Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome.

Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs

Operation of rain gauge and ground-water monitoring networks for the Imperial Valley Water Authority, year six: September 1997 - August 1998

The Illinois State Water Survey (ISWS), under contract to the Imperial Valley Water Authority (IVWA), has operated a network of rain gauges in Mason and Tazewell Counties since August 1992. The ISWS also established a network of ground-water observation wells in the Mason-Tazewell area. The networks are located in the most heavily irrigated region of the state. Ground water in various aquifers are the major source of the irrigation and domestic water supplies in the region. Recent extreme weather events (e.g., the drought of 1988 and the great flood of 1993) resulted in large fluctuations of the ground-water levels in the Imperial Valley area. The purpose of the rain gauge network and the ground-water observation well network is to collect a long-term series of data to determine the rate of ground-water drawdown in dry periods and during the growing season, and the rate at which the aquifers recharge. Precipitation is recorded for each storm that traverses the Imperial Valley, and ground-water levels at the 13 observation wells are measured the first of each month. The database from these networks consists of 6 years of precipitation data and 4 years of ground-water observations. At the beginning of the ground-water observations in 1995, the water levels were at the highest in the four years of observation. These high ground-water levels were the result of the very wet 1992-1995 period when annual precipitation was above the 30-year normals at both Havana and Mason City. From September 1995-August 1997 precipitation in the region was below the 30-year normal. The 1997-1998 observation year had rainfall above the 30-year normal. Ground-water levels in the observation wells mirrored these rainfall patterns, showing a general downward trend during the dry years and a recovery in the wet 1997-1998 year. Seasonal increases in the ground-water levels were observed at most wells during the late spring and early summer, followed by decreases in August-November ground water levels. Analysis indicates that the ground-water levels are affected by both the precipitation in the Imperial Valley area and the Illinois River stages. The observation wells closest to the Illinois River show an increase in water levels whenever the river stage is high. Generally, the water levels in the wells correlate best with precipitation and Illinois River stages one to two months before the water levels are measured, i.e., the June ground-water levels are most highly correlated with the Illinois River stage or precipitation that occurs in either April or May. The analyses conducted indicate the need for continued operation of both networks due to inconsistencies associated with ground-water levels, precipitation, and the Illinois River stage. For instance, the Mason-Tazwell observation well number 2 (MTOW-2) is located near the center of Mason County well away from the Illinois River, but it has an equal correlation with the Illinois River stage and the precipitation in the area. Additional analysis needs to be undertaken to explain this unusual finding

Influence of Type of Cigarette on Peripheral versus Central Lung Cancer

Objectives: Adenocarcinoma has replaced squamous cell carcinoma as the most common cell type of lung cancer in the United States. It has been proposed that this shift is due to the increased use of filter and lower-tar cigarettes, resulting in increased delivery of smoke to peripheral regions of the lungs, where adenocarcinoma usually occurs. We reviewed radiologic data to evaluate the hypothesis that tumors in smokers of cigarettes with lower-tar yield are more likely to occur peripherally than tumors in smokers of higher-yield cigarettes. Methods: At two urban academic medical centers, we reviewed computed tomographic scans, chest radiographs, and medical records to assign tumor location (peripheral or central) for 330 smokers diagnosed with carcinoma of the lung between 1993 and 1999. We compared the proportion of tumors in a peripheral versus central location by lifetime filter use and average lifetime tar rating (<21 and ≥21 mg). Results: Tumor location (69% peripheral and 31% central) was unrelated to cigarette filter use. Smokers of cigarettes with lower-tar ratings were more likely than those with higher ratings to have peripheral rather than central tumors (odds ratio, 1.76; 95% confidence interval, 0.89-3.47). When restricted to subjects with adenocarcinoma or squamous cell carcinoma, the odds ratio (95% confidence interval) was 2.31 (1.05-5.08). Conclusions: Among cigarette smokers with lung cancer, use of cigarettes with lower-tar yield was associated with preferential occurrence of tumors in peripheral sites. Our findings support the hypothesis that changes in smoking associated with lower-tar cigarettes have led to a shift in the location of smoking-related lung cancer

Temporal Experiment for Storms and Tropical Systems Technology Demonstration (TEMPEST-D) Mission: Enabling Time-Resolved Cloud and Precipitation Observations from 6U-Class Satellite Constellations

The Temporal Experiment for Storms and Tropical Systems Technology Demonstration (TEMPEST-D) mission is to demonstrate the capability of 6U-Class satellite constellations to perform repeat-pass radiometry to measure clouds and precipitation with high temporal resolution on a global basis. The TEMPEST mission concept is to improve understanding of clouds and precipitation by providing critical information on their time evolution in different climatic regimes. Measuring at five frequencies from 89 to 182 GHz, TEMPEST-D millimeter-wave radiometers are capable of penetrating into the cloud to observe changes as precipitation begins or ice accumulates inside the storm. The TEMPEST-D flight model radiometer instrument has been completed, passed functional testing, vibration testing and self-compatibility testing with the XB1 spacecraft bus. The next steps for the TEMPEST-D millimeter-wave radiometer are thermal vacuum testing and antenna pattern measurements. The complete TEMPEST-D flight system will be delivered to NanoRacks for launch integration in the autumn of 2017, in preparation for launch to the ISS in the second quarter of 2018, with deployment shortly thereafter into a nominal orbit at 400-km altitude and 51.6° inclination

Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins

AbstractTransgenic FVB/N mice overexpressing human (Hu) or mouse (Mo) Alzheimer amyloid precursor protein (APP695) die early and develop a CNS disorder that includes neophobia and impaired spatial alternation, with diminished glucose utilization and astrogliosis mainly in the cerebrum. Age at onset of neophobia and age at death decrease with increasing levels of brain APP. HuAPP transgenes induce death much earlier than MoAPP transgenes expressed at similar levels. No extracellular amyloid was detected, indicating that some deleterious processes related to APP overexpression are dissociated from formation of amyloid. A similar clinical syndrome occurs spontaneously in ∼20% of nontransgenic mice when they reach mid-to late-adult life, suggesting that APP overexpression may accelerate a naturally occuring age-related CNS disorder in FVB/N mice

Atmospheric fates of Criegee intermediates in the ozonolysis of isoprene

We use a large laboratory, modeling, and field dataset to investigate the isoprene + O_3 reaction, with the goal of better understanding the fates of the C_1 and C_4 Criegee intermediates in the atmosphere. Although ozonolysis can produce several distinct Criegee intermediates, the C_1 stabilized Criegee (CH_2OO, 61 ± 9%) is the only one observed to react bimolecularly. We suggest that the C_4 Criegees have a low stabilization fraction and propose pathways for their decomposition. Both prompt and non-prompt reactions are important in the production of OH (28% ± 5%) and formaldehyde (81% ± 16%). The yields of unimolecular products (OH, formaldehyde, methacrolein (42 ± 6%) and methyl vinyl ketone (18 ± 6%)) are fairly insensitive to water, i.e., changes in yields in response to water vapor (≤4% absolute) are within the error of the analysis. We propose a comprehensive reaction mechanism that can be incorporated into atmospheric models, which reproduces laboratory data over a wide range of relative humidities. The mechanism proposes that CH_2OO + H_2O (k_((H_2O)) ∼ 1 × 10^(−15) cm^3 molec^(−1) s^(−1)) yields 73% hydroxymethyl hydroperoxide (HMHP), 6% formaldehyde + H_2O_2, and 21% formic acid + H_2O; and CH_2OO + (H_2O)_2 (k_((H_2O)_2) ∼ 1 × 10^(−12) cm^3 molec^(−1) s^(−1)) yields 40% HMHP, 6% formaldehyde + H_2O_2, and 54% formic acid + H_2O. Competitive rate determinations (k_(SO_2/k(H_2O)n=1,2) ∼ 2.2 (±0.3) × 10^4) and field observations suggest that water vapor is a sink for greater than 98% of CH2OO in a Southeastern US forest, even during pollution episodes ([SO_2] ∼ 10 ppb). The importance of the CH_2OO + (H_2O)n reaction is demonstrated by high HMHP mixing ratios observed over the forest canopy. We find that CH_2OO does not substantially affect the lifetime of SO_2 or HCOOH in the Southeast US, e.g., CH_2OO + SO_2 reaction is a minor contribution (<6%) to sulfate formation. Extrapolating, these results imply that sulfate production by stabilized Criegees is likely unimportant in regions dominated by the reactivity of ozone with isoprene. In contrast, hydroperoxide, organic acid, and formaldehyde formation from isoprene ozonolysis in those areas may be significant

The 1980-1981 drought in Illinois causes, dimensions, and impact

Hydrologic, meteorological, and climatological aspects of the 1980-1981 drought in Illinois are addressed. The drought is evaluated in terms of precipitation, streamflow, lakes and reservoirs, and groundwater resources of the state. The meteorological conditions that produced the drought also are addressed. Impacts and problems resulting from the drought are discussed along with various actions taken to ameliorate the problems. Although the primary goal of the study was to quantify the drought, primarily in a physical sense, an important secondary goal was to assess the impacts and the actions employed, to derive information needed in future planning and handling of Illinois droughts. The report thus ends with a set of recommendations for coping with future droughts. The 1980-1981 drought was not one of the extreme droughts of record; however, it is important in that it was the most severe drought since those of the early 1950’s. As such, it reflects some new types of impacts on the state’s water resources due to technological, hydrological, and institutional changes since the 1950’s.publishedpeer reviewedOpe

Microwave Spectroscopy of Thermally Excited Quasiparticles in YBa_2Cu_3O_{6.99}

We present here the microwave surface impedance of a high purity crystal of $YBa_2Cu_3O_{6.99}$ measured at 5 frequencies between 1 and 75 GHz. This data set reveals the main features of the conductivity spectrum of the thermally excited quasiparticles in the superconducting state. Below 20 K there is a regime of extremely long quasiparticle lifetimes, due to both the collapse of inelastic scattering below $T_c$ and the very weak impurity scattering in the high purity $BaZrO_3$-grown crystal used in this study. Above 20 K, the scattering increases dramatically, initially at least as fast as $T^4$.Comment: 13 pages with 10 figures. submitted to Phys Rev

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.We thank the two anonymous reviewers for their constructive comments. This research was supported by the National Institutes of Health (NIH) grant R01CA169122; P.W. was supported by NIH grants R01HL116720 and R21HL126032. S.H.O. was supported by NIH grant P30CA008748. R.E.N. and the Queensland Pancreatic Cancer Study were funded by the Australian National Health and Medical Research Council. The authors thank Ms. Jessica Swann and the National Institute of Statistical Sciences writing workshop for editorial assistance and suggestions. The authors acknowledge the Texas Advanced Computing Center at The University of Texas at Austin for providing computing resources. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. The authors declare that there is no conflict of interest

The lifetime of nitrogen oxides in an isoprene-dominated forest

The lifetime of nitrogen oxides (NO_x) affects the concentration and distribution of NO_x and the spatial patterns of nitrogen deposition. Despite its importance, the lifetime of NO_x is poorly constrained in rural and remote continental regions. We use measurements from a site in central Alabama during the Southern Oxidant and Aerosol Study (SOAS) in summer 2013 to provide new insights into the chemistry of NO_x and NO_x reservoirs. We find that the lifetime of NO_x during the daytime is controlled primarily by the production and loss of alkyl and multifunctional nitrates (ΣANs). During SOAS, ΣAN production was rapid, averaging 90 ppt h^(−1) during the day, and occurred predominantly during isoprene oxidation. Analysis of the ΣAN and HNO_3 budgets indicate that ΣANs have an average lifetime of under 2 h, and that approximately 45 % of the ΣANs produced at this site are rapidly hydrolyzed to produce nitric acid. We find that ΣAN hydrolysis is the largest source of HNO_3 and the primary pathway to permanent removal of NO_x from the boundary layer in this location. Using these new constraints on the fate of ΣANs, we find that the NO_x lifetime is 11 ± 5 h under typical midday conditions. The lifetime is extended by storage of NO_x in temporary reservoirs, including acyl peroxy nitrates and ΣANs