The elemental mechanism of transcriptional pausing.

Transcriptional pausing underlies regulation of cellular RNA biogenesis. A consensus pause sequence that acts on RNA polymerases (RNAPs) from bacteria to mammals halts RNAP in an elemental paused state from which longer-lived pauses can arise. Although the structural foundations of pauses prolonged by backtracking or nascent RNA hairpins are recognized, the fundamental mechanism of the elemental pause is less well-defined. Here we report a mechanistic dissection that establishes the elemental pause signal (i) is multipartite; (ii) causes a modest conformational shift that puts γ-proteobacterial RNAP in an off-pathway state in which template base loading but not RNA translocation is inhibited; and (iii) allows RNAP to enter pretranslocated and one-base-pair backtracked states easily even though the half-translocated state observed in paused cryo-EM structures rate-limits pause escape. Our findings provide a mechanistic basis for the elemental pause and a framework to understand how pausing is modulated by sequence, cellular conditions, and regulators

The pause-initiation limit restricts transcription activation in human cells.

Eukaryotic gene transcription is often controlled at the level of RNA polymerase II (Pol II) pausing in the promoter-proximal region. Pausing Pol II limits the frequency of transcription initiation ('pause-initiation limit'), predicting that the pause duration must be decreased for transcriptional activation. To test this prediction, we conduct a genome-wide kinetic analysis of the heat shock response in human cells. We show that the pause-initiation limit restricts transcriptional activation at most genes. Gene activation generally requires the activity of the P-TEFb kinase CDK9, which decreases the duration of Pol II pausing and thereby enables an increase in the productive initiation frequency. The transcription of enhancer elements is generally not pause limited and can be activated without CDK9 activity. Our results define the kinetics of Pol II transcriptional regulation in human cells at all gene classes during a natural transcription response

Big words, small phrases: Mismatches between pause units and the polysynthetic word in Dalabon

This article uses instrumental data from natural speech to examine the phenomenon of pause placement within the verbal word in Dalabon, a polysynthetic Australian language of Arnhem Land. Though the phenomenon is incipient and in two sample texts occurs in only around 4% of verbs, there are clear possibilities for interrupting the grammatical word by pause after the pronominal prefix and some associated material at the left edge, though these within-word pauses are significantly shorter, on average, than those between words. Within-word pause placement is not random, but is restricted to certain affix boundaries; it requires that the paused-after material be at least dimoraic, and that the remaining material in the verbal word be at least disyllabic. Bininj Gun-wok, another polysynthetic language closely related to Dalabon, does not allow pauses to interrupt the verbal word, and the Dalabon development appears to be tied up with certain morphological innovations that have increased the proportion of closed syllables in the pronominal prefix zone of the verb. Though only incipient and not yet phonologized, pause placement in Dalabon verbs suggests a phonology-driven route by which polysynthetic languages may ultimately become less morphologically complex by fracturing into smaller units

The "52 week, 24 hour" university

The article seeks to consider the cultural and educational implications of ignoring times for pause and reflection by moving to service industry model of delivery higher education based on market considerations

A Dopamine-Acetylcholine Cascade: Simulating Learned and Lesion-Induced Behavior of Striatal Cholinergic Interneurons

The "teaching signal" that modulates reinforcement learning at cortico-striatal synapses may be a sequence composed of an adaptively scaled DA burst, a brief ACh burst, and a scaled ACh pause. Such an interpretation is consistent with recent data on cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with characteristic pauses to novel events and to appetitive and aversive conditioned stimuli. Fluctuations in acetylcholine release by TANs modulate performance- and learning- related dynamics in the striatum. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from thalamic centromedian-parafascicular nuclei, and dopaminergic inputs from midbrain are required for the generation of pause responses. No prior computational models encompass both intrinsic and synaptically-gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing, and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If the latter inhibition, probably mediated by GABAergic NOS interneurons, exceeds a threshold, its effect is amplified by a KIR current to generate a prolongued pause. In the model, the intrinsic mechanisms and external inputs are both modulated by learning-dependent dopamine (DA) signals and our simulations revealed that many learning-dependent behaviors of TANs are explicable without recourse to learning-dependent changes in synapses onto TANs

Economic pause - some perspective and interpretation

Economic conditions

Frozen rights?: The right to develop Maori treaty and aboriginal rights

Bishop Manuhuia Bennett often asked the question: "What did Maori call New Zealand before the arrival of the Pakeha [Europeans]?" After a deliberate pause, he would then simply utter: "Ours"