Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of influenza A virus.

Viral proteins frequently mutate to evade or antagonize host innate immune responses, yet the impact of these mutations on the molecular energy landscape remains unclear. Epistasis, the intramolecular communications between mutations, often renders the combined mutational effects unpredictable. Nonstructural protein 1 (NS1) is a major virulence factor of the influenza A virus (IAV) that activates host PI3K by binding to its p85ß subunit. Here, we present the deep analysis for the impact of evolutionary mutations in NS1 that emerged between the 1918 pandemic IAV strain and its descendant PR8 strain. Our analysis reveal how the mutations rewired inter-residue communications which underlies long-range allosteric and epistatic networks in NS1. Our findings show that PR8 NS1 binds to p85ß with approximately 10-fold greater affinity than 1918 NS1 due to allosteric mutational effects. Notably, these mutations also exhibited long-range epistatic effects. NMR chemical shift perturbation and methyl-axis order parameter analyses revealed that the mutations induced long-range structural and dynamic changes in PR8 NS1, enhancing its affinity to p85ß. Complementary MD simulations and graph-based network analysis uncover how these mutations rewire dynamic residue interaction networks, which underlies the long-range epistasis and allosteric effects on p85ß-binding affinity. Significantly, we find that conformational dynamics of residues with high betweenness centrality play a crucial role in communications between network communities and are highly conserved across influenza A virus evolution. These findings advance our mechanistic understanding of the allosteric and epistatic communications between distant residues and provides insight into their role in the molecular evolution of NS1.

Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients.

BACKGROUND: Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion. METHODS: Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments. RESULTS: Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis. CONCLUSIONS: The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.

Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial.

Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN.

Assessment of biogeochemical natural attenuation and treatment of chlorinated solvents, Altus Air Force Base, Altus, Oklahoma.

Biogeochemical reductive dechlorination (BiRD) is a newly recognized method for the remediation or natural attenuation of chlorinated solvents. Chlorinated solvents are rapidly treated by abiotic reaction with reduced mineral iron sulfides. Iron sulfides are formed by naturally occurring sulfate-reducing bacteria when sufficient SO(4)(2-) and organic carbon are present or supplied to sediments containing mineral iron. An example of site characterization focusing on BiRD is presented focusing on mineral phases. Methods demonstrated here may be employed at other sites to evaluate naturally occurring BiRD or to evaluate an engineered BiRD remediation. A field investigation was performed at a TCE contaminated site at Altus AFB with naturally high concentrations of SO(4)(2-) and Fe(III) minerals and where an accidental fuel spill provided organic carbon. In the area of this fuel spill significant mineral iron sulfides were found, sulfate was almost completely removed, and TCE was absent. Only small amounts of daughter products were found, further indicating that the BiRD pathway was operative. Mass balance data indicates all of the remaining TCE (182 kg) could be treated by the remaining FeS (66.5 kg) in the upper aquifer; however, the FeS was not co-located with TCE to enable complete reaction. Laboratory microcosm tests with FeS amended and FeS-rich sediment from Altus AFB also suggest that BiRD is capable of destroying TCE. The results suggest that an engineered BiRD treatment is possible for this site.

Examination of physical and regulatory variables leading to small dam removal in Wisconsin.

The decision to remove or repair a dam depends on multiple variables, many of which encompass both physical and social factors. In Wisconsin, the Department of Natural Resources is mandated to inspect small dams every ten years. A safety inspection often acts as a trigger event to a dam removal or repair decision. Although the issues surrounding a dam removal decision are often couched as ecological, these decisions are influenced by their social and regulatory context. In this work, we examine descriptive variables of Wisconsin dams that were inspected and consequently removed or maintained between 1985 and 1990. We hypothesize that geographic location, height of dam, size of impoundment, age of dam, and type of ownership determine the likelihood of a safety inspection, and the subsequent likelihood of removal. Using a logistic model, we find that publicly owned dams had the greatest probability of inspection after 1985. Of these dams, older dams and those with smaller impoundments were most likely to be removed. We were unable to build a strong predictive model for dam removal with our suite of variables, suggesting that a community's decision to remove or maintain a dam is complex and heterogeneous.

MAROS: a decision support system for optimizing monitoring plans.

The Monitoring and Remediation Optimization System (MAROS), a decision-support software, was developed to assist in formulating cost-effective ground water long-term monitoring plans. MAROS optimizes an existing ground water monitoring program using both temporal and spatial data analyses to determine the general monitoring system category and the locations and frequency of sampling for future compliance monitoring at the site. The objective of the MAROS optimization is to minimize monitoring locations in the sampling network and reduce sampling frequency without significant loss of information, ensuring adequate future characterization of the contaminant plume. The interpretive trend analysis approach recommends the general monitoring system category for a site based on plume stability and site-specific hydrogeologic information. Plume stability is characterized using primary lines of evidence (i.e., Mann-Kendall analysis and linear regression analysis) based on concentration trends, and secondary lines of evidence based on modeling results and empirical data. The sampling optimization approach, consisting of a two-dimensional spatial sampling reduction method (Delaunay method) and a temporal sampling analysis method (Modified CES method), provides detailed sampling location and frequency results. The Delaunay method is designed to identify and eliminate redundant sampling locations without causing significant information loss in characterizing the plume. The Modified CES method determines the optimal sampling frequency for a sampling location based on the direction, magnitude, and uncertainty in its concentration trend. MAROS addresses a variety of ground water contaminants (fuels, solvents, and metals), allows import of various data formats, and is designed for continual modification of long-term monitoring plans as the plume or site conditions change over time.

Groundwater monitoring plans at small-scale sites--an innovative spatial and temporal methodology.

An innovative methodology for improving existing groundwater monitoring plans at small-scale sites is presented. The methodology consists of three stand-alone methods: a spatial redundancy reduction method, a well-siting method for adding new sampling locations, and a sampling frequency determination method. The spatial redundancy reduction method eliminates redundant wells through an optimization process that minimizes the errors in plume delineation and the average plume concentration estimation. The well-siting method locates possible new sampling points for an inadequately delineated plume via regression analysis of plume centerline concentrations and estimation of plume dispersivity values. The sampling frequency determination method recommends the future frequency of sampling for each sampling location based on the direction, magnitude, and uncertainty of the concentration trend derived from representative historical concentration data. Although the methodology is designed for small-scale sites, it can be easily adopted for large-scale site applications. The proposed methodology is applied to a small petroleum hydrocarbon-contaminated site with a network of 12 monitoring wells to demonstrate its effectiveness and validity.