CyVerse: Cyberinfrastructure for open science.

CyVerse, the largest publicly-funded open-source research cyberinfrastructure for life sciences, has played a crucial role in advancing data-driven research since the 2010s. As the technology landscape evolved with the emergence of cloud computing platforms, machine learning and artificial intelligence (AI) applications, CyVerse has enabled access by providing interfaces, Software as a Service (SaaS), and cloud-native Infrastructure as Code (IaC) to leverage new technologies. CyVerse services enable researchers to integrate institutional and private computational resources, custom software, perform analyses, and publish data in accordance with open science principles. Over the past 13 years, CyVerse has registered more than 124,000 verified accounts from 160 countries and was used for over 1,600 peer-reviewed publications. Since 2011, 45,000 students and researchers have been trained to use CyVerse. The platform has been replicated and deployed in three countries outside the US, with additional private deployments on commercial clouds for US government agencies and multinational corporations. In this manuscript, we present a strategic blueprint for creating and managing SaaS cyberinfrastructure and IaC as free and open-source software.

Cysteine Enrichment Mediates Co-Option of Uricase in Reptilian Skin and Transition to Uricotelism.

Uric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that the Gallus gallus gene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property that we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with the transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with ß-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin.

In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

Comparing Unicompartmental Knee Arthroplasty and High Tibial Osteotomy for Isolated Medial Compartment Knee Osteoarthritis.

¼: Both unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) allow for compartment-specific intervention on an arthritic knee joint that preserves bone stock and native soft tissue compared to a total knee arthroplasty (TKA). Both operations give a more natural feeling with native proprioception compared with a TKA. ¼: HTO is better suited in patients who are younger (<55 years-of-age), have a body mass index (BMI) <30 kg/m2, high activity requirements, mechanical malalignment, asymmetric varus, isolated anterior cruciate ligament insufficiency, need for multiplanar correction, and a preference for joint preserving interventions. Recent data suggest that age (>55 years-of-age) should not solely contraindicate a HTO. ¼: UKA may be chosen in patients who are older (>55 years-of-age), low activity requirements, have a BMI <40 kg/m2, severe osteoarthritis with significant joint space narrowing, acceptable coronal alignment, symmetric varus, and patient preference for arthroplasty.

Designed Iron Catalysts for Allylic C-H Functionalization of Propylene and Simple Olefins.

Propylene gas is produced worldwide by steam cracking on million-metric-ton scale per year. It serves as a valuable starting material for π-bond functionalization but is rarely applied in transition metal-catalyzed allylic C-H functionalization for fine chemical synthesis. Herein, we report that a newly-developed cationic cyclopentadienyliron dicarbonyl complex allows for the conversion of propylene to its allylic C-C bond coupling products under catalytic conditions. This approach was also found applicable to the allylic functionalization of simple α-olefins with distinctive branched selectivity. Experimental and computational mechanistic studies supported the allylic deprotonation of the metal-coordinated alkene as the turnover-limiting step and led to insights into the multifaceted roles of the newly designed ligand in promoting allylic C-H functionalization with enhanced reactivity and stereoselectivity.

Towards equitable conservation: Social capital, fear and livestock loss shape perceived benefit from a protected area.

Providing sufficient benefits to local people can be an important component of effective and equitable conservation, especially where local communities face substantial opportunity costs or disbenefits from conservation. However, the distribution of benefits to local people is often inadequate or inequitable. In this study we investigated the heterogeneity in the extent to which people living near Hwange National Park (HNP), Zimbabwe, perceive benefit from the presence of the park. Specifically, we examined the relationships between a diverse set of candidate predictor variables and perceived benefit from HNP. Our candidate predictor variables broadly relate to personal assets, social capital, value orientation, fear of lions, and belief and participation in human-wildlife conflict mitigation schemes. One third of respondents reported that their household experienced at least some benefits from HNP. Of all respondents, 6% perceived their household to benefit strongly from HNP and 2% very strongly. Livestock loss to wildlife was the most important factor for predicting perceived benefit, with those suffering more loss less likely to perceive benefit. Multiple demographic factors predicted perceived benefit with, for instance, older people and those with less education perceiving less benefit. Employment in conservation-related work positively affected perceived benefit, whereas fear of lions had a negative impact. Social capital appeared to have a positive influence on perceived benefit from HNP. The relationship between social capital and perceived benefit was positive and plateauing, which suggests that social capital is especially impactful on the benefit perceived by individuals reporting the least social capital. We also found a positive association between belief in compensation schemes and perceived benefit from HNP. We posit hypotheses for this association but are unable to determine the underlying drivers of this relationship. Finally, participation in the community guardians programme, a human-lion conflict mitigation programme, was positively related to perceived benefit from HNP. Thus, our findings emphasise the value of considering a diverse array of factors when investigating park-people relationships and yield insights for improving the equitability of conservation in and around HNP and similar systems.

Antidotal treatment of botulism in rats by continuous infusion with 3,4-diaminopyridine.

Botulinum neurotoxins (BoNTs) are highly potent, select agent toxins that inhibit neurotransmitter release at motor nerve terminals, causing muscle paralysis and death by asphyxiation. Other than post-exposure prophylaxis with antitoxin, the only treatment option for symptomatic botulism is intubation and supportive care until recovery, which can require weeks or longer. In previous studies, we reported the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses early botulism symptoms and prolongs survival in lethally intoxicated mice. However, the symptomatic benefits of 3,4-DAP are limited by its rapid clearance. Here we investigated whether 3,4-DAP could sustain symptomatic benefits throughout the full course of respiratory paralysis in lethally intoxicated rats. First, we confirmed serial injections of 3,4-DAP stabilized toxic signs and prolonged survival in rats challenged with 2.5 LD50 BoNT/A. Rebound of toxic signs and death occurred within hours after the final 3,4-DAP treatment, consistent with the short half-life of 3,4-DAP in rats. Based on these data, we next investigated whether the therapeutic benefits of 3,4-DAP could be sustained throughout the course of botulism by continuous infusion. To ensure administration of 3,4-DAP at clinically relevant doses, three infusion dose rates (0.5, 1.0 and 1.5 mg/kg∙h) were identified that produced steady-state serum levels of 3,4-DAP consistent with clinical dosing. We then compared dose-dependent effects of 3,4-DAP on toxic signs and survival in rats intoxicated with 2.5 LD50 BoNT/A. In contrast to saline vehicle, which resulted in 100% mortality, infusion of 3,4-DAP at ≥ 1.0 mg/kg∙h from 1 to 14 d after intoxication produced 94.4% survival and full resolution of toxic signs, without rebound of toxic signs after infusion was stopped. In contrast, withdrawal of 3,4-DAP infusion at 5 d resulted in re-emergence of toxic sign and death within 12 h, confirming antidotal outcomes require sustained 3,4-DAP treatment for longer than 5 d after intoxication. We exploited this novel survival model of lethal botulism to explore neurophysiological parameters of diaphragm paralysis and recovery. While neurotransmission was nearly eliminated at 5 d, neurotransmission was significantly improved at 21 d in 3,4-DAP-infused survivors, although still depressed compared to naïve rats. 3,4-DAP is the first small molecule to reverse systemic paralysis and promote survival in animal models of botulism, thereby meeting a critical treatment need that is not addressed by post-exposure prophylaxis with conventional antitoxin. These data contribute to a growing body of evidence supporting the use of 3,4-DAP to treat clinical botulism.

Mortality of various-age larval winter ticks, Dermacentor albipictus, following surface contact with entomopathogenic fungi.

The larval stage of the one-host tick, Dermacentor albipictus Packard (Acari: Ixodidae), the winter tick, is spent aggregated on the ground in summer until they quest for hosts in the autumn. Metarhizium brunneum (Petch) and Beauveria bassiana (Balsamo-Crivelli) Vuillemin are promising fungal biocontrol agents of ticks. The success of tick biocontrol using entomopathogenic fungi relies on infective propagule contact with a susceptible host at the right time within their life cycle and stage. The susceptibility of various-age D. albipictus larvae to commercial isolates of M. brunneum strain F52 (Mb-F52) and B. bassiana strain GHA (Bb-GHA) was assessed over a three-week period after contact with surfaces treated with 1.3 × 106 conidia/cm2. Larvae of four ages were examined (a) upon eclosion from eggs, (b) 2-weeks, (c) 1.5-months and (d) 3-months-old. Mortality of larvae exposed to fungus-treated surfaces ranged from 4 to 51% for Bb-GHA and 64-100% for Mb-F52 after three weeks. Significantly greater mortality was observed when larvae were exposed to Mb-F52 than Bb-GHA. Larval susceptibility was significantly greater within 2 weeks of eclosion from eggs and after 3 months of age. These results demonstrate the varying susceptibility of larvae to mycoacaricides at different times within their non-parasitic larval life stage.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Search for magnetic monopoles produced via the Schwinger mechanism.

Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism1. By electromagnetic duality, a sufficiently strong magnetic field would similarly produce magnetic monopoles, if they exist2. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model3-7 but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size8,9 and strong coupling to photons2,10. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb-Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe11. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 109, of Pb-Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.

Culex nigripalpus Distribution Expansion: First Record in Virginia, New County Records in North Carolina, and Revised United States Map.

Theobald first described Culex nigripalpus in 1901 from St. Lucia Island of the Lesser Antilles. It is a Neotropical mosquito species that is documented throughout Central and South America, the Caribbean, and the southeastern USA. Reports within the last 3 decades show the species has expanded its range farther into North America and is not only being discovered sporadically but appears to be establishing itself in several states, of which data are underreported and difficult to find. Five female specimens were collected-4 on October 13 and 1 on December 6, 2017-at 3 separate sites in the city of Suffolk, VA-2 in a BG-Sentinel 2® trap, 3 in Centers for Disease Control and Prevention light traps-during routine mosquito surveillance; subsequent collections were made in 2019 and 2020. These findings represent the 1st record of Cx. nigripalpus in the state of Virginia and the most northeastern records in the USA. An updated mosquito species checklist for the state of Virginia is provided. Additionally, this report serves to update the records of North Carolina to 28 total counties reporting Cx. nigripalpus. These new records, along with other reports and published studies, show this species now documented in 201 jurisdictions in 16 states of the USA. As recent literature on this species is scarce, we provide a review of the bionomics, defining morphological characters, and an updated US distribution map.

Geochemical and isotopic evidence for pumping-induced impacts to bedrock groundwater quality in the City of Guelph, Canada.

Groundwater can be a key water resource in urban environments, providing a source of freshwater for community needs. The City of Guelph relies on groundwater for a population of over 130,000 people. Thus, groundwater quality is a critical component of long-term water management. This study assesses the effect of urban, industrial and agriculture activities on groundwater quality using a suite of multidisciplinary methods including geological, hydrological, geochemical, and isotopic tools. Multi-level systems (with depth-discrete ports), conventional well clusters, and municipal production wells were used to monitor hydraulic head and collect groundwater samples. Geochemical and isotopic measurements included redox parameters, major anions and cations, VOC, tritium and δ34S and δ18O in sulfate. Hydraulic head data show vertical gradient profiles characteristic of a multi-layered flow system within a shallow and deep Silurian bedrock aquifer and an intermediate aquitard varying in occurrence. Head loss disappears near production wells, showing enhanced vertical hydraulic connectivity between shallow and deep aquifers, attributed to pumping and long open intervals. Hydrochemical data show no impact of nitrate and high chloride is observed in the shallow and deep aquifer, attributed to seasonal road salt and the underlying aquitard unit, respectively. The aquitard unit also control the high sulfate in the deep aquifer which is supported by the isotope data on sulfate. Facilitated transport of shallow groundwater into the deeper aquifer is supported by the tritium data, showing the presence of recent groundwater throughout the whole depth of the two aquifers in some areas, likely due to the varying aquitard presence and enhanced vertical flow due to proximity from pumping municipal wells and active rock quarry. The results of this research suggest long term implications for groundwater resource management of sedimentary bedrock aquifers, where there is increasing groundwater demand due to population growth and potential for continual water quality degradation.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Pulse arrival time, a novel sleep cardiovascular marker: the multi-ethnic study of atherosclerosis.

BACKGROUND: Pulse arrival time (PAT) is commonly used to estimate blood pressure response. We hypothesised that PAT response to obstructive respiratory events would be associated with increased cardiovascular risk in people with obstructive sleep apnoea. METHODS: PAT, defined as the time interval between electrocardiography R wave and pulse arrival by photoplethysmography, was measured in the Multi-Ethnic Study of Atherosclerosis Sleep study participants. The PAT response to apnoeas/hypopnoeas was defined as the area under the PAT waveform following respiratory events. Cardiovascular outcomes included markers of subclinical cardiovascular disease (CVD): left ventricular mass, carotid plaque burden score and coronary artery calcification (CAC) (cross-sectional) and incident composite CVD events (prospective). Multivariable logistic and Cox proportional hazard regressions were performed. RESULTS: A total of 1407 participants (mean age 68.4 years, female 47.5%) were included. Higher PAT response (per 1 SD increase) was associated with higher left ventricular mass (5.7 g/m2 higher in fourth vs first quartile, p<0.007), higher carotid plaque burden score (0.37 higher in fourth vs first quartile, p=0.02) and trended to greater odds of CAC (1.44, 95% CI 0.98 to 2.15, p=0.06). A total of 65 incident CVD events were observed over the mean of 4.1 (2.6) years follow-up period. Higher PAT response was associated with increased future CVD events (HR: 1.20, 95% CI 1.02 to 1.42, p=0.03). CONCLUSION: PAT is independently associated with markers of subclinical CVD and incident CVD events. Respiratory-related PAT response is a novel and promising polysomnography metric with cardiovascular implications.

First Search for Dyons with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions.

The MoEDAL trapping detector consists of approximately 800 kg of aluminum volumes. It was exposed during run 2 of the LHC program to 6.46 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminum volumes comprising the detector through a superconducting quantum interference device (SQUID) magnetometer. The presence of a trapped dyon would be signaled by a persistent current induced in the SQUID magnetometer. On the basis of a Drell-Yan production model, we exclude dyons with a magnetic charge ranging up to five Dirac charges (5g_{D}) and an electric charge up to 200 times the fundamental electric charge for mass limits in the range 870-3120 GeV and also monopoles with magnetic charge up to and including 5g_{D} with mass limits in the range 870-2040 GeV.

A Novel Radiographic Finding of Intracapsular Heterotopic Ossification: A Report of Two Cases.

Symptomatic heterotopic ossification (HO) is a complication of hip arthroscopy that occurs in less than 1% of cases. To our knowledge, there are no reported cases of symptomatic intracapsular HO. We present 2 patients with a radiographic finding associated with intracapsular HO. Both patients underwent revision hip arthroscopy and required capsular reconstruction due to void of the iliofemoral ligament following excision of HO. We believe this radiographic finding may be useful to hip preservationists as it may be associated with capsular deficiency necessitating capsular reconstruction upon revision hip arthroscopy.

Birth of a pathway for sulfur metabolism in early amniote evolution.

Among amniotes, reptiles and mammals are differently adapted to terrestrial life. It is generally appreciated that terrestrialization required adaptive changes of vertebrate metabolism, particularly in the mode of nitrogen excretion. However, the current paradigm is that metabolic adaptation to life on land did not involve synthesis of enzymatic pathways de novo, but rather repurposing of existing ones. Here, by comparing the inventory of pyridoxal 5'-phosphate-dependent enzymes in different amniotes, we identify in silico a pathway for sulfur metabolism present in chick embryos but not in mammals. Cysteine lyase contains haem and pyridoxal 5'-phosphate co-factors and converts cysteine and sulfite into cysteic acid and hydrogen sulfide, respectively. A specific cysteic acid decarboxylase produces taurine, while hydrogen sulfide is recycled into cysteine by cystathionine beta-synthase. This reaction sequence enables the formation of sulfonated amino acids during embryo development in the egg at no cost of reduced sulfur. The pathway originated around 300 million years ago in a proto-reptile by cystathionine beta-synthase duplication, cysteine lyase neofunctionalization and cysteic acid decarboxylase co-option. Our findings indicate that adaptation to terrestrial life involved innovations in metabolic pathways, and reveal the molecular mechanisms by which such innovations arose in amniote evolution.

Multiple phenotypes conferred by a single insect symbiont are independent.

Many microbial symbionts have multiple phenotypic consequences for their animal hosts. However, the ways in which different symbiont-mediated phenotypes combine to affect fitness are not well understood. We investigated whether there are correlations between different symbiont-mediated phenotypes. We used the symbiont Spiroplasma, a striking example of a bacterial symbiont conferring diverse phenotypes on insect hosts. We took 11 strains of Spiroplasma infecting pea aphids (Acyrthosiphon pisum) and assessed their ability to provide protection against the fungal pathogen Pandora neoaphidis and the parasitoids Aphidius ervi and Praon volucre. We also assessed effects on male offspring production for five of the Spiroplasma strains. All but one of the Spiroplasma strains provided very strong protection against the parasitoid P. volucre. As previously reported, variable protection against P. neoaphidis and A. ervi was also present; male-killing was likewise a variable phenotype. We find no evidence of any correlation, positive or negative, between the different phenotypes, nor was there any evidence of an effect of symbiont phylogeny on protective phenotype. We conclude that multiple symbiont-mediated phenotypes can evolve independently from one another without trade-offs between them.

Characterization and treatment of spontaneous recurrent seizures following nerve agent-induced status epilepticus in mice.

PURPOSE: To develop and characterize a mouse model of spontaneous recurrent seizures following nerve agent-induced status epilepticus (SE) and test the efficacy of existing antiepileptic drugs. METHODS: SE was induced in telemeterized male C57Bl6/J mice by soman exposure, and electroencephalographic activity was recorded for 4-6 weeks. Mice were treated with antiepileptic drugs (levetiracetam, valproic acid, phenobarbital) or corresponding vehicles for 14 d after exposure, followed by 14 d of drug washout. Survival, body weight, seizure characteristics, and histopathology were used to characterize the acute and chronic effects of nerve agent exposure and to evaluate the efficacy of treatments in mitigating or preventing neurological effects. RESULTS: Spontaneous recurrent seizures manifested in all survivors, but the number and frequency of seizures varied considerably among mice. In untreated mice, seizures became longer over time. Moderate to severe histopathology was observed in the amygdala, piriform cortex, and CA1. Levetiracetam provided modest improvements in neurological parameters such as reduced spike rate and improved histopathology scores, whereas valproic acid and phenobarbital were largely ineffective. CONCLUSIONS: This model of post-SE spontaneous recurrent seizures differs from other experimental models in the brief latency to seizure development, the occurrence of seizures in 100 % of exposed animals, and the lack of damage to CA4/dentate gyrus. It may serve as a useful tool for rapidly and efficiently screening novel therapies that would be effective against severe epilepsy cases.

Five-century record of climate and groundwater recharge variability in southern California.

Modifications to the rates of water flowing from the surface to groundwater (groundwater recharge) due to climate variability are the most difficult to assess because of the lack of direct long-term observations. Here, we analyze the chloride salt distribution below the surface soil on a plateau near Los Angeles to reconstruct the amount of recharge that occurred in the last five centuries. Over this time interval, periods of major high and low recharge with different duration follow each other and this cyclicity is consistent with long-term atmospheric forcing patterns, such as the Pacific Decadal Oscillation. This study determines the range and the natural variability of recharge to groundwater, which sustains local freshwater flow system, and helps forecast future availability of groundwater resource in southern California, where water scarcity is critical to both local and global populations.