W.M. Keck Science Center

Parasites and pathogens can influence the survivorship, behavior, and very structure of their host species. For example, experimental studies have shown that trematode parasites can cause high frequencies of severe limb malformations in amphibians. In a broad-scale field survey covering parts of California, Oregon, Washington, Idaho, and Montana, we examined relationships between the frequency and types of morphological abnormalities in amphibians and the abundance of trematode parasite infection, pH, concentrations of 61 pesticides, and levels of orthophosphate and total nitrate. We recorded severe malformations at frequencies ranging from 1% to 90% in nine amphibian species from 53 aquatic systems. Infection of larvae by the trematode Ribeiroia ondatrae was associated with, and functionally related to, higher frequencies of amphibian limb malformations than found in uninfected populations (≤5%). Parasites were concentrated around the basal tissue of hind limbs in infected anurans, and malformations associated with infection included skin webbings, supernumerary limbs and digits, and missing or malformed hind limbs. In the absence of Ribeiroia, amphibian populations exhibited low (0–5%) frequencies of abnormalities involving missing digits or distal portions of a hind limb. Species were affected differentially by the parasite, and Ambystoma macrodactylum, Hyla regilla, Rana aurora, R. luteiventris, and Taricha torosa typically exhibited the highest frequencies of abnormalities. None of the water-quality variables measured was associated with malformed amphibians, but aquatic snail hosts (Planorbella spp.) were significant predictors of the presence and abundance of Ribeiroia infection. Morphological comparisons of adult specimens of Ribeiroia collected from different sites and raised in experimental definitive hosts suggested that all samples represented the same species—R. ondatrae. These field results, coupled with experimental research on the effects of Ribeiroia on amphibians, demonstrate that Ribeiroia infection is an important and widespread cause of amphibian limb malformations in the western United States. The relevance of trematode infection to declines of amphibian populations and the influence of habitat modification on the pathology and life cycle of Ribeiroia are emphasized as areas requiring further research.

Higher cognitive function depends on accurate detection and processing of subtle features of sensory stimuli. Such precise computations require neural circuits to be modulated over rapid timescales, yet this modulation is poorly understood. Brain-derived steroids (neurosteroids) can act as fast signaling molecules in the vertebrate central nervous system and could therefore modulate sensory processing and guide behavior, but there is no empirical evidence for this possibility. Here we report that acute inhibition of estrogen production within a cortical-like region involved in complex auditory processing disrupts a songbird's ability to behaviorally respond to song stimuli. Identical manipulation of local estrogen levels rapidly changes burst firing of single auditory neurons. This acute estrogen-mediated modulation targets song and not other auditory stimuli, possibly enabling discrimination among species-specific signals. Our results demonstrate a crucial role for neuroestrogen synthesis among vertebrates for enhanced sensory encoding. Cognitive impairments associated with estrogen depletion, including verbal memory loss in humans, may therefore stem from compromised moment-by-moment estrogen actions in higher-order cortical circuits.

The inverted pendulum is frequently used as a starting point for discussions of how human balance is maintained during standing and locomotion. Here we examine three experimental paradigms of time-delayed balance control: (1) mechanical inverted time-delayed pendulum, (2) stick balancing at the fingertip, and (3) human postural sway during quiet standing. Measurements of the transfer function (mechanical stick balancing) and the two-point correlation function (Hurst exponent) for the movements of the fingertip (real stick balancing) and the fluctuations in the center of pressure (postural sway) demonstrate that the upright fixed point is unstable in all three paradigms. These observations imply that the balanced state represents a more complex and bounded time-dependent state than a fixed-point attractor. Although mathematical models indicate that a sufficient condition for instability is for the time delay to make a corrective movement, tau(n), be greater than a critical delay tau(c) that is proportional to the length of the pendulum, this condition is satisfied only in the case of human stick balancing at the fingertip. Thus it is suggested that a common cause of instability in all three paradigms stems from the difficulty of controlling both the angle of the inverted pendulum and the position of the controller simultaneously using time-delayed feedback. Considerations of the problematic nature of control in the presence of delay and random perturbations ("noise") suggest that neural control for the upright position likely resembles an adaptive-type controller in which the displacement angle is allowed to drift for small displacements with active corrections made only when theta exceeds a threshold. This mechanism draws attention to an overlooked type of passive control that arises from the interplay between retarded variables and noise.

We provide detailed contextual information on 25 14 C dates for unusually well-preserved archaeological and paleontological remains from Daisy Cave. Paleontological materials, including faunal and floral remains, have been recovered from deposits spanning roughly the past 16,000 yr, while archaeological materials date back to ca. 10,500 BP. Multidisciplinary investigations at the site provide a detailed record of environmental and cultural changes on San Miguel Island during this time period. This record includes evidence for the local or regional extinction of a number of animal species, as well as some of the earliest evidence for the human use of boats and other maritime activities in the Americas. Data from Daisy Cave contribute to a growing body of evidence that Paleoindians had adapted to a wide variety of New World environments prior to 10,000 PB. Analysis of shell-charcoal pairs, along with isotopic analysis of associated marine shells, supports the general validity of marine shell dating, but also provides evidence for temporal fluctuations in the reservoir effect within the Santa Barbara Channel region.

Insects cope with environmental threats using a broad array of strategies. A key strategy, widespread among insects but unappreciated until recently, is the use of molecular defenses from symbiotic microbes. Insect-microbe defensive symbioses span the diversity of insect lineages and microbial partners and use molecules ranging from reactive oxygen species to small molecules to protein toxins to defend against predators, parasites, and microbial pathogens. These systems have a strong initial track record as sources of novel biologically active compounds with therapeutic potential. This review surveys the molecular basis for insect-microbe defensive symbioses with a focus on the ecological contexts for defense and on emerging lessons about molecular diversity from bacterial genomes.

We suggest that the cosmic rays are accelerated primarily out of the supernova ejecta-enriched matter in the interiors of superbubbles. These hot, low-density superbubbles, which reach dimensions of several hundred parsecs, are generated by the winds and ejecta of supernova explosions of massive stars formed in giant molecular cloud OB associations that last for tens of megayears. Since these bubbles expand with shell velocities that are much faster than the dispersion velocities of the O and B star progenitors of the supernovae that power the bubbles, the bulk of the supernovae occur in their cores. The expanding remnants of each of these supernovae fill only less than 1% of this core before they have slowed to sonic velocities. Thus, the bulk of these supernovae remnants, together with their metal-rich grain and gas ejecta and their cosmic-ray-accelerating shocks, are well confined within the cores of superbubbles. These cores can thus provide a source of cosmic-ray matter of essentially constant metallicity throughout the age of the Galaxy, which is required to account for the constancy of cosmic-ray-produced Be relative to supernova-produced Fe observed in halo stars formed in the early Galaxy. The interactions of the grains and gas in metal-rich superbubbles, with recurrent supernova shocks every ~3×105 yr, also reconcile the requirement of a supernova ejecta source of cosmic rays with the recent observations that require a greater than 105 yr delay between nucleosynthesis and acceleration for the cosmic-ray metals. Supernova-enriched bubble metallicity may also explain the X-ray emission from the interiors of superbubbles in the Large Magellanic Cloud.

Time series of abundances are critical for understanding how abiotic factors and species interactions affect population dynamics, but are rarely linked with experiments and also scarce for bee pollinators. This gap is important given concerns about declines in some bee species. I monitored honey bee (Apis mellifera) and bumble bee (Bombus spp.) foragers in coastal California from 1999, when feral A. mellifera populations were low due to Varroa destructor, until 2014. Apis mellifera increased substantially, except between 2006 and 2011, coinciding with declines in managed populations. Increases in A. mellifera strongly correlated with declines in Bombus and reduced diet overlap between them, suggesting resource competition consistent with past experimental results. Lower Bombus numbers also correlated with diminished floral resources. Declines in floral abundances were associated with drought and reduced spring rainfall. These results illustrate how competition with an introduced species may interact with climate to drive local decline of native pollinators.

A dynamical analogy supported by five scale-free statistics (the Gutenberg-Richter distribution of event sizes, the distribution of interevent intervals, the Omori and inverse Omori laws, and the conditional waiting time until the next event) is shown to exist between two classes of seizures ("focal" in humans and generalized in animals) and earthquakes. Increments in excitatory interneuronal coupling in animals expose the system's dependence on this parameter and its dynamical transmutability: moderate increases lead to power-law behavior of seizure energy and interevent times, while marked ones to scale-free (power-law) coextensive with characteristic scales and events. The coextensivity of power law and characteristic size regimes is predicted by models of coupled heterogeneous threshold oscillators of relaxation and underscores the role of coupling strength in shaping the dynamics of these systems.

A model for human postural balance is considered in which the time-delayed feedback depends on position, velocity and acceleration (proportional-derivative-acceleration (PDA) feedback). It is shown that a PDA controller is equivalent to a predictive controller, in which the prediction is based on the most recent information of the state, but the control input is not involved into the prediction. A PDA controller is superior to the corresponding proportional-derivative controller in the sense that the PDA controller can stabilize systems with approximately 40 per cent larger feedback delays. The addition of a sensory dead zone to account for the finite thresholds for detection by sensory receptors results in highly intermittent, complex oscillations that are a typical feature of human postural sway.

We have considered the effects of both the spatial and temporal clustering of OB stars and their subsequent core-collapse supernovae on their generation of superbubbles and their resultant role as the primary source of cosmic rays. Employing a wide range of astronomical and astrophysical observations, we determine quantitatively the fraction of Galactic core-collapse supernovae that occur in superbubbles. We show that the fraction of core-collapse supernovae occurring in superbubbles is high, ranging from ~80% (solely temporal correlations) to ~90% (only spatial correlations). In addition, we find that the singleton end of our stellar cluster distribution is sufficient to reproduce the observed relative number of OB field stars. Core-collapse supernovae (Types II and Ib/c) constitute 85% of Galactic supernovae; only a small fraction of the remaining class of supernovae, Type Ia, occur in superbubbles. Thus, ~75% of all Galactic supernovae are expected to occur within superbubbles. The occurrence of the great majority of Galactic supernovae in superbubbles has major implications for cosmic-ray acceleration. Acceleration of cosmic-ray nuclei heavier than He in enriched (ZSB ≈ 3 Z☉) superbubble interiors can consistently explain the anomalous cosmic-ray 22Ne/20Ne ratio, the cosmic-ray actinde/Pt group and UPuCm/Th ratios, and the constant LiBeB/(C+O) ratio observed in very old, metal-poor stars. Finally, although only ~75% of supernovae occur in superbubbles, ~88% of the cosmic-ray heavy particles are accelerated there because of the factor of ~3 enhanced superbubble core metallicity.

Soft gamma-ray repeaters (SGRs) and anomalous x-ray pulsars (AXPs) are young and radio-quiet x-ray pulsars which have been rapidly spun-down to slow spin periods clustered in the range 5-12 s. If the unusual properties of SGRs and AXPs were due to an innate feature, such as a superstrong magnetic field, then the pre-supernova environments of SGRs and AXPs should be typical of neutron star progenitors. This is not the case, however, as we demonstrate that the interstellar media which surrounded the SGR and AXP progenitors and their SNRs were unusually dense compared to the environments around most young radio pulsars and SNRs. Thus, if these SNR associations are real the SGRs and AXPs can not be the result of a purely innate property. We suggest instead that the environments surrounding SGRs and AXPs play a key role in their development, and we explore a scenario in which the SGRs and AXPs are high velocity neutron stars spun-down by propeller effect winds driven by their interactions with co-moving ejecta from their supernova explosions. We show that such an origin can directly account for the observed properties of the SGRs and AXPs, including the clustering of their periods and their observed number in our Galaxy.

The ratio of the luminosity of diffuse 511 keV positron annihilation radiation, measured by INTEGRAL in its four years, from a Galactic "positron bulge" (<1.5 kpc) compared to that of the disk is ~1.4. This ratio is roughly 4 times larger than that expected simply from the stellar bulge-to-disk ratio of ~0.33 of the Galactic supernovae (SNe), which are thought to be the principal source of the annihilating positrons through the decay of radionuclei made by explosive nucleosynthesis in the SNe. This large discrepancy has prompted a search for new sources. Here, however, we show that the measured 511 keV luminosity ratio can be fully understood in the context of a Galactic SN origin when the differential propagation of these ~ MeV positrons in the various phases of the interstellar medium is taken into consideration, since these relativistic positrons must first slow down to energies ≤10 eV before they can annihilate. Moreover, without propagation, none of the proposed positron sources, new or old, can explain the two basic properties on the Galactic annihilation radiation: the fraction of the annihilation that occurs through positronium formation and the ratio of the broad/narrow components of the 511 keV line. In particular, we show that in the neutral phases of the interstellar medium, which fill most of the disk (>3.5 kpc), the cascade of the magnetic turbulence, which scatters the positrons, is damped by ion-neutral friction, allowing positrons to stream along magnetic flux tubes. We find that nearly 1/2 of the positrons produced in the disk escape from it into the halo. On the other hand, we show that within the extended, or interstellar, bulge (<3.5 kpc), essentially all of the positrons are born in the hot plasmas which fill that volume. We find that the diffusion mean free path is long enough that only a negligible fraction annihilate there and ~80% of them escape down into the H II and H I envelopes of molecular clouds that lie within 1.5 kpc before they slow down and annihilate, while the remaining ~20% escape out into the halo and the disk beyond. This propagation accounts for the low observed annihilation radiation luminosity of the disk compared to the bulge. In addition, we show that the primary annihilation sites of the propagating positrons in both the bulge and the disk are in the warm ionized phases of the interstellar medium. Such annihilation can also account for those two basic properties of the emission, the fraction (~93% ± 7%) of annihilation via positronium and the ratio (~0.5) of broad (~5.4 keV) to narrow (~1.3 keV) components of the bulge 511 keV line emission. Moreover, we expect that the bulk of this broad line emission comes from the tilted disk region (0.5 < R < 1.5 kpc) with a very large broad/narrow flux ratio of ~6, while much of the narrow line emission comes from the inner bulge (R < 0.5 kpc) with a negligible broad/narrow flux ratio. Separate spectral analyses of the 511 keV line emission from these two regions should be able to test this prediction, and further probe the structure of the interstellar medium. Lastly, we show that the asymmetry in the inner disk annihilation line flux, which has been suggested as added evidence for new sources, can also be fully understood from positron propagation and the asymmetry in the inner spiral arms as viewed from our solar perspective without any additional sources.

The platinum(IV) hydroxide and methoxide complexes fac-(dppbz)PtMe3(OR) (dppbz = o-bis(diphenylphosphino)benzene; R = H (1), CH3 (2)) have been prepared and characterized. Thermolysis of hydroxide 1 produces (dppbz)PtMe2 (3) and methanol in a rare example of directly observed sp3 carbon−oxygen reductive elimination from a metal center to form an alcohol. Competitive carbon−carbon reductive elimination to form (dppbz)PtMe(OH) (5) and ethane also occurs. In contrast, the major reaction observed upon thermolysis of the methoxide analog 2 is neither carbon−oxygen nor carbon−carbon reductive elimination. Instead, products expected from formal β-hydride elimination followed by carbon−hydrogen reductive elimination are detected. Mechanistic studies suggest the operation of an alternative mechanism to that most commonly accepted for this fundamental reaction; a dissociative β-hydride abstraction pathway is proposed.

Experimental observations indicate that positive feedback plays an important role for maintaining human balance in the upright position. This observation is used to motivate an investigation of a simple switch-like controller for postural sway in which corrective movements are made only when the vertical displacement angle exceeds a certain threshold. This mechanism is shown to be consistent with the experimentally observed variations in the two-point correlation for human postural sway. Analysis of first-passage times for this model suggests that this control strategy may slow escape by taking advantage of two intrinsic properties of a stochastic unstable first-order delay differential equation: (i) time delay and (ii) the possibility that the dynamics can be 'temporarily confined' near the origin.

Pyridine carboxamides are a class of medicinal agents with activity that includes the reduction of iron-induced renal damage, the regulation of nicotinamidase activity, and radio- and chemosensitization. Such pharmacological activities, and the prevalence of the carboxamide moiety and the importance of amide rotations in biology, motivate detailed investigation of energetics in these systems. In this study, we report the use of dynamic nuclear magnetic resonance to measure the amide rotational barriers in the pyridine carboxamides picolinamide and nicotinamide. The activation enthalpies and entropies of DeltaH++ = 12.9 +/- 0.3 kcal/mol and DeltaS++ = -7.7 +/- 0.9 cal/mol K for nicotinamide and DeltaH++ = 18.3 +/- 0.4 kcal/mol and DeltaS++ = +1.3 +/- 1.0 cal/mol K for picolinamide report a substantial energetic difference for these regioisomers. Ab initio calculations of the rotational barriers are in good agreement with the experimentally determined values and help partition the 5.4 kcal/mol enthalpy difference into its major contributions. Of principal importance are the variations in steric interactions in the ground states of picolinamide and nicotinamide, superior pi electron donation from the pyridine ring in the transition state of nicotinamide, and an intramolecular hydrogen bond in the ground state of picolinamide.

Game theory provides an untapped framework for predicting how below-ground competition will influence root proliferation in a spatially explicit environment. We model root competition for space as an evolutionary game. In response to nutrient competition between plants, an individual's optimal strategy (the spatial distribution of root proliferation) depends on the rooting strategies of neighbouring plants. The model defines and predicts the fundamental (in the absence of competition) and realized (in the presence of competition) root space of an individual plant. Overlapping fundamental root spaces guarantee smaller, yet still overlapping, realized root spaces as individuals concede some but not all space to a neighbour's roots. Root overlap becomes an intentional consequence of the neighbouring plants playing a nutrient foraging game. Root proliferation and regions of root overlap should increase with soil fertility, decline with the distance cost of root production (e.g. soil compactness) and shift with competitive asymmetries. Seemingly erratic patterns of root proliferation and root overlap become the expected outcome of nutrient foraging games played in soils with small-scale heterogeneities in nutrient availability.

Multi-drug resistance due in part to membrane pumps such as P-glycoprotein (Pgp) is a major clinical problem in human cancers. We tested the ability of liposomally-encapsulated daunorubicin (DR) to overcome resistance to this drug. A widely used breast carcinoma cell line originally selected for resistance in doxorubicin (MCF7ADR) was 4-fold resistant to DR compared to the parent MCF7 cells (IC50 79 nM vs. 20 nM). Ovarian carcinoma cells (SKOV3) were made resistant by retroviral transduction of MDR1 cDNA and selection in vinblastine. The resulting SKOV3MGP1 cells were 130-fold resistant to DR compared to parent cells (IC50 5700 nM vs. 44 nM). Small-cell lung carcinoma cells (H69VP) originally selected for resistance to etoposide were 6-fold resistant to DR compared to H69 parent cells (IC50 180 nM vs. 30 nM). In all three cases, encapsulation of DR in liposomes as Daunoxome (Gilead) did not change the IC50 of parent cells relative to free DR. However, liposomal DR overcame resistance in MCF7ADR breast carcinoma cells (IC50 20 nM), SKOV3MGP1 ovarian carcinoma cells (IC50 237 nM) and H69VP small-cell lung carcinoma cells (IC50 27 nM). Empty liposomes did not affect the IC50 for free DR in the three resistant cell lines, nor did empty liposomes affect the IC50 for other drugs that are part of the multi-drug resistance phenotype (etoposide, vincristine) in lung carcinoma cells. These data indicate the possible value of liposomal DR in overcoming Pgp-mediated drug resistance in human cancer.

Photochirogenesis, the control of chirality in photoreactions, is one of the most challenging problems in stereocontrolled photochemistry, in which the stereodifferentiation has to be imprinted within the short lifetime of the electronically excited state. Singlet oxygen (1O2), an electronically excited molecule that is known to be sensitive to vibrational deactivation, has been selected as a model case for testing stereoselective control by vibrational deactivation. The stereoselectivity in the reaction of 1O2 with E/Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been examined for the mode selectivity ([2 + 2]-cycloaddition versus ene-reaction) and the stereoselectivity in the oxidative cleavage of the alkenyl functionality to the methyldesoxybenzoin (MDB) product. Through the appropriate choice of substituents in the enecarbamate, the mode selectivity (ene versus [2 + 2]), which depends on the alkene geometry (E or Z), the steric bulk of the oxazolidinone substituent at the C-4 position, and the C-3' configuration on the side chain, may be manipulated. Phenethyl substitution gives exclusively the [2 + 2]-cycloaddition product, irrespective of the alkene geometry. The stereoselection in the resulting methyldesoxybenzoin (MDB) product is examined in a variety of solvents as a function of temperature by using chiral GC analysis. The extent (% ee) as well as the sense (R versus S) of the stereoselectivity in the MDB formation for the E isomer depends significantly on solvent and temperature, whereas the corresponding Z isomers are not affected by such variations. The complex temperature and solvent effects are scrutinized in terms of the differential activation parameters (DeltaDeltaS++, DeltaDeltaH++) for the photooxygenation of E/Z-enecarbamates in various solvents at different temperatures. The enthalpy-entropy compensations provide a mechanistic understanding of the temperature dependence of the ee values for the MDB product and the difference in the behavior between the Z and E enecarbamates. The E enecarbamates show a relatively high contribution from the entropy term and an appreciable contribution from the enthalpy term; both terms possess the same sign. In contrast, the corresponding relative insensitivity of Z enecarbamates to temperature and solvent variation is convincingly explained by the near-zero DeltaDelta S++ and DeltaDelta H++. Such effects, associated with temperature- and solvent-dependent conformational factors, are most likely dictated by the stereogenic center at the C-3' phenethyl substituent. The high stereocontrol during the photooxygenation of the chiral enecarbamates is shown to be independent of the steric demand of the oxazolidinone substituent at the C-4 position. In view of the reduced stereocontrol on deuteration of the oxazolidinone substituent at the C-4 position, we propose that the unusual stereoselective vibrational quenching of the attacking singlet oxygen (excited-state reactivity), a novel mechanistic concept, works in concert with the usual steric impositions (ground-state reactivity) exercised by the substituents to afford the high stereoselectivity observed in the dioxetane product during the [2 + 2] cycloaddition. Such synergistic interplay is held responsible for the highly stereoselective photooxidative cleavage of the chiral enecarbamates. The efficacy of stereocontrol in this photooxidation is demonstrated by kinetically resolving the epimers of the enecarbamate cleavage product (MDB) in essentially perfect stereoselectivity, a new methodology that we coin "photo-Pasteur-type kinetic resolution".

To obtain a better understanding of the olfactory processes that allow mosquitoes to identify human hosts, a molecular study has been performed to identify and characterize molecules in the olfactory signalling pathway of the African malaria vector Anopheles gambiae. Using cDNA libraries from antennae of females and males, a collection of cDNAs encoding odorant binding proteins and other novel antennal proteins were isolated and characterized, which represent various families of putative carrier proteins with homologues in other insects. Using filter array hybridizations and quantitative RT PCR, regulation and gender specificity of expression of these genes was investigated. Significant differences in steady-state levels of some of these putative carrier protein genes were detected between the sexes and after blood feeding in females.

Recent advances in the study of delay differential equations draw attention to the potential benefits of the interplay between random perturbations ('noise') and delay in neural control. The phenomena include transient stabilizations of unstable steady states by noise, control of fast movements using time-delayed feedback and the occurrence of long-lived delay-induced transients. In particular, this research suggests that the interplay between noise and delay necessitates the use of intermittent, discontinuous control strategies in which corrective movements are made only when controlled variables cross certain thresholds. A potential benefit of such strategies is that they may be optimal for minimizing energy expenditures associated with control. In this paper, the concepts are made accessible by introducing them through simple illustrative examples that can be readily reproduced using software packages, such as XPPAUT.