Molecular dissection of I(A) in cortical pyramidal neurons reveals three distinct components encoded by Kv4.2, Kv4.3, and Kv1.4 alpha-subunits

The rapidly activating and inactivating voltage-gated K(+) (Kv) current, I(A), is broadly expressed in neurons and is a key regulator of action potential repolarization, repetitive firing, backpropagation (into dendrites) of action potentials, and responses to synaptic inputs. Interestingly, results from previous studies on a number of neuronal cell types, including hippocampal, cortical, and spinal neurons, suggest that macroscopic I(A) is composed of multiple components and that each component is likely encoded by distinct Kv channel alpha-subunits. The goals of the experiments presented here were to test this hypothesis and to determine the molecular identities of the Kv channel alpha-subunits that generate I(A) in cortical pyramidal neurons. Combining genetic disruption of individual Kv alpha-subunit genes with pharmacological approaches to block Kv currents selectively, the experiments here revealed that Kv1.4, Kv4.2, and Kv4.3 alpha-subunits encode distinct components of I(A) that together underlie the macroscopic I(A) in mouse (male and female) cortical pyramidal neurons. Recordings from neurons lacking both Kv4.2 and Kv4.3 (Kv4.2(-/-)/Kv4.3(-/-)) revealed that, although Kv1.4 encodes a minor component of I(A), the Kv1.4-encoded current was found in all the Kv4.2(-/-)/Kv4.3(-/-) cortical pyramidal neurons examined. Of the cortical pyramidal neurons lacking both Kv4.2 and Kv1.4, 90% expressed a Kv4.3-encoded I(A) larger in amplitude than the Kv1.4-encoded component. The experimental findings also demonstrate that the targeted deletion of the individual Kv alpha-subunits encoding components of I(A) results in electrical remodeling that is Kv alpha-subunit specific

Constraint-based semantics

Montague\u27s famous characterization of the homomorphic relation between syntax and semantics naturally gives way in computational applications to CONSTRAINT-BASED formulations. This was originally motivated by the close harmony it provides with syntax, which is universally processed in a constraint-based fashion. Employing the same processing discipline in syntax and semantics allows that their processing (and indeed other processing) can be as tightly coupled as one wishes - indeed, there needn\u27t be any fundamental distinction between them at all. In this paper, we point out several advantages of the constraint-based view of semantics processing over standard views. These include (i) the opportunity to incorporate nonsyntactic constraints on semantics, such as those arising from phonology and context; (ii) the opportunity to formulate principles which generalize over syntax and semantics, such as those found in HEAD-DRIVEN PHRASE STRUCTURE GRAMMAR; (iii) a characterization of semantic ambiguity, which in turn provides a framework in which to describe disambiguation, and (iv) the opportunity to underspecify meanings in a way difficult to reconcile with other views. The last point is illustrated with an application to scope ambiguity in which a scheme is developed which underspecifies scope but eschews auxiliary levels of logical form

Representing grammar, meaning and knowledge

Among the expertises relevant for successful natural language understanding are grammar, meaning and background knowledge, all of which must be represented in order to decode messages from text (or speech). The present paper is a sketch of one cooperation of grammar and meaning representations -- with some remarks about knowledge representation -- which allows that the representations involved be heterogeneous even while cooperating closely. The modules cooperate in what might be called a PLURALIST fashion, with few assumptions about the representations involved. In point of fact, the proposal is compatible with state-of-the-art representations from all three areas. The paper proceeeds from the nearly universal assumption that the grammar formalism is feature-based and insufficiently expressive for use in meaning representation. It then demonstrates how feature formalisms may be employed as a semantic metalanguage in order that semantic constraints may be expressed in a single formalism with grammatical constraints. This allows a tight coupling of syntax and semantics, the incorporation of nonsyntactic constraints (e.g., from knowledge representation) and the opportunity to underspecify meanings in novel ways -- including, e.g., ways which distinguish ambiguity and underspecification (vagueness). We retain scepticism vis-à-vis more ASSIMILATIONIST proposals for the interaction of these -- i.e., proposals which foresee common formalisms for grammar, meaning and knowledge representation. While such proposals rightfully claim to allow for closer integration, they fail to account for the motivations which distinguish formalisms - elaborate expressive strength in the case of semantic representations, monotonic (and preferably decidable) computation in the case of grammar formalisms, and the characterization of taxonomic reasoning in the case of knowledge representation

A feature-based syntax/semantics interface

Syntax/Semantics interfaces using unification-based or feature-based formalisms are increasingly common in the existing computational linguistics literature. The primary reason for attempting to specify a syntax/semantics interface in feature structures is that it harmonizes so well with the way in which syntax is now normally described; this close harmony means that syntactic and semantic processing (and indeed other processing, see below) can be as tightly coupled as one wishes - indeed, there need not be any fundamental distinction between them at all. In this paper, we first point out several advantages of the unification-based view of the syntax/semantics interface over standard views. These include (i) a more flexible relation to nonsyntactic constraints on semantics; (ii) a characterization of semantic ambiguity, which in turn provides a framework in which to describe disambiguation, and (iii) the opportunity to underspecify meanings in a way difficult to reconcile with other views. The last point is illustrated with an application to the notorious scope ambiguity problem

Photoinduced Removal of Nifedipine Reveals Mechanisms of Calcium Antagonist Action on Single Heart Cells

The currents through voltage-activated calcium channels in heart cell membranes are suppressed by dihydropyridine calcium antagonists such as nifedipine. Nifedipine is photolabile, and the reduction of current amplitude by this drug can be reversed within a few milliseconds after a 1-ms light flash. The blockade by nifedipine and its removal by flashes were studied in isolated myocytes from neonatal rat heart using the whole-cell clamp method. The results suggest that nifedipine interacts with closed, open, and inactivated calcium channels. It is likely that at the normal resting potential of cardiac cells, the suppression of current amplitude arises because nifedipine binds to and stabilizes channels in the resting, closed state. Inhibition is enhanced at depolarized membrane potentials, where interaction with inactivated channels may also become important. Additional block of open channels is suggested when currents are carried by Ba^(2+) but is not indicated with Ca^(2+) currents. Numerical simulations reproduce the experimental observations with molecular dissociation constants on the order of 10^(-7) M for closed and open channels and 10^(-8) M for inactivated channels

Time Course of the Increase in the Myocardial Slow Inward Current after a Photochemically Generated Concentration Jump of Intracellular cAMP

Voltage-clamped atrial trabeculae from bullfrog hearts were exposed to membrane-permeant photolyzable o-nitrobenzyl esters of cAMP and cGMP. UV flashes produced intracellular concentration jumps of cAMP or cGMP. With the cAMP derivative, flashes resulted in an increased slow inward current (Isi), producing a broadened action potential. The Isi reached a maximum 10-30 sec after the flash and decreased over the next 60-300 sec. The first increases were observable within 150 msec; this value is an upper limit imposed by the instrumentation. Responses to flashes lasted longer at higher drug concentrations and in the presence of the phosphodiesterase inhibitor papaverine; effects of flashes developed and decreased faster at higher temperature. Although the amplitude of the Isi was increased, its waveform and voltage sensitivity were not affected. Intracellular concentration jumps of cAMP failed to affect the muscarinic K+ conductance. There were no observable effects of cGMP concentration jumps. The data confirm (i) that cAMP regulates the Isi and (ii) that the 5- to 10-sec delay between application of ß-agonists and the onset of positive inotropic effects, observed in previous studies, has been correctly ascribed to events prior to the interaction between cAMP and protein kinase

Inheritance and complementation : a case study of easy adjectives and related nouns

Mechanisms for representing lexically the bulk of syntactic and semantic information for a language have been under active development, as is evident in the recent studies contained in this volume. Our study serves to highlight some of the most useful tools available for structured lexical representation, in particular, (multiple) inheritance, default specification, and lexical rules. It then illustrates the value of these mechanisms in illuminating one corner of the lexicon involving an unusual kind of complementation among a group of adjectives exemplified by easy. The virtures of the structured lexicon are its succinctness and its tendency to highlight significant clusters of linguistic properties. From its succinctness follow two practical advantages, namely its ease of maintenance and modifiability. In order to suggest how important these may be practically, we extend the analysis of adjectival complementation in several directions. These further illustrate how the use of inheritance in lexical representation permits exact and explicit characterizations of phenomena in the language under study. We demonstrate how the use of the mechanisms employed in the analysis of easy enable us to give a unified account of related phenomena featuring nouns like pleasure, and even the adverbs (adjectival specifiers) too and enough. Along the way we motivate some elaborations of the Head-Driven Phrase Structure Grammar (HPSG) framework in which we couch our analysis, and offer several avenues for further study of this part of the English lexicon