Inferring HIV escape rates from multi-locus genotype data

Cytotoxic T-lymphocytes (CTLs) recognize viral protein fragments displayed by major histocompatibility complex (MHC) molecules on the surface of virally infected cells and generate an anti-viral response that can kill the infected cells. Virus variants whose protein fragments are not efficiently presented on infected cells or whose fragments are presented but not recognized by CTLs therefore have a competitive advantage and spread rapidly through the population. We present a method that allows a more robust estimation of these escape rates from serially sampled sequence data. The proposed method accounts for competition between multiple escapes by explicitly modeling the accumulation of escape mutations and the stochastic effects of rare multiple mutants. Applying our method to serially sampled HIV sequence data, we estimate rates of HIV escape that are substantially larger than those previously reported. The method can be extended to complex escapes that require compensatory mutations. We expect our method to be applicable in other contexts such as cancer evolution where time series data is also available

Rate of Adaptation in Large Sexual Populations

Adaptation often involves the acquisition of a large number of genomic changes which arise as mutations in single individuals. In asexual populations, combinations of mutations can fix only when they arise in the same lineage, but for populations in which genetic information is exchanged, beneficial mutations can arise in different individuals and be combined later. In large populations, when the product of the population size N and the total beneficial mutation rate U_b is large, many new beneficial alleles can be segregating in the population simultaneously. We calculate the rate of adaptation, v, in several models of such sexual populations and show that v is linear in NU_b only in sufficiently small populations. In large populations, v increases much more slowly as log NU_b. The prefactor of this logarithm, however, increases as the square of the recombination rate. This acceleration of adaptation by recombination implies a strong evolutionary advantage of sex

Synaptotagmin has an essential function in synaptic vesicle positioning for synchronous release in addition to its role as a calcium sensor.

SummaryA multitude of synaptic proteins interact at the active zones of nerve terminals to achieve the high temporal precision of neurotransmitter release in synchrony with action potentials. Though synaptotagmin has been recognized as the Ca2+ sensor for synchronous release, it may have additional roles of action. We address this question at the calyx of Held, a giant presynaptic terminal, that allows biophysical dissection of multiple roles of molecules in synaptic transmission. Using high-level expression recombinant adenoviruses, in conjunction with a stereotactic surgery in postnatal day 1 rats, we overcame the previous inability to moleculary perturb the calyx by overexpression of a mutated synaptotagmin. We report that this mutation leaves intrinsic Ca2+ sensitivity of vesicles intact while it destabilizes the readily releasable pool of vesicles and loosens the tight coupling between Ca2+ influx and release, most likely by interfering with the correct positioning of vesicles with respect to Ca2+ channels

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Mechanisms that ensure robust long-term performance of synaptic transmission over a wide range of activity are crucial for the integrity of neuronal networks, for processing sensory information and for the ability to learn and store memories. Recent experiments have revealed that such robust performance requires a tight coupling between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. Distinct presynaptic scaffolding proteins are essential for fulfilling this requirement, providing either ultrastructural coordination or acting as signalling hubs

Reduced tillage, but not organic matter input, increased nematode diversity and food web stability in European long‐term field experiments

Soil nematode communities and food web indices can inform about the complexity, nutrient flows and decomposition pathways of soil food webs, reflecting soil quality. Relative abundance of nematode feeding and life‐history groups are used for calculating food web indices, i.e., maturity index (MI), enrichment index (EI), structure index (SI) and channel index (CI). Molecular methods to study nematode communities potentially offer advantages compared to traditional methods in terms of resolution, throughput, cost and time. In spite of such advantages, molecular data have not often been adopted so far to assess the effects of soil management on nematode communities and to calculate these food web indices. Here, we used high‐throughput amplicon sequencing to investigate the effects of tillage (conventional vs. reduced) and organic matter addition (low vs. high) on nematode communities and food web indices in 10 European long‐term field experiments and we assessed the relationship between nematode communities and soil parameters. We found that nematode communities were more strongly affected by tillage than by organic matter addition. Compared to conventional tillage, reduced tillage increased nematode diversity (23% higher Shannon diversity index), nematode community stability (12% higher MI), structure (24% higher SI), and the fungal decomposition channel (59% higher CI), and also the number of herbivorous nematodes (70% higher). Total and labile organic carbon, available K and microbial parameters explained nematode community structure. Our findings show that nematode communities are sensitive indicators of soil quality and that molecular profiling of nematode communities has the potential to reveal the effects of soil management on soil quality

Functional expression of the calcium release channel from skeletal muscle ryanodine receptor cDNA.

Combined patch-clamp and fura-2 measurements were performed to study the calcium release properties of Chinese hamster ovary (CHO) cells transfected with the rabbit skeletal muscle ryanodine receptor cDNA carried by an expression vector. Both caffeine (1–50 mM) and ryanodine (100 μM) induced release of calcium from intracellular stores of transformed CHO cells but not from control (non-transfected) CHO cells. The calcium responses to caffeine and ryanodine closely resembled those commonly observed in skeletal muscle. Repetitive applications of caffeine produced characteristic all-or-none rises in intracellular calcium. Inositol 1,4,5-trisphosphate (IP3) neither activated the ryanodine receptor channel nor interfered with the caffeine-elicited calcium release. These results indicate that functional calcium release channels are formed by expression of the ryanodine receptor cDNA

A very high altitude survey of the effect of latitude upon cosmic-ray intensities - and an attempt at a general interpretation of cosmic-ray phenomena

The results of a very high altitude geographical survey extending in airplanes from Northern Canada to Peru, to altitudes of 22,000 feet, and, in three stratosphere flights made within the United States, to altitudes of 60,000 feet, are interpreted in the light of (1) the Epstein and the Lemaitre-Vallarta analysis of the effect of the earth's magnetic field, and (2) the Bowen-Millikan proof that the immediate agents responsible for the ionization of the atmosphere are electrons (+ and -), rather than protons or heavier nuclei. The main conclusions reached are: (1) that the resistance of the atmosphere to incoming electrons is 1 billion volts because of extranuclear encounters, 5 billion volts because of nuclear encounters; (2) that nuclear electron encounters produce only very soft secondaries, both photons and electrons; (3) that incoming photons produce most of the ionization found at sea-level or at sub-sea-level depths; (4) that nearly all of the non-field sensitive part of the ionization of the atmosphere above sea-level is due to photons of energy 200±170 million electron volts; (5) that in the equatorial belt a small part of the ionization is due to incoming secondary electrons of energies as high as 10 billion volts; (6) that these are responsible for the east-west effect and the longitude effect found in the equatorial belt; (7) that the field sensitive part of the ionization increases rapidly with increasing latitude in going from Panama to Spokane because incoming secondaries of energies decreasing from 8 billion to 2 billion volts get through the blocking effect of the field in rapidly increasing numbers with increasing latitude and add greatly in northern latitudes to the underlying ionization of the upper-air produced by the incoming photons; (8) that the only source now in sight of the observed cosmic-ray energies is matter-annihilation; (9) that the softest components of the cosmic rays have the energies corresponding to the partial annihilation or atom building hypothesis, while the hardest components have energies corresponding to the complete atom-annihilation hypothesis; (10) that these processes may conceivably be taking place (1) because of the very low temperatures that facilitate the clustering of hydrogen in interstellar space, or (2) because of such extreme temperature conditions of the opposite sort as are found in novae, as suggested by Zwicky

New evidence as to the nature of the incoming cosmic rays, their absorbability in the atmosphere, and the secondary character of the penetrating rays found in such abundance at sea level and below

The intensity of latitude-sensitive cosmic rays as would be measured by an electroscope placed just outside the atmosphere has been calculated. The ionization due to incoming electrons of 10 billion electron volts energy in this same electroscope placed 1/20th of an atmosphere beneath the top is found to be 13 times that outside. Electrons do not become penetrating by virtue of high energies even up to 17 billion electron volts. Neither protons nor other penetrating particles of any sort enter the atmosphere in significant numbers from outside the atmosphere. The observed penetrating particles and all other cosmic-ray effects, latitude-sensitive and non-latitude-sensitive, found in the lower atmosphere are practically all secondary effects—splashes from the absorption of electrons, or photons, or both taking place in the outer layers of the atmosphere

Alkylated-C-60 based soft materials: regulation of self-assembly and optoelectronic properties by chain branching

Derivatization of fullerene (C60) with branched aliphatic chains softens C60-based materials and enables the formation of thermotropic liquid crystals and room temperature nonvolatile liquids. This work demonstrates that by carefully tuning parameters such as type, number and substituent position of the branched chains, liquid crystalline C60 materials with mesophase temperatures suited for photovoltaic cell fabrication and room temperature nonvolatile liquid fullerenes with tunable viscosity can be obtained. In particular, compound 1, with branched chains, exhibits a smectic liquid crystalline phase extending from 84 °C to room temperature. Analysis of bulk heterojunction (BHJ) organic solar cells with a ca. 100 nm active layer of compound 1 and poly(3-hexylthiophene) (P3HT) as an electron acceptor and an electron donor, respectively, reveals an improved performance (power conversion efficiency, PCE: 1.6 ± 0.1%) in comparison with another compound, 10 (PCE: 0.5 ± 0.1%). The latter, in contrast to 1, carries linear aliphatic chains and thus forms a highly ordered solid lamellar phase at room temperature. The solar cell performance of 1 blended with P3HT approaches that of PCBM/P3HT for the same active layer thickness. This indicates that C60 derivatives bearing branched tails are a promising class of electron acceptors in soft (flexible) photovoltaic devices