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1.
Sci Data ; 11(1): 827, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39068191

ABSTRACT

Anthropogenic and climatic changes affect the water and energy cycles in High Mountain Asia (HMA), home to over two billion people and the largest reservoirs of freshwater outside the polar zone. Despite their significant importance for water management, consistent and reliable estimates of water storage and fluxes over the region are lacking because of the high uncertainties associated with the estimates of atmospheric conditions and human management. Here, we relied on multivariate data assimilation (MVDA) to provide estimates of energy and water storage and fluxes that reflect the processes occurring in the region such as greening and irrigation-driven groundwater depletion. We developed and employed an ensemble precipitation estimate by blending different precipitation products thereby reducing the uncertainties and inconsistencies associated with precipitation in HMA. Then, we assimilated five variables that capture the changes in hydrology in response to climate change and anthropogenic activities. Overall, our results have shown that MVDA has allowed a better representation of the land surface processes including greening and irrigation-driven groundwater depletion in HMA.

2.
Nat Ecol Evol ; 8(2): 229-238, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38168941

ABSTRACT

A steady rise in fires in the Western United States, coincident with intensifying droughts, imparts substantial modifications to the underlying vegetation, hydrology and overall ecosystem. Drought can compound the ecosystem disturbance caused by fire, although how these compound effects on hydrologic and ecosystem recovery vary among ecosystems is poorly understood. Here we use remote sensing-derived high-resolution evapotranspiration (ET) estimates from before and after 1,514 fires to show that ecoregions dominated by grasslands and shrublands are more susceptible to drought, which amplifies fire-induced ET decline and, subsequently, shifts water flux partitioning. In contrast, severely burned forests recover from fire slowly or incompletely, but are less sensitive to dry extremes. We conclude that moisture limitation caused by droughts influences the dynamics of water balance recovery in post-fire years. This finding explains why moderate to extreme droughts aggravate impacts on the water balance in non-forested vegetation, while moisture accessed by deeper roots in forests helps meet evaporative demands unless severe burns disrupt internal tree structure and deplete fuel load availability. Our results highlight the dominant control of drought on altering the resilience of vegetation to fires, with critical implications for terrestrial ecosystem stability in the face of anthropogenic climate change in the West.


Subject(s)
Ecosystem , Fires , United States , Droughts , Forests , Water
3.
J Sch Psychol ; 98: 1-15, 2023 06.
Article in English | MEDLINE | ID: mdl-37253574

ABSTRACT

Doctoral training programs educate future practitioners, scholars, and researchers. They therefore are an important site of inquiry for critical school psychologists interested in interrogating and confronting the inequities that exist within the field. We conducted four focus groups with 15 Black, Indigenous, and Women of Color (BIWOC) students in various APA-accredited school psychology Ph.D. programs to understand how they experienced their programs. We argue that the programs delivered a hidden curriculum to the participants through various socializing, vicarious, and disciplinary events, in addition to the official curriculum delivered to all students. Data analysis indicated that the hidden curriculum was delivered in four settings and consisted of six lessons, including (a) you do not belong here, (b) you cannot be trusted, (c) you are on your own, (d) you are not safe here, (e) you are a token, and (f) you will only get performative allyship from us. We discuss each of these lessons and contemplate on ways in which programs and faculty can combat their deleterious impact on the students.


Subject(s)
Psychology, Educational , Skin Pigmentation , Female , Humans , Curriculum , Faculty , Schools , Psychology/education
4.
Sch Psychol ; 38(5): 330-336, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37141042

ABSTRACT

To understand the evolution and current status of qualitative research in School Psychology, we reviewed 4,346 articles published across seven school psychology journals between 2006 and 2021. The bibliometric analysis indicates that publication of qualitative research has increased over the years, but remains small (3%) when seen against the total volume of journal publications. Less than 5% of articles in all but one journal were qualitative. The most commonly explored topic was diversity, equity, and social justice accounting for 23% of the qualitative articles. In total, 55% of the studies were conducted in the United States. Although many studies did not specify participants' race and gender, the most commonly reported research participants were K-12 students, female, White, and from the United States. We discuss these findings and provide recommendations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Periodicals as Topic , Humans , Female , United States , Psychology, Educational , Bibliometrics , Qualitative Research , Schools
5.
Sch Psychol ; 38(5): 308-318, 2023 Sep.
Article in English | MEDLINE | ID: mdl-36892897

ABSTRACT

There are growing calls to diversify the ranks of school psychology practitioners, graduate educators, and researchers by recruiting more students of color in school psychology doctoral programs. Past research on retention across many fields in higher education indicates that Black, Indigenous, and women of color (BIWOC) students entering doctoral programs encounter isolation, lack of support, and microaggressions. Although this literature has illuminated how doctoral programs can push out BIWOC students, it has been critiqued for overlooking the creative and strategic means they use to stay in their programs. We analyzed 12 focus group interviews conducted with 15 BIWOC students in school psychology doctoral programs across the United States. Using the analytical construct of agency, we coded the transcripts to identify agentic actions of BIWOC that went beyond standard graduate school demands. We identified six types of actions that BIWOC carried out to combat the systemic barriers they encountered: teaching, protecting others, self-advocating, organizing, searching for community, and self-editing. Given that these actions were in addition to the basic program requirements, we argue that they are instances of the invisible work that BIWOC students did to persist in their doctoral programs. We discuss the implications of this invisible work and provide various recommendations for school psychology doctoral programs to reduce the burden of invisible work on BIWOC students. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Psychology, Educational , Students , Humans , Female , United States , Focus Groups , Schools
6.
Sci Rep ; 13(1): 3411, 2023 Feb 28.
Article in English | MEDLINE | ID: mdl-36854885

ABSTRACT

Hydrologic extremes often involve a complex interplay of several processes. For example, flood events can have a cascade of impacts, such as saturated soils and suppressed vegetation growth. Accurate representation of such interconnected processes while accounting for associated triggering factors and subsequent impacts of flood events is difficult to achieve with conceptual hydrological models alone. In this study, we use the 2019 flood in the Northern Mississippi and Missouri Basins, which caused a series of hydrologic disturbances, as an example of such a flood event. This event began with above-average precipitation combined with anomalously high snowmelt in spring 2019. This series of anomalies resulted in above normal soil moisture that prevented crops from being planted over much of the corn belt region. In the present study, we demonstrate that incorporating remote sensing information within a hydrologic modeling system adds substantial value in representing the processes that lead to the 2019 flood event and the resulting agricultural disturbances. This remote sensing data infusion improves the accuracy of soil moisture and snowmelt estimates by up to 16% and 24%, respectively, and it also improves the representation of vegetation anomalies relative to the reference crop fraction anomalies.

7.
Proc Natl Acad Sci U S A ; 120(4): e2212338120, 2023 01 24.
Article in English | MEDLINE | ID: mdl-36649421

ABSTRACT

To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K+) channel SLO3 [C. M. Santi et al., FEBS Lett. 584, 1041-1046 (2010)]. In human sperm, it has long been unclear whether hyperpolarization depends on SLO3 or the ubiquitous K+ channel SLO1 [N. Mannowetz, N. M. Naidoo, S. A. S. Choo, J. F. Smith, P. V. Lishko, Elife 2, e01009 (2013), C. Brenker et al., Elife 3, e01438 (2014), and S. A. Mansell, S. J. Publicover, C. L. R. Barratt, S. M. Wilson, Mol. Hum. Reprod. 20, 392-408 (2014)]. In this work, we identified the first selective inhibitor for human SLO3-VU0546110-and showed that it completely blocked heterologous SLO3 currents and endogenous K+ currents in human sperm. This compound also prevented sperm from hyperpolarizing and undergoing hyperactivated motility and induced acrosome reaction, which are necessary to fertilize an egg. We conclude that SLO3 is the sole K+ channel responsible for hyperpolarization and significantly contributes to the fertilizing ability of human sperm. Moreover, SLO3 is a good candidate for contraceptive development, and mutation of this gene is a possible cause of idiopathic male infertility.


Subject(s)
Infertility, Male , Large-Conductance Calcium-Activated Potassium Channels , Humans , Male , Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Membrane Potentials/physiology , Semen , Spermatozoa/physiology
8.
J Adv Model Earth Syst ; 14(11): e2022MS003040, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36582299

ABSTRACT

Representation of irrigation in Earth System Models has advanced over the past decade, yet large uncertainties persist in the effective simulation of irrigation practices, particularly over locations where the on-ground practices and climate impacts are less reliably known. Here we investigate the utility of assimilating remotely sensed vegetation data for improving irrigation water use and associated fluxes within a land surface model. We show that assimilating optical sensor-based leaf area index estimates significantly improves the simulation of irrigation water use when compared to the USGS ground reports. For heavily irrigated areas, assimilation improves the evaporative fluxes and gross primary production (GPP) simulations, with the median correlation increasing by 0.1-1.1 and 0.3-0.6, respectively, as compared to the reference datasets. Further, bias improvements in the range of 14-35 mm mo-1 and 10-82 g m-2 mo-1 are obtained in evaporative fluxes and GPP as a result of incorporating vegetation constraints, respectively. These results demonstrate that the use of remotely sensed vegetation data is an effective, observation-informed, globally applicable approach for simulating irrigation and characterizing its impacts on water and carbon states.

9.
Sci Rep ; 12(1): 16163, 2022 09 28.
Article in English | MEDLINE | ID: mdl-36171251

ABSTRACT

Human and climate induced land surface changes resulting from irrigation, snow cover decreases, and greening impact the surface albedo over High Mountain Asia (HMA). Here we use a partial information decomposition approach and remote sensing data to quantify the effects of the changes in leaf area index, soil moisture, and snow cover on the surface albedo in HMA, home to over a billion people, from 2003 to 2020. The study establishes strong evidence of anthropogenic agricultural water use over irrigated lands (e.g., Ganges-Brahmaputra) which causes the highest surface albedo decreases (≤ 1%/year). Greening and decreased snow cover from warming also drive changes in visible and near-infrared surface albedo in different areas of HMA. The significant role of irrigation and greening in influencing albedo suggests the potential of a positive feedback cycle where albedo decreases lead to increased evaporative demand and increased stress on water resources.


Subject(s)
Climate Change , Snow , Asia , Humans , Soil , Water
10.
Mol Pharmacol ; 101(5): 357-370, 2022 05.
Article in English | MEDLINE | ID: mdl-35246480

ABSTRACT

Heteromeric Kir4.1/Kir5.1 (KCNJ10/KCNJ16) inward rectifier potassium (Kir) channels play key roles in the brain and kidney, but pharmacological tools for probing their physiology and therapeutic potential have not been developed. Here, we report the discovery, in a high-throughput screening of 80,475 compounds, of the moderately potent and selective inhibitor VU0493690, which we selected for characterization and chemical optimization. VU0493690 concentration-dependently inhibits Kir4.1/5.1 with an IC50 of 0.96 µM and exhibits at least 10-fold selectivity over Kir4.1 and ten other Kir channels. Multidimensional chemical optimization of VU0493690 led to the development of VU6036720, the most potent (IC50 = 0.24 µM) and selective (>40-fold over Kir4.1) Kir4.1/5.1 inhibitor reported to date. Cell-attached patch single-channel recordings revealed that VU6036720 inhibits Kir4.1/5.1 activity through a reduction of channel open-state probability and single-channel current amplitude. Elevating extracellular potassium ion by 20 mM shifted the IC50 6.8-fold, suggesting that VU6036720 is a pore blocker that binds in the ion-conduction pathway. Mutation of the "rectification controller" asparagine 161 to glutamate (N161E), which is equivalent to small-molecule binding sites in other Kir channels, led to a strong reduction of inhibition by VU6036720. Renal clearance studies in mice failed to show a diuretic response that would be consistent with inhibition of Kir4.1/5.1 in the renal tubule. Drug metabolism and pharmacokinetics profiling revealed that high VU6036720 clearance and plasma protein binding may prevent target engagement in vivo. In conclusion, VU6036720 represents the current state-of-the-art Kir4.1/5.1 inhibitor that should be useful for probing the functions of Kir4.1/5.1 in vitro and ex vivo. SIGNIFICANCE STATEMENT: Heteromeric inward rectifier potassium (Kir) channels comprising Kir4.1 and Kir5.1 subunits play important roles in renal and neural physiology and may represent inhibitory drug targets for hypertension and edema. Herein, we employ high-throughput compound library screening, patch clamp electrophysiology, and medicinal chemistry to develop and characterize the first potent and specific in vitro inhibitor of Kir4.1/5.1, VU6036720, which provides proof-of-concept that drug-like inhibitors of this channel may be developed.


Subject(s)
Potassium Channels, Inwardly Rectifying , Animals , Gene Library , High-Throughput Screening Assays , Mice , Potassium/metabolism , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism
11.
ChemMedChem ; 16(2): 319-327, 2021 01 19.
Article in English | MEDLINE | ID: mdl-32926544

ABSTRACT

Zika virus (ZIKV), dengue fever (DENV) and chikungunya (CHIKV) are arboviruses that are spread to humans from the bite of an infected adult female Aedes aegypti mosquito. As there are no effective vaccines or therapeutics for these diseases, the primary strategy for controlling the spread of these viruses is to prevent the mosquito from biting humans through the use of insecticides. Unfortunately, the commonly used classes of insecticides have seen a significant increase in resistance, thus complicating control efforts. Inhibiting the renal inward rectifier potassium (Kir) channel of the mosquito vector Aedes aegypti has been shown to be a promising target for the development of novel mosquitocides. We have shown that Kir1 channels play key roles in mosquito diuresis, hemolymph potassium homeostasis, flight, and reproduction. Previous work from our laboratories identified a novel (phenylsulfonyl)piperazine scaffold as potent AeKir channel inhibitors with activity against both adult and larval mosquitoes. Herein, we report further SAR work around this scaffold and have identified additional compounds with improved in vitro potency and mosquito larvae toxicity.


Subject(s)
Aedes/drug effects , Culicidae/drug effects , Piperazine/pharmacology , Animals , Larva/drug effects , Piperazine/chemistry , Structure-Activity Relationship
12.
Remote Sens (Basel) ; 12(13): 2148, 2020 Jul 04.
Article in English | MEDLINE | ID: mdl-33425378

ABSTRACT

Traditional watershed modeling often overlooks the role of vegetation dynamics. There is also little quantitative evidence to suggest that increased physical realism of vegetation dynamics in process-based models improves hydrology and water quality predictions simultaneously. In this study, we applied a modified Soil and Water Assessment Tool (SWAT) to quantify the extent of improvements that the assimilation of remotely sensed Leaf Area Index (LAI) would convey to streamflow, soil moisture, and nitrate load simulations across a 16,860 km2 agricultural watershed in the midwestern United States. We modified the SWAT source code to automatically override the model's built-in semiempirical LAI with spatially distributed and temporally continuous estimates from Moderate Resolution Imaging Spectroradiometer (MODIS). Compared to a "basic" traditional model with limited spatial information, our LAI assimilation model (i) significantly improved daily streamflow simulations during medium-to-low flow conditions, (ii) provided realistic spatial distributions of growing season soil moisture, and (iii) substantially reproduced the long-term observed variability of daily nitrate loads. Further analysis revealed that the overestimation or underestimation of LAI imparted a proportional cascading effect on how the model partitions hydrologic fluxes and nutrient pools. As such, assimilation of MODIS LAI data corrected the model's LAI overestimation tendency, which led to a proportionally increased rootzone soil moisture and decreased plant nitrogen uptake. With these new findings, our study fills the existing knowledge gap regarding vegetation dynamics in watershed modeling and confirms that assimilation of MODIS LAI data in watershed models can effectively improve both hydrology and water quality predictions.

13.
Article in English | MEDLINE | ID: mdl-31807496

ABSTRACT

Changes in terrestrial water storage (TWS) in High Mountain Asia (HMA) could have major societal impacts, as the region's large reservoirs of glaciers, snow, and groundwater provide a freshwater source to more than one billion people. We seek to quantify and close the budget of secular changes in TWS over the span of the GRACE satellite mission (2003-2016). To assess the TWS trend budget we consider a new high-resolution mass trend product determined directly from GRACE L1B data, glacier mass balance derived from Digital Elevation Models (DEMs), groundwater variability determined from confined and unconfined well observations, and terrestrial water budget estimates from a suite of land surface model simulations with the NASA Land Information System (LIS). This effort is successful at closing the aggregated TWS trend budget over the entire HMA region, the glaciated portion of HMA, and the Indus and Ganges basins, where the full-region trends are primarily due to the glacier mass balance and groundwater signals. Additionally, we investigate the closure of TWS trends at individual 1-arc-degree mascons (area ≈12,000 km2); a significant improvement in spatial resolution over previous analyses of GRACE-derived trends. This mascon-level analysis reveals locations where the TWS trends are well-explained by the independent datasets, as well as regions where they are not; identifying specific geographic areas where additional data and model improvements are needed. The accurate characterization of total TWS trends and its components presented here is critical to understanding the complex dynamics of the region, and is a necessary step toward projecting future water mass changes in HMA.

14.
Physiol Rep ; 7(23): e14303, 2019 12.
Article in English | MEDLINE | ID: mdl-31814333

ABSTRACT

There has been a resurgence of interest in the volume-regulated anion channel (VRAC) since the recent cloning of the LRRC8A-E gene family that encodes VRAC. The channel is a heteromer comprised of LRRC8A and at least one other family member; disruption of LRRC8A expression abolishes VRAC activity. The best-in-class VRAC inhibitor, DCPIB, suffers from off-target activity toward several different channels and transporters. Considering that some anion channel inhibitors also suppress mitochondrial respiration, we systematically explored whether DCPIB inhibits respiration in wild type (WT) and LRRC8A-knockout HAP-1 and HEK-293 cells. Knockout of LRRC8A had no apparent effects on cell morphology, proliferation rate, mitochondrial content, or expression of several mitochondrial genes in HAP-1 cells. Addition of 10 µM DCPIB, a concentration typically used to inhibit VRAC, suppressed basal and ATP-linked respiration in part through uncoupling the inner mitochondrial membrane (IMM) proton gradient and membrane potential. Additionally, DCPIB inhibits the activity of complex I, II, and III of the electron transport chain (ETC). Surprisingly, the effects of DCPIB on mitochondrial function are also observed in HAP-1 and HEK-293 cells which lack LRRC8A expression. Finally, we demonstrate that DCPIB activates ATP-inhibitable potassium channels comprised of heterologously expressed Kir6.2 and SUR1 subunits. These data indicate that DCPIB suppresses mitochondrial respiration and ATP production by dissipating the mitochondrial membrane potential and inhibiting complexes I-III of the ETC. They further justify the need for the development of sharper pharmacological tools for evaluating the integrative physiology and therapeutic potential of VRAC in human diseases.


Subject(s)
Cyclopentanes/pharmacology , Indans/pharmacology , Membrane Proteins/antagonists & inhibitors , Mitochondria/drug effects , Adenosine Triphosphate/metabolism , Cell Line, Tumor , Cell Respiration/drug effects , Electron Transport Chain Complex Proteins/metabolism , HEK293 Cells , Humans , KATP Channels/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mitochondria/metabolism
15.
J Pharmacol Exp Ther ; 370(3): 350-359, 2019 09.
Article in English | MEDLINE | ID: mdl-31201216

ABSTRACT

Glucose-stimulated insulin secretion from pancreatic ß-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of ß-cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.


Subject(s)
Ion Channel Gating/drug effects , Potassium Channels, Inwardly Rectifying/metabolism , Sulfonylurea Receptors/metabolism , Xanthines/pharmacology , Xanthines/pharmacokinetics , Animals , Ductus Arteriosus/drug effects , Ductus Arteriosus/physiology , Glucose/pharmacology , HEK293 Cells , Humans , Insulin Secretion/drug effects , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Mice , Structure-Activity Relationship , Vasodilation/drug effects , Xanthines/chemistry
16.
ACS Infect Dis ; 5(6): 917-931, 2019 06 14.
Article in English | MEDLINE | ID: mdl-30832472

ABSTRACT

Mosquito-borne arboviral diseases such as Zika, dengue fever, and chikungunya are transmitted to humans by infected adult female Aedes aegypti mosquitoes and affect a large portion of the world's population. The Kir1 channel in Ae. aegypti ( AeKir1) is an important ion channel in the functioning of mosquito Malpighian (renal) tubules and one that can be manipulated in order to disrupt excretory functions in mosquitoes. We have previously reported the discovery of various scaffolds that are active against the AeKir1 channel. Herein we report the synthesis and biological characterization of a new 2-nitro-5-(4-(phenylsulfonyl) piperazin-1-yl)- N-(pyridin-4-ylmethyl)anilines scaffold as inhibitors of AeKir1. This new scaffold is more potent in vitro compared to the previously reported scaffolds, and the molecules kill mosquito larvae.


Subject(s)
Aedes/drug effects , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Insect Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Piperazines/pharmacology , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Animals , Female , High-Throughput Screening Assays , Larva/drug effects , Sulfonamides/chemistry
17.
ACS Chem Neurosci ; 10(1): 358-370, 2019 01 16.
Article in English | MEDLINE | ID: mdl-30136838

ABSTRACT

G protein-gated, inwardly rectifying, potassium (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are heterotetrameric and homotetrameric combinations of the Kir3.1-4 (GIRK1-4) subunits. Different subunit combinations are expressed throughout the central nervous system (CNS) and the periphery, and most of these combinations contain a GIRK1 subunit. For example, the predominance of GIRK channels in the CNS are composed of GIRK1 and GIRK2 subunits, while the GIRK channels in cardiac atrial myocytes are made up mostly of GIRK1 and GIRK4 subunits. Although the vast majority of GIRK channels contain a GIRK1 subunit, discrete populations of cells that express non-GIRK1-containing GIRK (non-GIRK1/X) channels do exist. For instance, dopaminergic neurons in the ventral tegmental area of the brain, associated with addiction and reward, do not express the GIRK1 subunit. Targeting these non-GIRK1/X channels with subunit-selective pharmacological probes could lead to important insights into how GIRK channels are involved in reward and addiction. Such insights may, in turn, reveal therapeutic opportunities for the treatment or prevention of addiction. Previously, our laboratory discovered small molecules that can specifically modulate the activity of GIRK1-containing GIRK channels. However, efforts to generate compounds active on non-GIRK1/X channels from these scaffolds have been unsuccessful. Recently, ivermectin was shown to modulate non-GIRK1/X channels, and historically, ivermectin is known to modulate a wide variety of neuronal channels and receptors. Further, ivermectin is a complex natural product, which makes it a challenging starting point for development of more selective, effective, and potent compounds. Thus, while ivermectin provides proof-of-concept as a non-GIRK1/X channel activator, it is of limited utility. Therefore, we sought to discover a synthetic small molecule that would serve as a starting point for the development of non-GIRK1/X channel modulators. To accomplish this, we used a high-throughput thallium flux assay to screen a 100 000-compound library in search of activators of homomeric GIRK2 channels. Using this approach, we discovered VU0529331, the first synthetic small molecule reported to activate non-GIRK1/X channels, to our knowledge. This discovery represents the first step toward developing potent and selective non-GIRK1/X channel probes. Such molecules will help elucidate the role of GIRK channels in addiction, potentially establishing a foundation for future development of therapies utilizing targeted GIRK channel modulation.


Subject(s)
Drug Discovery/methods , G Protein-Coupled Inwardly-Rectifying Potassium Channels/agonists , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , Ion Channel Gating/drug effects , Pyrazines/chemistry , Pyrazines/pharmacology , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Ion Channel Gating/physiology , Neurons/drug effects , Neurons/metabolism
18.
Article in English | MEDLINE | ID: mdl-33479598

ABSTRACT

This study explores the uncertainties in terrestrial water budget estimation over High Mountain Asia (HMA) using a suite of uncoupled land surface model (LSM) simulations. The uncertainty in the water balance components of precipitation (P), evapotranspiration (ET), runoff(R), and terrestrial water storage (TWS) is significantly impacted by the uncertainty in the driving meteorology, with precipitation being the most important boundary condition. Ten gridded precipitation datasets along with a mix of model-, satellite-, and gauge-based products, are evaluated first to assess their suitability for LSM simulations over HMA. The datasets are evaluated by quantifying the systematic and random errors of these products as well as the temporal consistency of their trends. Though the broader spatial patterns of precipitation are generally well captured by the datasets, they differ significantly in their means and trends. In general, precipitation datasets that incorporate information from gauges are found to have higher accuracy with low Root Mean Square Errors and high correlation coefficient values. An ensemble of LSM simulations with selected subset of precipitation products is then used to produce the mean annual fluxes and their uncertainty over HMA in P, ET, and R to be 2.11±0.45, 1.26±0.11, and 0.85±0.36 mm per day, respectively. The mean annual estimates of the surface mass (water) balance components from this model ensemble are comparable to global estimates from prior studies. However, the uncertainty/spread of P, ET, and R is significantly larger than the corresponding estimates from global studies. A comparison of ET, snow cover fraction, and changes in TWS estimates against remote sensing-based references confirms the significant role of the input meteorology in influencing the water budget characterization over HMA and points to the need for improving meteorological inputs.

19.
Article in English | MEDLINE | ID: mdl-33869235

ABSTRACT

Toward qualifying hydrologic changes in the High Mountain Asia (HMA) region, this study explores the use of a hyper-resolution (1 km) land data assimilation (DA) framework developed within the NASA Land Information System using the Noah Multi-parameterization Land Surface Model (Noah-MP) forced by the meteorological boundary conditions from Modern-Era Retrospective analysis for Research and Applications, Version 2 data. Two different sets of DA experiments are conducted: (1) the assimilation of a satellite-derived snow cover map (MOD10A1) and (2) the assimilation of the NASA MEaSUREs landscape freeze/thaw product from 2007 to 2008. The performance of the snow cover assimilation is evaluated via comparisons with available remote sensing-based snow water equivalent product and ground-based snow depth measurements. For example, in the comparison against ground-based snow depth measurements, the majority of the stations (13 of 14) show slightly improved goodness-of-fit statistics as a result of the snow DA, but only four are statistically significant. In addition, comparisons to the satellite-based land surface temperature products (MOD11A1 and MYD11A1) show that freeze/thaw DA yields improvements (at certain grid cells) of up to 0.58 K in the root-mean-square error (RMSE) and 0.77 K in the absolute bias (relative to model-only simulations). In the comparison against three ground-based soil temperature measurements along the Himalayas, the bias and the RMSE in the 0-10 cm soil temperature are reduced (on average) by 10 and 7%, respectively. The improvements in the top layer of soil estimates also propagate through the deeper soil layers, where the bias and the RMSE in the 10-40 cm soil temperature are reduced (on average) by 9 and 6%, respectively. However, no statistically significant skill differences are observed for the freeze/thaw DA system in the comparisons against ground-based surface temperature measurements at mid-to-low altitude. Therefore, the two proposed DA schemes show the potential of improving the predictability of snow mass, surface temperature, and soil temperature states across HMA, but more ground-based measurements are still required, especially at high-altitudes, in order to document a more statistically significant improvement as a result of the two DA schemes.

20.
J Hydrometeorol ; 20(8): 1595-1617, 2019 Aug.
Article in English | MEDLINE | ID: mdl-32908457

ABSTRACT

Terrestrial hydrologic trends over the conterminous United States are estimated for 1980-2015 using the National Climate Assessment Land Data Assimilation System (NCA-LDAS) reanalysis. NCA-LDAS employs the uncoupled Noah version 3.3 land surface model at 0.125°× 1258° forced with NLDAS-2 meteorology, rescaled Climate Prediction Center precipitation, and assimilated satellite-based soil moisture, snow depth, and irrigation products. Mean annual trends are reported using the nonparametric Mann-Kendall test at p < 0.1 significance. Results illustrate the interrelationship between regional gradients in forcing trends and trends in other land energy and water stores and fluxes. Mean precipitation trends range from +3 to +9 mm yr-1 in the upper Great Plains and Northeast to -1 to -9 mm yr-1 in the West and South, net radiation flux trends range from 10.05 to 10.20 W m-2 yr-1 in the East to -0.05 to -0.20 W m-2 yr-1 in the West, and U.S.-wide temperature trends average about +0.03 K yr-1. Trends in soil moisture, snow cover, latent and sensible heat fluxes, and runoff are consistent with forcings, contributing to increasing evaporative fraction trends from west to east. Evaluation of NCA-LDAS trends compared to independent data indicates mixed results. The RMSE of U.S.-wide trends in number of snow cover days improved from 3.13 to 2.89 days yr-1 while trend detection increased 11%. Trends in latent heat flux were hardly affected, with RMSE decreasing only from 0.17 to 0.16 W m-2 yr-1, while trend detection increased 2%. NCA-LDAS runoff trends degraded significantly from 2.6 to 16.1 mm yr-1 while trend detection was unaffected. Analysis also indicated that NCA-LDAS exhibits relatively more skill in low precipitation station density areas, suggesting there are limits to the effectiveness of satellite data assimilation in densely gauged regions. Overall, NCA-LDAS demonstrates capability for quantifying physically consistent, U.S. hydrologic climate trends over the satellite era.

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