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In this response to Knut Melvær's discussion of "The Spiritual Illusion: Constructive Steps Toward Rectification and Redescription," I clarify some of the theoretical and methodological background that informed the original article, redress places where Melvær appears to have misread or miscast my positions, and offer some suggestions as to what may really be most at stake in this "spiritual" dispute. [ABSTRACT FROM AUTHOR]

Explores the mystical dimensions of the Neo-Confucianism works of Chinese philosopher Chu Hsi. Identification of the human heart and mind with both the heart-mind of heaven and earth and the heart-mind of the sage; Resistance of writing to purely analytical scrutiny; Emphasis on the primacy of rootedness and social responsibility.

Reservoirs balance multiple conflicting objectives, including flood control and water supply. In California, shifts in seasonal hydrologic patterns under climate change will amplify the difficulties in balancing flood control with water supply. Current flood control policies are based on fixed seasonal rule curves determined by the observed timing and magnitude of floods in the record. These rule curves generally require the release of wet season inflows, reducing the available stored water for use during the dry season. Here we investigate the potential for forecast-informed reservoir operations (FIRO) to increase water supply availability while minimizing additional flood risk at 14 reservoirs in the Sacramento, San Joaquin, and Tulare river basins. We use a differential evolution algorithm to train risk-based reservoir operation policies with an ensemble of historical forecasts over the period 2013–2023. Results show an average 8.1% increase in storage normalized by capacity, though this varies across reservoirs. The forecast-informed policies also reduce the occurrence of high-magnitude releases throughout the system. The accumulation of benefits is sensitive to the timing and magnitude of flood events, and most of the cumulative benefit is obtained during a few years. Under cross-validation, we find that large floods are needed in the training data to avoid overfitting the policy. We further examine the relationship between reservoir properties and FIRO benefits, finding that the ratio of peak inflow magnitude to maximum safe release correlates with increased storage under the FIRO policy, while the ratio of mean inflow to capacity correlates to the reduction of high-magnitude releases. This study highlights how adaptive reservoir management policies can yield water supply benefits without an increase in flood risk, given adequate historical data for policy training. These policies may be a valuable adaptation to climate change but require careful validation and out-of-sample testing. [ABSTRACT FROM AUTHOR]

Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0511-2) contains supplementary material, which is available to authorized users.

The adaptation of water resources infrastructure and operations to climate change can be framed as a control problem in which actions are chosen dynamically in response to observations and projections. Recent studies have developed adaptive policies based on tipping points or "signposts", which are threshold values of observed variables that indicate a future vulnerability and/or trigger a change in policy. Here we present a related approach, policy tree optimization, as a heuristic policy search method for control problems with discrete actions. Adaptive policies are represented as binary trees, making them highly interpretable, and they can be trained without predefining the tree structure. We demonstrate this method for an illustrative planning problem focused on reservoir expansion under climate change. In the process, a number of significant challenges are identified related to long-term uncertainty in ensemble streamflow projections, namely: (1) the combined roles of sample uncertainty and ensemble uncertainty in the estimation of extreme events at multiple timescales; (2) reduced performance in out-of-sample hydrologic scenarios, underscoring the need for cross-validation of optimized policies; and (3) the irreversibility of infrastructure decisions, which leads to a risk of incorrectly identifying or failing to identify a vulnerable scenario (false positives and false negatives, respectively). These challenges apply generally to any control method used for climate adaptation, and also apply to related application areas such as sea level rise. While this study demonstrates the policy tree optimization framework, the choice of optimization method is arguably less important than the choice of forcing scenarios in which policies are trained. The presentation will conclude with opportunities going forward to reconcile infrastructure and operations planning with long-term streamflow ensembles, which remain the best available projections of the future despite their severe uncertainty. [ABSTRACT FROM AUTHOR]

Forecasts and observations of hydrologic and climatic states have significant potential to improve water supply and flood control operations in multi-purpose reservoirs, which largely lack formal rules describing how to incorporate this dynamic information. This study develops reservoir control policies trained on a broad set of forecasts and observations that span short-term (1-3) and medium-range (1-15 day) timescales, including: an ensemble of synthetic short-term precipitation and temperature forecasts based on state-of-the-art dynamical hindcast products; hydrologic response, based on a rainfall-runoff model; and binary forecasts of regional storm occurrence to compensate for potential spatial bias. A simulation-optimization approach is used to train reservoir policies structured as trees, which are highly interpretable and provide insight into the value of information provided by different sources of observed and forecasted data. The approach is demonstrated on a case study of Folsom Reservoir in California, using a simulation model of reservoir operations combined with a simplified groundwater model to explore the potential for conjunctive use to improve the utility of forecasts. Results show that forecasts and current-state observations need only indicate the potential occurrence of a storm, rather than its intensity, to effectively inform management decisions in regions like California where wintertime, synoptic-scale atmospheric rivers dominate the flood regime. Further, increased conjunctive use capacity reduces the importance of forecast skill, because surface storage can be moved to groundwater during the flood season without sacrificing future water supply. Finally, the policy trees trained with this approach are validated against an out-of-sample hydrologic period to ensure their robustness. This analysis serves to better link hydroclimatic observations and predictions with water resources management decisions to improve the tradeoff between water supply and flood control objectives in large, multi-purpose reservoirs in California and other regions with similar flood hydroclimatology. [ABSTRACT FROM AUTHOR]

BACKGROUND. Sanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown. METHODS. This randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and wellcontrolled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/μL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later. RESULTS. There were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies. CONCLUSIONS. PfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa. [ABSTRACT FROM AUTHOR]

Background Studies have demonstrated the protective role of antibodies against malaria. Young children are known to be particularly vulnerable to malaria, pointing to the evolution of naturally acquired clinical immunity over time. However, whether changes in antibody functionality track with the acquisition of naturally acquired malaria immunity remains incompletely understood. Methods Using systems serology, we characterized sporozoite- and merozoite-specific antibody profiles of uninfected Malian children before the malaria season who differed in their ability to control parasitemia and fever following Plasmodium falciparum (Pf) infection. We then assessed the contributions of individual traits to overall clinical outcomes, focusing on the immunodominant sporozoite CSP and merozoite AMA1 and MSP1 antigens. Results Humoral immunity evolved with age, with an expansion of both magnitude and functional quality, particularly within blood-stage phagocytic antibody activity. Moreover, concerning clinical outcomes postinfection, protected children had higher antibody-dependent neutrophil activity along with higher levels of MSP1-specific IgG3 and IgA and CSP-specific IgG3 and IgG4 prior to the malaria season. Conclusions These data point to the natural evolution of functional humoral immunity to Pf with age and highlight particular antibody Fc-effector profiles associated with the control of malaria in children, providing clues for the design of next-generation vaccines or therapeutics. [ABSTRACT FROM AUTHOR]