@article{3992, abstract = {Computing the volume occupied by individual atoms in macromolecular structures has been the subject of research for several decades. This interest has grown in the recent years, because weighted volumes are widely used in implicit solvent models. Applications of the latter in molecular mechanics simulations require that the derivatives of these weighted volumes be known. In this article, we give a formula for the volume derivative of a molecule modeled as a space-filling diagram made up of balls in motion. The formula is given in terms of the weights, radii, and distances between the centers as well as the sizes of the facets of the power diagram restricted to the space-filling diagram. Special attention is given to the detection and treatment of singularities as well as discontinuities of the derivative.}, author = {Edelsbrunner, Herbert and Koehl, Patrice}, issn = {0027-8424}, journal = {PNAS}, number = {5}, pages = {2203 -- 2208}, publisher = {National Academy of Sciences}, title = {{The weighted-volume derivative of a space-filling diagram}}, doi = {10.1073/pnas.0537830100}, volume = {100}, year = {2003}, } @article{885, abstract = {We study fitness landscape in the space of protein sequences by relating sets of human pathogenic missense mutations in 32 proteins to amino acid substitutions that occurred in the course of evolution of these proteins. On average, ≈10% of deviations of a nonhuman protein from its human ortholog are compensated pathogenic deviations (CPDs), i.e., are caused by an amino acid substitution that, at this site, would be pathogenic to humans. Normal functioning of a CPD-containing protein must be caused by other, compensatory deviations of the nonhuman species from humans. Together, a CPD and the corresponding compensatory deviation form a Dobzhansky-Muller incompatibility that can be visualized as the corner on a fitness ridge. Thus, proteins evolve along fitness ridges which contain only ≈10 steps between sucessive corners. The fraction of CPDs among all deviations of a protein from its human ortholog does not increase with the evolutionary distance between the proteins, indicating that subtitutions that carry evolving proteins around these corners occur in rapid succession, driven by positive selection. Data on fitness of interspecies hybrids suggest that the compensatory change that makes a CPD fit usually occurs within the same protein. Data on protein structures and on cooccurrence of amino acids at different sites of multiple orthologous proteins often make it possible to provisionally identify the substitution that compensates a partiCUlar CPD.}, author = {Kondrashov, Alexey and Sunyaev, Shamil and Kondrashov, Fyodor}, issn = {0027-8424}, journal = {PNAS}, number = {23}, pages = {14878 -- 14883}, publisher = {National Academy of Sciences}, title = {{Dobzhansky-Muller incompatibilities in protein evolution}}, doi = {10.1073/pnas.232565499}, volume = {99}, year = {2002}, } @article{3800, abstract = {Networks of GABAergic interneurons are of critical importance for the generation of gamma frequency oscillations in the brain. To examine the underlying synaptic mechanisms, we made paired recordings from "basket cells" (BCs) in different subfields of hippocampal slices, using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the parvalbumin promoter. Unitary inhibitory postsynaptic currents (IPSCs) showed large amplitude and fast time course with mean amplitude-weighted decay time constants of 2.5, 1.2, and 1.8 ms in the dentate gyrus, and the cornu ammonis area 3 (CA3) and 1 (CA1), respectively (33-34 degrees C). The decay of unitary IPSCs at BC-BC synapses was significantly faster than that at BC-principal cell synapses, indicating target cell-specific differences in IPSC kinetics. In addition, electrical coupling was found in a subset of BC-BC pairs. To examine whether an interneuron network with fast inhibitory synapses can act as a gamma frequency oscillator, we developed an interneuron network model based on experimentally determined properties. In comparison to previous interneuron network models, our model was able to generate oscillatory activity with higher coherence over a broad range of frequencies (20-110 Hz). In this model, high coherence and flexibility in frequency control emerge from the combination of synaptic properties, network structure, and electrical coupling.}, author = {Bartos, Marlene and Vida, Imre and Frotscher, Michael and Meyer, Axel and Monyer, Hannah and Geiger, Jörg and Jonas, Peter M}, issn = {0027-8424}, journal = {PNAS}, number = {20}, pages = {13222 -- 13227}, publisher = {National Academy of Sciences}, title = {{Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks}}, doi = {10.1073/pnas.192233099}, volume = {99}, year = {2002}, } @article{874, abstract = {Sex is thought to facilitate accumulation of initially rare beneficial mutations by allowing simultaneous allele replacements at many loci. However, this advantage of sex depends on a restrictive assumption that the fitness of a genotype is determined by fitness potential, a single intermediate variable to which all loci contribute additively, so that new alleles can accumulate in any order. Individual-based simulations of sexual and asexual populations reveal that under generic selection, sex often retards adaptive evolution. When new alleles are beneficial only if they accumulate in a prescribed order, a sexual population may evolve two or more times slower than an asexual population because only asexual reproduction allows some overlap of successive allele replacements. Many other fitness surfaces lead to an even greater disadvantage of sex. Thus, either sex exists in spite of its impact on the rate of adaptive allele replacements, or natural fitness surfaces have rather specific properties, at least at the scale of intrapopulation genetic variability.}, author = {Kondrashov, Fyodor and Kondrashov, Alexey}, issn = {0027-8424}, journal = {PNAS}, number = {21}, pages = {12089 -- 12092}, publisher = {National Academy of Sciences}, title = {{Multidimensional epistasis and the disadvantage of sex}}, doi = {10.1073/pnas.211214298}, volume = {98}, year = {2001}, } @article{3496, abstract = {The mossy fiber-CA3 pyramidal neuron synapse is a main component of the hippocampal trisynaptic circuitry. Recent studies, however, suggested that inhibitory interneurons are the major targets of the mossy fiber system. To study the regulation of mossy fiber-interneuron excitation, we examined unitary and compound excitatory postsynaptic currents in dentate gyrus basket cells, evoked by paired recording between granule and basket cells or extracellular stimulation of mossy fiber collaterals. The application of an associative high-frequency stimulation paradigm induced posttetanic potentiation (PTP) followed by homosynaptic long-term potentiation (LTP). Analysis of numbers of failures, coefficient of variation, and paired-pulse modulation indicated that both PTP and LTP were expressed presynaptically. The Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) did not affect PTP or LTP at a concentration of 10 mM but attenuated LTP at a concentration of 30 mM. Both forskolin, an adenylyl cyclase activator, and phorbolester diacetate, a protein kinase C stimulator, lead to a long-lasting increase in excitatory postsynaptic current amplitude. H-89, a protein kinase A inhibitor, and bisindolylmaleimide, a protein kinase C antagonist, reduced PTP, whereas only bisindolylmaleimide reduced LTP. These results may suggest a differential contribution of protein kinase A and C pathways to mossy fiber-interneuron plasticity. Interneuron PTP and LTP may provide mechanisms to maintain the balance between synaptic excitation of interneurons and that of principal neurons in the dentate gyrus-CA3 network. }, author = {Alle, Henrik and Jonas, Peter M and Geiger, Jörg}, issn = {0027-8424}, journal = {PNAS}, number = {25}, pages = {14708 -- 14713}, publisher = {National Academy of Sciences}, title = {{PTP and LTP at a hippocampal mossy fiber-interneuron synapse}}, doi = {10.1073/pnas.251610898 }, volume = {98}, year = {2001}, } @article{3540, abstract = {What determines the firing rate of cortical neurons in the absence of external sensory input or motor behavior, such as during sleep? Hero we report that, in a familiar environment, the discharge frequency of simultaneously recorded individual CA1 pyramidal neurons and the coactivation of cell pairs remain highly correlated across sleep-wake-steep sequences. However, both measures were affected when new sets of neurons were activated in a novel environment. Nevertheless, the grand mean firing rate of the whole pyramidal cell population remained constant across behavioral states and testing conditions. The findings suggest that long-term firing patterns of single cells can be modified by experience. We hypothesize that increased firing rates of recently used neurons are associated with a concomitant decrease in the discharge activity of the remaining population, leaving the mean excitability of the hippocampal network unaltered.}, author = {Hirase, Hajima and Leinekugel, Xavier and Czurkó, András and Csicsvari, Jozsef L and Buzsáki, György}, issn = {0027-8424}, journal = {PNAS}, number = {16}, pages = {9386 -- 9390}, publisher = {National Academy of Sciences}, title = {{Firing rates of hippocampal neurons are preserved during subsequent sleep episodes and modified by novel awake experience}}, doi = {10.1073/pnas.161274398}, volume = {98}, year = {2001}, } @article{1956, abstract = { The plastid genomes of several plants contain ndh genes-homologues of genes encoding subunits of the proton-pumping NADH:ubiquinone oxidoreductase, or complex I, involved in respiration in mitochondria and eubacteria. From sequence similarities with these genes, the ndh gene products have been suggested to form a large protein complex (Ndh complex); however, the structure and function of this complex remains to be established. Herein we report the isolation of the Ndh complex from the chloroplasts of the higher plant Pisum sativum. The purification procedure involved selective solubilization of the thylakoid membrane with dodecyl maltoside, followed by two anion-exchange chromatography steps and one size-exclusion chromatography step. The isolated Ndh complex has an apparent total molecular mass of approximately 550 kDa and according to SDS/PAGE consists of at least 16 subunits including NdhA, NdhI, NdhJ, NdhK, and NdhH, which were identified by N-terminal sequencing and immunoblotting. The Ndh complex showed an NADH- and deamino-NADH-specific dehydrogenase activity, characteristic of complex I, when either ferricyanide or the quinones menadione and duroquinone were used as electron acceptors. This study describes the isolation of the chloroplast analogue of the respiratory complex I and provides direct evidence for the function of the plastid Ndh complex as an NADH:plastoquinone oxidoreductase. Our results are compatible with a dual role for the Ndh complex in the chloro-respiratory and cyclic photophosphorylation pathways.}, author = {Sazanov, Leonid A and Burrows, Paul and Nixon, Peter}, issn = {0027-8424}, journal = {PNAS}, number = {3}, pages = {1319 -- 1324}, publisher = {National Academy of Sciences}, title = {{The plastid ndh genes code for an NADH-specific dehydrogenase: Isolation of a complex I analogue from pea thylakoid membranes}}, doi = {10.1073/pnas.95.3.1319}, volume = {95}, year = {1998}, } @article{3632, abstract = {An important but controversial class of hypotheses concerning the evolution of female preferences for extreme male mating displays involves 'indirect selection.' Even in the absence of direct fitness effects, preference for males with high overall fitness can spread via a genetic correlation that develops between preference alleles and high fitness genotypes. Here we develop a quantitative expression for the force of indirect selection that (i) applies to any female mating behavior, (ii) is relatively insensitive to the underlying genetics, and (iii) is based on measurable quantities. In conjunction with the limited data now available, it suggests that the evolutionary force generated by indirect selection on preferences is weak in absolute terms. This finding raises the possibility that direct selection on preference genes may often be more important than indirect selection, but more data on the quantities identified by our model and on direct selection are needed to decide the question.}, author = {Kirkpatrick, Mark and Barton, Nicholas H}, issn = {0027-8424}, journal = {PNAS}, number = {4}, pages = {1282 -- 1286}, publisher = {National Academy of Sciences}, title = {{The strength of indirect selection on female mating preferences}}, doi = {10.1073/pnas.94.4.1282}, volume = {94}, year = {1997}, } @article{3466, abstract = {Amphibian myelinated nerve fibers were treated with collagenase and protease. Axons with retraction of the myelin sheath were patch-clamped in the nodal and paranodal region. One type of Na channel was found. It has a single-channel conductance of 11 pS (15 degrees C) and is blocked by tetrodotoxin. Averaged events show the typical activation and inactivation kinetics of macroscopic Na current. Three potential-dependent K channels were identified (I, F, and S channel). The I channel, being the most frequent type, has a single-channel conductance of 23 pS (inward current, 105 mM K on both sides of the membrane), activates between -60 and -30 mV, deactivates with intermediate kinetics, and is sensitive to dendrotoxin. The F channel has a conductance of 30 pS, activates between -40 and 60 mV, and deactivates with fast kinetics. The former inactivates within tens of seconds; the latter inactivates within seconds. The third type, the S channel, has a conductance of 7 pS and deactivates slowly. All three channels can be blocked by external tetraethylammonium chloride. We suggest that these distinct K channel types form the basis for the different components of macroscopic K current described previously.}, author = {Jonas, Peter M and Bräu, Michael and Hermsteiner, Markus and Vogel, Werner}, issn = {1091-6490}, journal = {PNAS}, number = {18}, pages = {7238 -- 7242}, publisher = {National Academy of Sciences}, title = {{Single-channel recording in myelinated nerve fibers reveals one type of Na channel but different K channels}}, doi = {10.1073/pnas.86.18.7238}, volume = {86}, year = {1989}, }