Protein Backbone Alteration in Non-Hairpin ß-Turns: Impacts on Tertiary Folded Structure and Folded Stability.

The importance of ß-turns to protein folding has motivated extensive efforts to stabilize the motif with non-canonical backbone connectivity. Prior work has focused almost exclusively on turns between strands in a ß-sheet (i. e., hairpins). Turns in other structural contexts are also common in nature and have distinct conformational preferences; however, design principles for their mimicry remain poorly understood. Here, we report strategies that stabilize non-hairpin ß-turns through systematic evaluation of the impacts of backbone alteration on the high-resolution folded structure and folded stability of a helix-loop-helix prototype protein. Several well-established hairpin turn mimetics are shown detrimental to folded stability and/or hydrophobic core packing, while less-explored modification schemes that reinforce alternate turn types lead to improved stability and more faithful structural mimicry. Collectively, these results have implications in control over protein folding through chemical modification as well as the design of protein mimetics.

Collaborative Use of Sensor Networks and Cyberinfrastructure to Understand Complex Ecosystem Interactions in a Tropical Rainforest: Challenges and Lessons Learned.

Collaborations between ecosystem ecologists and engineers have led to impressive progress in developing complex models of biogeochemical fluxes in response to global climate change. Ecology and engineering iteratively inform and transform each other in these efforts. Nested data streams from local sources, adjacent networks, and remote sensing sources together magnify the capacity of ecosystem ecologists to observe systems in near real-time and address questions at temporal and spatial scales that were previously unobtainable. We describe our research experiences working in a Costa Rican rainforest ecosystem with the challenges presented by constant high humidity, 4300 mm of annual rainfall, flooding, small invertebrates entering the tiniest openings, stinging insects, and venomous snakes. Over the past two decades, we faced multiple challenges and learned from our mistakes to develop a broad program of ecosystem research at multiple levels of integration. This program involved integrated networks of diverse sensors on a series of canopy towers linked to multiple belowground soil sensor arrays that could transport sensor data streams from the forest directly to an off-site location via a fiber optic cable. In our commentary, we highlight three components of our work: (1) the eddy flux measurements using canopy towers; (2) the soil sensor arrays for measuring the spatial and temporal patterns of CO2 and O2 fluxes at the soil-atmosphere interface; and (3) focused investigations of the ecosystem impact of leaf-cutter ants as "ecosystem engineers" on carbon fluxes.

Integration of Swimming-Related Synaptic Excitation and Inhibition by olig2+ Eurydendroid Neurons in Larval Zebrafish Cerebellum.

The cerebellum influences motor control through Purkinje target neurons, which transmit cerebellar output. Such output is required, for instance, for larval zebrafish to learn conditioned fictive swimming. The output cells, called eurydendroid neurons (ENs) in teleost fish, are inhibited by Purkinje cells and excited by parallel fibers. Here, we investigated the electrophysiological properties of glutamatergic ENs labeled by the transcription factor olig2. Action potential firing and synaptic responses were recorded in current clamp and voltage clamp from olig2+ neurons in immobilized larval zebrafish (before sexual differentiation) and were correlated with motor behavior by simultaneous recording of fictive swimming. In the absence of swimming, olig2+ ENs had basal firing rates near 8 spikes/s, and EPSCs and IPSCs were evident. Comparing Purkinje firing rates and eurydendroid IPSC rates indicated that 1-3 Purkinje cells converge onto each EN. Optogenetically suppressing Purkinje simple spikes, while preserving complex spikes, suggested that eurydendroid IPSC size depended on presynaptic spike duration rather than amplitude. During swimming, EPSC and IPSC rates increased. Total excitatory and inhibitory currents during sensory-evoked swimming were both more than double those during spontaneous swimming. During both spontaneous and sensory-evoked swimming, the total inhibitory current was more than threefold larger than the excitatory current. Firing rates of ENs nevertheless increased, suggesting that the relative timing of IPSCs and EPSCs may permit excitation to drive additional eurydendroid spikes. The data indicate that olig2+ cells are ENs whose activity is modulated with locomotion, suiting them to participate in sensorimotor integration associated with cerebellum-dependent learning.SIGNIFICANCE STATEMENT The cerebellum contributes to movements through signals generated by cerebellar output neurons, called eurydendroid neurons (ENs) in fish (cerebellar nuclei in mammals). ENs receive sensory and motor signals from excitatory parallel fibers and inhibitory Purkinje cells. Here, we report electrophysiological recordings from ENs of larval zebrafish that directly illustrate how synaptic inhibition and excitation are integrated by cerebellar output neurons in association with motor behavior. The results demonstrate that inhibitory and excitatory drive both increase during fictive swimming, but inhibition greatly exceeds excitation. Firing rates nevertheless increase, providing evidence that synaptic integration promotes cerebellar output during locomotion. The data offer a basis for comparing aspects of cerebellar coding that are conserved and that diverge across vertebrates.

Precipitation-drainage cycles lead to hot moments in soil carbon dioxide dynamics in a Neotropical wet forest.

Soil CO2 concentrations and emissions from tropical forests are modulated seasonally by precipitation. However, subseasonal responses to meteorological events (e.g., storms, drought) are less well known. Here, we present the effects of meteorological variability on short-term (hours to months) dynamics of soil CO2 concentrations and emissions in a Neotropical wet forest. We continuously monitored soil temperature, moisture, and CO2 for a three-year period (2015-2017), encompassing normal conditions, floods, a dry El Niño period, and a hurricane. We used a coupled model (Hydrus-1D) for soil water propagation, heat transfer, and diffusive gas transport to explain observed soil moisture, soil temperature, and soil CO2 concentration responses to meteorology, and we estimated soil CO2 efflux with a gradient-flux model. Then, we predicted changes in soil CO2 concentrations and emissions under different warming climate change scenarios. Observed short-term (hourly to daily) soil CO2 concentration responded more to precipitation than to other meteorological variables (including lower pressure during the hurricane). Observed soil CO2 failed to exhibit diel patterns (associated with diel temperature fluctuations in drier climates), except during the drier El Niño period. Climate change scenarios showed enhanced soil CO2 due to warmer conditions, while precipitation played a critical role in moderating the balance between concentrations and emissions. The scenario with increased precipitation (based on a regional model projection) led to increases of +11% in soil CO2 concentrations and +4% in soil CO2 emissions. The scenario with decreased precipitation (based on global circulation model projections) resulted in increases of +4% in soil CO2 concentrations and +18% in soil CO2 emissions, and presented more prominent hot moments in soil CO2 outgassing. These findings suggest that soil CO2 will increase under warmer climate in tropical wet forests, and precipitation patterns will define the intensity of CO2 outgassing hot moments.

Synthesis of Bacterial-Derived Peptidoglycan Cross-Linked Fragments.

Peptidoglycan (PG) is the core structural motif of the bacterial cell wall. Fragments released from the PG serve as fundamental recognition elements for the immune system. The structure of the PG, however, encompasses a variety of chemical modifications among different bacterial species. Here, the applicability of organic synthetic methods to address this chemical diversity is explored, and the synthesis of cross-linked PG fragments, carrying biologically relevant amino acid modifications and peptide cross-linkages, is presented using solution and solid phase approaches.

Diel pattern driven by free convection controls leaf-cutter ant nest ventilation and greenhouse gas emissions in a Neotropical rain forest.

Leaf-cutter ant nests are biogeochemical hot spots where ants live and import vegetation to grow fungus. Metabolic activity and (in wet tropical forests) soil gas flux to the nest may result in high nest CO2 concentrations if not adequately ventilated. Wind-driven ventilation mitigates high CO2 concentrations in grasslands, but little is known about exchange for forest species faced with prolonged windless conditions. We studied Atta cephalotes nests located under dense canopy (leaf area index > 5) in a wet tropical rainforest in Costa Rica, where wind events are infrequent. We instrumented nests with thermocouples and flow-through CO2 sensing chambers. The results showed that CO2 concentrations exiting leaf-cutter ant nests follow a diel pattern with higher values at night. We developed an efflux model based on pressure differences that evaluated the observed CO2 diel pattern in terms of ventilation by (1) free convection (warm, less dense air rises out the nest more prominently at night) and (2) episodic wind-forced convection events providing occasional supplemental ventilation during daytime. Average greenhouse gas emissions were estimated through nest vents at about 78 kg CO2eq nest-1 year-1. At the ecosystem level, leaf-cutter ant nest vents accounted for 0.2% to 1% of total rainforest soil emissions. In wet, clayey tropical soils, leaf-cutter ant nests act as free convection-driven conduits for exporting CO2 and other greenhouse gases produced within the nest (fungus and ant respiration, refuse decay), and by roots and soil microbes surrounding the nest. This allows A. cephalotes nests to be ventilated without reliable wind conditions.

High resolution synoptic salinity mapping to identify groundwater--surface water discharges in lowland rivers.

Quantifying distributed lateral groundwater contributions to surface water (GW-SW discharges) is a key aspect of tracking nonpoint-source pollution (NPSP) within a watershed. In this study, we characterized distributed GW-SW discharges and associated salt loading using elevated GW specific conductance (SC) as a tracer along a 38 km reach of the Lower Merced River in Central California. High resolution longitudinal surveys for multiple flows (1.3-150 m(3) s(-1)) revealed river SC gradients that mainly decreased with increasing flow, suggesting a dilution effect and/or reduced GW-SW discharges due to hydraulic gradient reductions. However, exceptions occurred (gradients increasing with increasing flow), pointing to complex spatiotemporal influences on GW-SW dynamics. The surveys revealed detailed variability in salinity gradients, from which we estimated distributed GW-SW discharge and salt loading using a simple mixing model. Modeled cumulative GW discharges for two surveys unaffected by ungauged SW discharges were comparable in magnitude to differential gauging-based discharge estimates and prior GW-SW studies along the same river reach. Ungauged lateral inlets and sparse GW data limited the study, and argue for enhancing monitoring efforts. Our approach provides a rapid and economical method for characterizing NPSP for gaining rivers in the context of integrated watershed modeling and management.

Ontogeny of septohippocampal modulation of delay eyeblink conditioning.

The current study investigated the effects of disrupting the septohippocampal theta system on the developmental emergence of delay eyeblink conditioning. Theta oscillations are defined as electroencephalographic (EEG) waveforms with a frequency between 3-8 Hz. Hippocampal theta oscillations are generated by inputs from the entorhinal cortex and the medial septum. Theta activity has been shown to facilitate learning in a variety of paradigms, including delay eyeblink conditioning. Lesions of the medial septum disrupt theta activity and slow the rate at which delay eyeblink conditioning is learned (Berry & Thompson, [1979] Science 200:1298-1300). The role of the septohippocampal theta system in the ontogeny of eyeblink conditioning has not been examined. In the current study, infant rats received an electrolytic lesion of the medial septum on postnatal day (P) 12. Rats were later given eyeblink conditioning for 6 sessions with an auditory conditioned stimulus on P17-19, P21-23, or P24-26. Lesions impaired eyeblink conditioning on P21-23 and P24-26 but not on P17-19. The results suggest that the septohippocampal system comes online to facilitate acquisition of eyeblink conditioning between P19 and P21. Developmental changes in septohippocampal modulation of the cerebellum may play a significant role in the ontogeny of eyeblink conditioning.

Visual cortical contributions to associative cerebellar learning.

Eye-blink conditioning (EBC) is a form of associative learning that depends on the cerebellum. Previous reports suggested that sensory cortex is necessary for trace EBC but not for delay EBC. The trace and delay EBC procedures used in these studies differed by the presence or absence of a temporal gap between the end of the conditioned stimulus and the onset of the unconditioned stimulus (trace interval) and in the interval between the onset of the CS and the US (inter-stimulus interval, ISI). The current study examined the role of the visual cortex in delay, long-delay, and trace EBC, matching CS duration and inter-stimulus interval between groups. In Experiment 1, extensive removal of the visual cortex impaired acquisition of long-delay and trace EBC but had no effect on delay EBC. In Experiment 2, bilateral inactivation of the visual cortex impaired acquisition and retention of long-delay and trace EBC, but had no effect on delay EBC. In Experiment 3, unilateral inactivation of the visual cortex impaired long-delay EBC but had no effect on trace EBC. The results indicate that the visual cortex facilitates EBC with relatively long ISIs, regardless of whether there is a trace interval or not. Moreover, the ipsilateral projections from the visual cortex to the pontine nuclei are sufficient for modulating long-delay EBC, whereas trace EBC involves bilateral visual cortical interactions with forebrain systems including the hippocampus and prefrontal cortex.

Leaf-cutter ants - mycorrhizal fungi: observations and research questions from an unexpected mutualism.

Leaf-cutter ants (LCAs) are widely distributed and alter the physical and biotic architecture above and below ground. In neotropical rainforests, they create aboveground and belowground disturbance gaps that facilitate oxygen and carbon dioxide exchange. Within the hyperdiverse neotropical rainforests, arbuscular mycorrhizal (AM) fungi occupy nearly all of the forest floor. Nearly every cubic centimeter of soil contains a network of hyphae of Glomeromycotina, fungi that form arbuscular mycorrhizae. Our broad question is as follows: how can alternative mycorrhizae, which are-especially ectomycorrhizae-essential for the survival of some plant species, become established? Specifically, is there an ant-mycorrhizal fungus interaction that facilitates their establishment in these hyperdiverse ecosystems? In one lowland Costa Rican rainforest, nests of the LCA Atta cephalotes cover approximately 1.2% of the land surface that is broadly scattered throughout the forest. On sequencing the DNA from soil organisms, we found the inocula of many AM fungi in their nests, but the nests also contained the inocula of ectomycorrhizal, orchid mycorrhizal, and ericoid mycorrhizal fungi, including Scleroderma sinnamariense, a fungus critical to Gnetum leyboldii, an obligate ectomycorrhizal plant. When the nests were abandoned, new root growth into the nest offered opportunities for new mycorrhizal associations to develop. Thus, the patches created by LCAs appear to be crucial sites for the establishment and survival of shifting mycorrhizal plant-fungal associations, in turn facilitating the high diversity of these communities. A better understanding of the interactions of organisms, including cross-kingdom and ant-mycorrhizal fungal interactions, would improve our understanding of how these ecosystems might tolerate environmental change.

Chemical Shifts of Artificial Monomers Used to Construct Heterogeneous-Backbone Protein Mimetics in Random Coil and Folded States.

The construction of protein-sized synthetic chains that blend natural amino acids with artificial monomers to create so-called heterogeneous-backbones is a powerful approach to generate complex folds and functions from bio-inspired agents. A variety of techniques from structural biology commonly used to study natural proteins have been adapted to investigate folding in these entities. In NMR characterization of proteins, proton chemical shift is a straightforward to acquire, information-rich metric that bears directly on a variety of properties related to folding. Leveraging chemical shift to gain insight into folding requires a set of reference chemical shift values corresponding to each building block type (i.e., the 20 canonical amino acids in the case of natural proteins) in a random coil state and knowledge of systematic changes in chemical shift associated with particular folded conformations. Although well documented for natural proteins, these issues remain unexplored in the context of protein mimetics. Here, we report random coil chemical shift values for a library of artificial amino acid monomers frequently used to construct heterogeneous-backbone protein analogues as well as a spectroscopic signature associated with one monomer class, ß3-residues bearing proteinogenic side chains, adopting a helical folded conformation. Collectively, these results will facilitate the continued utilization of NMR for the study of structure and dynamics in protein-like artificial backbones.

Water, environment, and socioeconomic justice in California: A multi-benefit cropland repurposing framework.

Low-income, rural frontline communities of California's Central Valley experience environmental and socioeconomic injustice, water insecurity, extremely poor air quality, and lack of fundamental infrastructure (sewage, green areas, health services), which makes them less resilient. Many communities depend financially on agriculture, while water scarcity and associated policy may trigger farmland retirement further hindering socioeconomic opportunities. Here we propose a multi-benefit framework to repurpose cropland in buffers inside and around (400-m and 1600-m buffers) 154 rural disadvantaged communities of the Central Valley to promote socioeconomic opportunities, environmental benefits, and business diversification. We estimate the potential for (1) reductions in water and pesticide use, nitrogen leaching, and nitrogen gas emissions, (2) managed aquifer recharge, and (3) economic and employment impacts associated with clean industries and solar energy. Retiring cropland within 1600-m buffers can result in reductions in water use of 2.18 km3/year, nitrate leaching into local aquifers of 105,500 t/year, greenhouse gas emissions of 2,232,000 t CO2-equivalent/year, and 5388 t pesticides/year, with accompanying losses in agricultural revenue of US$4213 million/year and employment of 25,682 positions. Buffer repurposing investments of US$27 million/year per community for ten years show potential to generate US$101 million/year per community (total US$15,578 million/year) for 30 years and 407 new jobs/year (total 62,697 jobs/year) paying 67 % more than prior farmworker jobs. In the San Joaquin Valley (southern Central Valley), where groundwater overdraft averages 2.3 km3/year, potential water use reduction is 1.8 km3/year. We have identified 99 communities with surficial soils adequate for aquifer recharge and canals/rivers within 1600 m. This demonstrates the potential of managed aquifer recharge in buffered zones to substantially reduce overdraft. The buffers framework shows that well-planned land repurposing near disadvantaged communities can create multiple benefits for farmers and industry stakeholders, while improving quality of life in disadvantaged communities and producing positive externalities for society.

Seasonal ammonia losses from spray-irrigation with secondary-treated recycled water.

This work examines ammonia volatilization associated with agricultural irrigation employing recycled water. Effluent from a secondary wastewater treatment plant was applied using a center pivot irrigation system on a 12 ha agricultural site in Palmdale, California. Irrigation water was captured in shallow pans and ammonia concentrations were quantified in four seasonal events. The average ammonia loss ranged from 15 to 35% (averaging 22%) over 2-h periods. Temporal mass losses were well-fit using a first-order model. The resulting rate constants correlated primarily with temperature and secondarily with wind speed. The observed application rates and timing were projected over an entire irrigation season using meteorological time series data from the site, which yielded volatilization estimates of 0.03 to 0.09 metric tons NH(3)-N/ha per year. These rates are consistent with average rates (0.04 to 0.08 MT NH(3)-N/ha per year) based on 10 to 20 mg NH(3)-N/L effluent concentrations and a 22% average removal. As less than 10% of the treated effluent in California is currently reused, there is potential for this source to increase, but the increase may be offset by a corresponding reduction in synthetic fertilizers usage. This point is a factor for consideration with respect to nutrient management using recycled water.

Heterogeneous-Backbone Proteomimetic Analogues of Lasiocepsin, a Disulfide-Rich Antimicrobial Peptide with a Compact Tertiary Fold.

The emergence of resistance to clinically used antibiotics by bacteria presents a significant problem in public health. Natural antimicrobial peptides (AMPs) are a valuable source of antibiotics that act by a mechanism less prone to the evolutionary development of resistance. In an effort to realize the promise of AMPs while overcoming limitations such as poor biostability, researchers have sought sequence-defined oligomers with artificial amide-based backbones that show membrane-disrupting functions similar to natural agents. Most of this precedent has focused on short peptidomimetic analogues of unstructured chains or secondary folds; however, the natural antimicrobial arsenal includes a number of small- and medium-sized proteins that act via an ordered tertiary structure. Generating proteomimetic analogues of these scaffolds poses a challenge due to the increased complexity of the target for mimicry. Here, we report the development of heterogeneous-backbone variants of lasiocepsin, a 27-residue disulfide-rich AMP found in bee venom that adopts a compact tertiary fold. Iterative cycles of design, synthesis, and biological evaluation yielded analogues of the natural domain with ∼30 to 40% artificial backbone content, comparable antibacterial activity, reduced host cell toxicity, and improved stability to proteolytic degradation. High-resolution structures determined for several variants by NMR provide insights into the interplay among backbone composition, tertiary fold, and biological properties. Collectively, the results reported here broaden the scope of protein functional mimicry by artificial backbone analogues of tertiary folding patterns and suggest protein backbone engineering as a means to tune protein function by exerting site-specific control over protein folded structure.

Autonomous real-time adaptive management of soil salinity using a receding horizon control algorithm: a pilot-scale demonstration.

Soil salinization is a potentially negative side effect of irrigation with reclaimed water. While optimization schemes have been applied to soil salinity control, these have typically failed to take advantage of real-time sensor feedback. This study incorporates current soil observation technologies into the optimal feedback-control scheme known as Receding Horizon Control (RHC) to enable successful autonomous control of soil salinization. RHC uses real-time sensor measurements, physically-based state prediction models, and optimization algorithms to drive field conditions to a desired environmental state by manipulating application rate or irrigation duration/frequency. A simulation model including the Richards equation coupled to energy and solute transport equations is employed as a state estimator. Vertical multi-sensor arrays installed in the soil provide initial conditions and continuous feedback to the control scheme. An optimization algorithm determines the optimal irrigation rate or frequency subject to imposed constraints protective of soil salinization. A small-scale field test demonstrates that the RHC scheme is capable of autonomously maintaining specified salt levels at a prescribed soil depth. This finding suggests that, given an adequately structured and trained simulation model, sensor networks, and optimization algorithms can be integrated using RHC to autonomously achieve water reuse and agricultural objectives while managing soil salinization.

Environmental sensor networks in ecological research.

Environmental sensor networks offer a powerful combination of distributed sensing capacity, real-time data visualization and analysis, and integration with adjacent networks and remote sensing data streams. These advances have become a reality as a combined result of the continuing miniaturization of electronics, the availability of large data storage and computational capacity, and the pervasive connectivity of the Internet. Environmental sensor networks have been established and large new networks are planned for monitoring multiple habitats at many different scales. Projects range in spatial scale from continental systems designed to measure global change and environmental stability to those involved with the monitoring of only a few meters of forest edge in fragmented landscapes. Temporal measurements have ranged from the evaluation of sunfleck dynamics at scales of seconds, to daily CO2 fluxes, to decadal shifts in temperatures. Above-ground sensor systems are partnered with subsurface soil measurement networks for physical and biological activity, together with aquatic and riparian sensor networks to measure groundwater fluxes and nutrient dynamics. More recently, complex sensors, such as networked digital cameras and microphones, as well as newly emerging sensors, are being integrated into sensor networks for hierarchical methods of sensing that promise a further understanding of our ecological systems by revealing previously unobservable phenomena.

Distinct responses of Purkinje neurons and roles of simple spikes during associative motor learning in larval zebrafish.

To study cerebellar activity during learning, we made whole-cell recordings from larval zebrafish Purkinje cells while monitoring fictive swimming during associative conditioning. Fish learned to swim in response to visual stimulation preceding tactile stimulation of the tail. Learning was abolished by cerebellar ablation. All Purkinje cells showed task-related activity. Based on how many complex spikes emerged during learned swimming, they were classified as multiple, single, or zero complex spike (MCS, SCS, ZCS) cells. With learning, MCS and ZCS cells developed increased climbing fiber (MCS) or parallel fiber (ZCS) input during visual stimulation; SCS cells fired complex spikes associated with learned swimming episodes. The categories correlated with location. Optogenetically suppressing simple spikes only during visual stimulation demonstrated that simple spikes are required for acquisition and early stages of expression of learned responses, but not their maintenance, consistent with a transient, instructive role for simple spikes during cerebellar learning in larval zebrafish.

Two-stage aquifer pumping subject to slow desorption and persistent sources.

This work focuses on improving pump-and-treat remediation by optimizing a two-stage operational scheme to reduce volumes extracted when confronted with nonequilibrium desorption, low-permeability units, and continuous contaminant sources such as non-aqueous phase liquids (NAPL). Q1 and Q2 are the initial short-term high pumping rate and later long-term low pumping rate, respectively. A two-dimensional ground water flow and transport management model was used to test the proposed strategy for plumes developed from finite (NAPL-free) and continuous (NAPL-driven) contaminant sources in homogeneous and nonhomogeneous (zoned) aquifers. Remediation scenarios were simulated over durations of 2000, 6000, and 15,000 d to determine (1) the optimal time to switch from a preset Q1 to Q2 and (2) the value of Q2. The problem was constrained by mass removal requirements, maximum allowable downgradient concentrations, and practical bounds on Q2. Q1 was fixed at preset values 50% to 200% higher than the single-stage pumping rates (i.e., steady pumping rates during entire remediation period) necessary to achieve a desired cleanup level and capture the plume. Results for the NAPL-free homogeneous case under nonequilibrium desorption conditions achieved the same level of cleanup as single-stage pumping, while reducing extracted volumes by up to 36%. Comparable savings were obtained with NAPL-driven sources only when the source concentration was reduced by at least 2 orders of magnitude. For the zoned aquifer, the proposed strategy provided volume savings of up to 24% under NAPL-free and reduced source conditions.

Developmental Changes in Hippocampal CA1 Single Neuron Firing and Theta Activity during Associative Learning.

Hippocampal development is thought to play a crucial role in the emergence of many forms of learning and memory, but ontogenetic changes in hippocampal activity during learning have not been examined thoroughly. We examined the ontogeny of hippocampal function by recording theta and single neuron activity from the dorsal hippocampal CA1 area while rat pups were trained in associative learning. Three different age groups [postnatal days (P)17-19, P21-23, and P24-26] were trained over six sessions using a tone conditioned stimulus (CS) and a periorbital stimulation unconditioned stimulus (US). Learning increased as a function of age, with the P21-23 and P24-26 groups learning faster than the P17-19 group. Age- and learning-related changes in both theta and single neuron activity were observed. CA1 pyramidal cells in the older age groups showed greater task-related activity than the P17-19 group during CS-US paired sessions. The proportion of trials with a significant theta (4-10 Hz) power change, the theta/delta ratio, and theta peak frequency also increased in an age-dependent manner. Finally, spike/theta phase-locking during the CS showed an age-related increase. The findings indicate substantial developmental changes in dorsal hippocampal function that may play a role in the ontogeny of learning and memory.

Exploring the Potential Health Impact and Cost-Effectiveness of AIDS Vaccine within a Comprehensive HIV/AIDS Response in Low- and Middle-Income Countries.

BACKGROUND: The Investment Framework Enhanced (IFE) proposed in 2013 by the Joint United Nations Programme on HIV/AIDS (UNAIDS) explored how maximizing existing interventions and adding emerging prevention options, including a vaccine, could further reduce new HIV infections and AIDS-related deaths in low- and middle-income countries (LMICs). This article describes additional modeling which looks more closely at the potential health impact and cost-effectiveness of AIDS vaccination in LMICs as part of UNAIDS IFE. METHODS: An epidemiological model was used to explore the potential impact of AIDS vaccination in LMICs in combination with other interventions through 2070. Assumptions were based on perspectives from research, vaccination and public health experts, as well as observations from other HIV/AIDS interventions and vaccination programs. Sensitivity analyses varied vaccine efficacy, duration of protection, coverage, and cost. RESULTS: If UNAIDS IFE goals were fully achieved, new annual HIV infections in LMICs would decline from 2.0 million in 2014 to 550,000 in 2070. A 70% efficacious vaccine introduced in 2027 with three doses, strong uptake and five years of protection would reduce annual new infections by 44% over the first decade, by 65% the first 25 years and by 78% to 122,000 in 2070. Vaccine impact would be much greater if the assumptions in UNAIDS IFE were not fully achieved. An AIDS vaccine would be cost-effective within a wide range of scenarios. INTERPRETATION: Even a modestly effective vaccine could contribute strongly to a sustainable response to HIV/AIDS and be cost-effective, even with optimistic assumptions about other interventions. Higher efficacy would provide even greater impact and cost-effectiveness, and would support broader access. Vaccine efficacy and cost per regimen are critical in achieving cost-effectiveness, with cost per regimen being particularly critical in low-income countries and at lower efficacy levels.