The past decade has seen a major increase in the study of noncoding RNAs (ncRNAs). However, there remains a great deal of confusion and debate over the levels of functionality and mechanisms of ...action of the majority of these new transcripts. This Opinion article addresses several of these issues, focusing particularly on long ncRNAs (lncRNAs). We reemphasize the unique abilities of RNAs to form myriad structures as well as to interact with other RNAs, DNA, and proteins, which provide them with unique and powerful abilities. One of these, the ability to interact sequence specifically with DNA, has been largely overlooked. Accumulating evidence suggests that evolution has taken advantage of RNA’s properties via the rapid acquisition of new noncoding genes in testes, with subsequent gains of function in other tissues. This amplification process appears to be one of the major forces driving metazoan evolution and diversity.
The majority of RNAs transcribed by the human genome are in the form of long noncoding RNAs (lncRNAs).
The number of lncRNAs with validated functions is growing exponentially. lncRNAs are associated with virtually all diseases.
The number of lncRNA genes is proportional to organismal complexity.
lncRNAs that regulate epigenetic processes act as DNA sequence-specific guides.
The majority of lncRNAs are probably localized in the cytoplasm.
The tissue with the highest levels and diversity of noncoding RNA expression is the testis.
The majority of new lncRNA genes are believed to have evolved in the testis.
Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation ...(H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.
A critical edition of the book that paved the way for the democratization of American higher education If you have ever attended a town meeting or business lunch, or participated in a church group or ...department meeting, or served on a faculty senate or maybe just watched C-SPAN, then you have likely encountered Robert's Rules of Order. This critical edition of Henry M. Robert's essential guide to parliamentary procedure features the original text from 1876 along with a companion essay by Christopher Loss, who artfully recounts the book's publication and popular reception, and sheds light on its enduring value for one of the most vital bastions of democracy itself—the modern university.Loss deftly explains why Robert's simple, elegant handbook to democratic governance captured the imagination of so many ordinary citizens during the Gilded Age and how it has shaped the development of our colleges and universities ever since. He shows how Robert's rules can help faculty, administrators, and students to solve problems and overcome challenges through collaboration, disciplined thinking, trust in the facts, and honesty and fairness from all sides.At a time when people's faith in democracy and higher education has been shaken to its core, Robert's Rules of Order offers a powerful reminder of the importance of democratic norms and practices in American life and institutions.
We propose a new version of the "theory theory" grounded in the computational framework of probabilistic causal models and Bayesian learning. Probabilistic models allow a constructivist but rigorous ...and detailed approach to cognitive development. They also explain the learning of both more specific causal hypotheses and more abstract framework theories. We outline the new theoretical ideas, explain the computational framework in an intuitive and nontechnical way, and review an extensive but relatively recent body of empirical results that supports these ideas. These include new studies of the mechanisms of learning. Children infer causal structure from statistical information, through their own actions on the world and through observations of the actions of others. Studies demonstrate these learning mechanisms in children from 16 months to 4 years old and include research on causal statistical learning, informal experimentation through play, and imitation and informal pedagogy. They also include studies of the variability and progressive character of intuitive theory change, particularly theory of mind. These studies investigate both the physical and the psychological and social domains. We conclude with suggestions for further collaborative projects between developmental and computational cognitive scientists. (Contains 5 figures.)
Summary A previously well infant aged 9 months presented with an acute, self-limiting illness characterised by high fever and a papular eruption that started on the face. Although fever subsided ...within 3 days, the rash worsened and extended over the whole body, with some papules evolving into vesiculobullous lesions. The infant had been exposed to children with a similar illness 1 week before onset. PCR of vesicular swabs and stool samples taken on day 6 of illness showed Coxsackie virus A6. The illness resolved within 10 days of onset, although onychomadesis was seen on both big toes at follow-up 5 weeks later. Our case exemplifies the severe, atypical cases of hand, foot, and mouth disease that have been reported worldwide since 2008, and in the USA since the 2011. Atypical hand, foot, and mouth disease is caused by a new lineage of Coxsackie virus A6 and is characterised by high fever and vesiculobullous eruptions on the calves and backs of the hands. Infants with eczema might be predisposed to severe disease.
Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to encode proteins. This finding ...has led to vigorous debate over the functional importance of the transcribed but untranslated portions of the genome. Currently, scientists tend to assume coding genes are functional until proven not to be, while the opposite is true for noncoding genes. This review takes a new look at the evidence for and against widespread noncoding gene functionality. We focus in particular on long noncoding RNA (noncoding RNAs longer than 200 nucleotides) genes and their ‘junk’ associates, transposable elements, and satellite repeats. Taken together, the suggestion put forward is that more of this junk DNA may be functional than nonfunctional and that noncoding RNAs and transposable elements act symbiotically to drive evolution.
Most lncRNA genes are expressed during spermatogenesis and are localized to many different subcellular locations.Solubility issues and alternative 3ʹ end processing have resulted in underestimates of lncRNA abundance.The diversity of known lncRNA molecular and subcellular functions is growing rapidly and may approach those of proteins.lncRNA and transposable element expression are coordinated during periods when spermatocyte heterochromatin is removed and replaced by protamines.Most lncRNAs contain transposable element sequences and many are expressed under the control of transposable element promoters.
► Enzymes of the mevalonate pathway of isoprenoid biosynthesis. ► Structure/function correlations for the mevalonate pathway enzymes. ► Inhibitors and regulators of the mevalonate pathway enzymes. ► ...Variations on the mevalonate pathway.
The mevalonate pathway accounts for conversion of acetyl-CoA to isopentenyl 5-diphosphate, the versatile precursor of polyisoprenoid metabolites and natural products. The pathway functions in most eukaryotes, archaea, and some eubacteria. Only recently has much of the functional and structural basis for this metabolism been reported. The biosynthetic acetoacetyl-CoA thiolase and HMG-CoA synthase reactions rely on key amino acids that are different but are situated in active sites that are similar throughout the family of initial condensation enzymes. Both bacterial and animal HMG-CoA reductases have been extensively studied and the contrasts between these proteins and their interactions with statin inhibitors defined. The conversion of mevalonic acid to isopentenyl 5-diphosphate involves three ATP-dependent phosphorylation reactions. While bacterial enzymes responsible for these three reactions share a common protein fold, animal enzymes differ in this respect as the recently reported structure of human phosphomevalonate kinase demonstrates. There are significant contrasts between observations on metabolite inhibition of mevalonate phosphorylation in bacteria and animals. The structural basis for these contrasts has also recently been reported. Alternatives to the phosphomevalonate kinase and mevalonate diphosphate decarboxylase reactions may exist in archaea. Thus, new details regarding isopentenyl diphosphate synthesis from acetyl-CoA continue to emerge.
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16
..., p21
and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
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