In contrast to the regions of inflammation, the infiltrates in these masses did not contain plasma cells, eosinophils, and eosinophilic granulomas. Immunohistochemically, the neoplastic lymphocytes expressed CD3 but not CD20 or kappa and lambda light chains, supporting a diagnosis of T-cell lymphosarcoma. Concurrent diagnoses of hypereosinophilic syndrome and lymphosarcoma in this horse and several humans suggest that the multisystemic eosinophilic and lymphoplasmacytic infiltrates were caused by the clonal proliferation of T-lymphocytes that secreted interleukin-5 triggering differentiation and activation of eosinophils.

Accurate pathogenicity prediction of missense variants is critically important in genetic studies and clinical diagnosis. Previously published prediction methods have facilitated the interpretation of missense variants but have limited performance. Here, we describe MVP (Missense Variant Pathogenicity prediction), a new prediction method that uses deep residual network to leverage large training data sets and many correlated predictors. We train the model separately in genes that are intolerant of loss of function variants and the ones that are tolerant in order to take account of potentially different genetic effect size and mode of action. We compile cancer mutation hotspots and de novo variants from developmental disorders for benchmarking. Overall, MVP achieves better performance in prioritizing pathogenic missense variants than previous methods, especially in genes tolerant of loss of function variants. Finally, using MVP, we estimate that de novo coding variants contribute to 7.8% of isolated congenital heart disease, nearly doubling previous estimates.

In the C, dicotyledonous grain plant amaranth (Amaranfhus hypochondriacus), a mitochondrial NAD-dependent malic enzyme (NAD-ME; EC 1.1.1.39) serves a specialized and essential role in photosynthetic carbon fixation. In this study we have examined specialized photosynthetic gene expression patterns for the NAD-ME (Y subunit. We show here that the (Y subunit gene is preferentially expressed in leaves and cotyledons (the most photosynthetically active tissues), and this expression is specific to the bundle-sheath cells of these tissues from the earliest stages of development. Synthesis of the (Y subunit polypeptide and accumulation of its corresponding mRNA are strongly light-dependent, but this regulation is also influenced by seedling development. In addition, light-dependent accumulation of the (Y subunit mRNA is regulated at transcriptional as well as posttranscriptional levels. Our findings demonstrate that the NAD-ME of amaranth has acquired numerous complex tissue-specific and light-mediated regulation patterns that define its specialized function as a key enzyme in the C, photosynthetic pathway.