Air pollution and suicide in rural and urban America: Evidence from wildfire smoke.

Air pollution poses well-established risks to physical health, but little is known about its effects on mental health. We study the relationship between wildfire smoke exposure and suicide risk in the United States in 2007 to 2019 using data on all deaths by suicide and satellite-based measures of wildfire smoke and ambient fine particulate matter (PM2.5) concentrations. We identify the causal effects of wildfire smoke pollution on suicide by relating year-over-year fluctuations in county-level monthly smoke exposure to fluctuations in suicide rates and compare the effects across local areas and demographic groups that differ considerably in their baseline suicide risk. In rural counties, an additional day of smoke increases monthly mean PM2.5 by 0.41 µg/m3 and suicide deaths by 0.11 per million residents, such that a 1-µg/m3 (13%) increase in monthly wildfire-derived fine particulate matter leads to 0.27 additional suicide deaths per million residents (a 2.0% increase). These effects are concentrated among demographic groups with both high baseline suicide risk and high exposure to outdoor air: men, working-age adults, non-Hispanic Whites, and adults with no college education. By contrast, we find no evidence that smoke pollution increases suicide risk among any urban demographic group. This study provides large-scale evidence that air pollution elevates the risk of suicide, disproportionately so among rural populations.

Distortion of the [FeNO]2 Core in Flavodiiron Nitric Oxide Reductase Models Inhibits N-N Bond Formation and Promotes Formation of Unusual Dinitrosyl Iron Complexes: Implications for Catalysis and Reactivity.

Flavodiiron nitric oxide reductases (FNORs) carry out the reduction of nitric oxide (NO) to nitrous oxide (N2O), allowing infectious pathogens to mitigate toxic levels of NO generated in the human immune response. We previously reported the model complex [Fe2(BPMP)(OPr)(NO)2](OTf)2 (1, OPr- = propionate) that contains two coplanar NO ligands and that is capable of quantitative NO reduction to N2O [White et al. J. Am. Chem. Soc. 2018, 140, 2562-2574]. Here we investigate, for the first time, how a distortion of the active site affects the ability of the diiron core to mediate N2O formation. For this purpose, we prepared several analogues of 1 that contain two monodentate ligands in place of the bridging carboxylate, [Fe2(BPMP)(X)2(NO)2]3+/1+ (2-X; X = triflate, 1-methylimidazole, or methanol). Structural data of 2-X show that without the bridging carboxylate, the diiron core expands, leading to elongated (O)N-N(O) distances (from 2.80 Å in 1 to 3.00-3.96 Å in 2-X) and distorted (O)N-Fe-Fe-N(O) dihedral angles (from coplanarity (5.9°) in 1 to 52.9-85.1° in 2-X). Whereas 1 produces quantitative amounts of N2O upon one-electron reduction, N2O production is substantially impeded in 2-X, to an initial 5-10% N2O yield. The main products after reduction are unprecedented hs-FeII/{Fe(NO)2}9/10 dinitrosyl iron complexes (DNICs). Even though mononuclear DNICs are stable and do not show N-N coupling (since it is a spin-forbidden process), the hs-FeII/{Fe(NO)2}9/10 DNICs obtained from 2-X show unexpected reactivity and produce up to quantitative N2O yields after 2 h. The implications of these results for the active site structure of FNORs are discussed.

Computational modeling reveals strategic and developmental differences in the behavioral impact of reward across adolescence.

Studies of reward effects on behavior in adolescence typically rely on performance metrics that confound myriad cognitive and non-cognitive processes, making it challenging to determine which process is impacted by reward. The present longitudinal study applied the diffusion decision model to a reward task to isolate the influence of reward on response caution from influences of processing and motor speed. Participants completed three annual assessments from early to middle adolescence (N = 387, 55% female, Mage  = 12.1 at Wave 1; Mage  = 13.1 at Wave 2, Mage  = 14.1 at Wave 3) and three annual assessments in late adolescence (Mages  = 17.8, 18.9, 19.9). At each assessment, participants completed a two-choice reaction time task under conditions of no-reward and a block in which points were awarded for speeded accuracy. Reward reduced response caution at all waves, as expected, but had a greater impact as teens moved from early to middle adolescence. Simulations to identify optimal response caution showed that teens were overly cautious in early adolescence but became too focused on speed over accuracy by middle adolescence. By late adolescence, participants adopted response styles that maximized reward. Further, response style was associated with both internalizing and externalizing symptoms in early-to-middle adolescence, providing evidence for the construct validity of a diffusion model approach in this developmental period.

Population Mortality and Laws Encouraging Influenza Vaccination for Hospital Workers.

BACKGROUND: Since 1995, 14 states have passed laws encouraging or mandating influenza vaccination for hospital workers. Although the Centers for Disease Control and Prevention recommends vaccinating health care workers to reduce disease transmission and patient risk, the effect of these laws on pneumonia and influenza mortality is unknown. OBJECTIVE: To measure the effect of state-level hospital worker influenza vaccination laws on pneumonia and influenza mortality. DESIGN: Quasi-experimental observational study. SETTING: United States. PARTICIPANTS: Population of all states from 1995 to 2017. INTERVENTION: State adoption of a law promoting influenza vaccination for hospital workers. MEASUREMENTS: Pneumonia and influenza mortality per 100 000 persons by state and by month, both population-wide and separately by age group, obtained from restricted-access National Vital Statistics System files. Linear and log-linear models were used to compare changes in mortality rates for adopting versus nonadopting states. RESULTS: Implementation of state laws requiring hospitals to offer influenza vaccination to their employees was associated with a 2.5% reduction in the monthly pneumonia and influenza mortality rate (-0.16 deaths per 100 000 persons [95% CI, -0.29 to -0.02]; P = 0.022) during the years when the vaccine was well matched to the circulating strains. The largest effects occurred among elderly persons and during peak influenza months. LIMITATION: Utilization of large-scale national data precluded analysis of more specific outcomes, such as laboratory-confirmed or hospital-acquired influenza. CONCLUSION: State laws promoting hospital worker vaccination against influenza may be effective in preventing pneumonia- and influenza-related deaths, particularly among elderly persons. Vaccinating hospital workers may substantially reduce the spread of influenza and protect the most vulnerable populations. PRIMARY FUNDING SOURCE: None.

A Monohydrosulfidodinitrosyldiiron Complex That Generates N2O as a Model for Flavodiiron Nitric Oxide Reductases: Reaction Mechanism and Electronic Structure.

Flavodiiron nitric oxide reductases (FNORs) protect microbes from nitrosative stress under anaerobic conditions by mediating the reduction of nitric oxide (NO) to nitrous oxide (N2O). The proposed mechanism for the catalytic reduction of NO by FNORs involves a dinitrosyldiiron intermediate with a [hs-{FeNO}7]2 formulation, which produces N2O and a diferric species. Moreover, both NO and hydrogen sulfide (H2S) have been implicated in several similar physiological functions in biology and are also known to cross paths in cell signaling. Here we report the synthesis, spectroscopic and theoretical characterization, and N2O production activity of an unprecedented monohydrosulfidodinitrosyldiiron compound, with a [(HS)hs-{FeNO}7/hs-{FeNO}7] formulation, that models the key dinitrosyl intermediate of FNORs. The generation of N2O from this unique compound follows a semireduced pathway, where one-electron reduction generates a reactive hs-{FeNO}8 center via the occupation of an Fe-NO antibonding orbital. In contrast to the well-known reactivity of H2S and NO, the coordinated hydrosulfide remains unreactive toward NO and acts only as a spectator ligand during the NO reduction process.

Metastudies for robust tests of theory.

We describe and demonstrate an empirical strategy useful for discovering and replicating empirical effects in psychological science. The method involves the design of a metastudy, in which many independent experimental variables-that may be moderators of an empirical effect-are indiscriminately randomized. Radical randomization yields rich datasets that can be used to test the robustness of an empirical claim to some of the vagaries and idiosyncrasies of experimental protocols and enhances the generalizability of these claims. The strategy is made feasible by advances in hierarchical Bayesian modeling that allow for the pooling of information across unlike experiments and designs and is proposed here as a gold standard for replication research and exploratory research. The practical feasibility of the strategy is demonstrated with a replication of a study on subliminal priming.

Functional Models for the Mono- and Dinitrosyl Intermediates of FNORs: Semireduction versus Superreduction of NO.

The reduction of NO to N2O by flavodiiron nitric oxide reductases (FNORs) is related to the disruption of the defense mechanism in mammals against invading pathogens. The proposed mechanism for this catalytic reaction involves both nonheme mono- and dinitrosyl diiron(II) species as the key intermediates. Recently, we reported an initial account for NO reduction activity of an unprecedented mononitrosyl diiron(II) complex, [Fe2(N-Et-HPTB)(NO)(DMF)3](BF4)3 (1) (N-Et-HPTB is the anion of N,N,N',N'-tetrakis(2-(l-ethylbenzimidazolyl))-2-hydroxy-1,3-diaminopropane; DMF = dimethylformamide) with [FeII{FeNO}7] formulation [Jana et al. J. Am. Chem. Soc. 2017, 139, 14380]. Here we report the full account for the selective synthesis, characterization, and reactivity of FNOR model complexes, which include a dinitrosyl diiron(II) complex, [Fe2(N-Et-HPTB)(NO)2(DMF)2](BF4)3 (2) with [{FeNO}7]2 formulation and a related, mixed-valent diiron(II, III) complex, [Fe2(N-Et-HPTB)(OH)(DMF)3](BF4)3 (3). Importantly, whereas complex 2 is able to produce 89% of N2O via a semireduced mechanism (1 equiv of CoCp2 per dimer = 50% of NO reduced), complex 1, under the same conditions (0.5 equiv of CoCp2 per dimer = 50% of NO reduced), generates only ∼50% of N2O. The mononitrosyl complex therefore requires superreduction for quantitative N2O generation, which constitutes an interesting dichotomy between 1 and 2. Reaction products obtained after N2O generation by 2 using 1 and 2 equiv of reductant were characterized by molecular structure determination and electron paramagnetic resonance spectroscopy. Despite several available literature reports on N2O generation by diiron complexes, this is the first case where the end products from these reactions could be characterized unambiguously, which clarifies a number of tantalizing observations about the nature of these products in the literature.

Individual differences in emotion processing: how similar are diffusion model parameters across tasks?

The goal of this study was to replicate findings of diffusion model parameters capturing emotion effects in a lexical decision task and investigating whether these findings extend to other tasks of implicit emotion processing. Additionally, we were interested in the stability of diffusion model parameters across emotional stimuli and tasks for individual subjects. Responses to words in a lexical decision task were compared with responses to faces in a gender categorization task for stimuli of the emotion categories: happy, neutral and fear. Main effects of emotion as well as stability of emerging response style patterns as evident in diffusion model parameters across these tasks were analyzed. Based on earlier findings, drift rates were assumed to be more similar in response to stimuli of the same emotion category compared to stimuli of a different emotion category. Results showed that emotion effects of the tasks differed with a processing advantage for happy followed by neutral and fear-related words in the lexical decision task and a processing advantage for neutral followed by happy and fearful faces in the gender categorization task. Both emotion effects were captured in estimated drift rate parameters-and in case of the lexical decision task also in the non-decision time parameters. A principal component analysis showed that contrary to our hypothesis drift rates were more similar within a specific task context than within a specific emotion category. Individual response patterns of subjects across tasks were evident in significant correlations regarding diffusion model parameters including response styles, non-decision times and information accumulation.

Non-Heme Diiron Model Complexes Can Mediate Direct NO Reduction: Mechanistic Insight into Flavodiiron NO Reductases.

Flavodiiron nitric oxide reductases (FNORs), a common enzyme family found in various types of pathogenic bacteria, are capable of reducing nitric oxide (NO) to nitrous oxide (N2O) as a protective detoxification mechanism. Utilization of FNORs in pathogenic bacteria helps them survive and proliferate in the human body, thus causing chronic infections. In this paper, we present a new diiron model complex, [Fe2((Py2PhO2)MP)(OPr)2](OTf), with bridging propionate ligands (OPr-) that is capable of directly reducing NO to N2O in quantitative yield without the need to (super)reduce the complex. We first prepared the diferric precursor and characterized it by UV-vis, IR, NMR and Mössbauer spectroscopies, cyclic voltammetry, and mass spectrometry. This complex can then conveniently be reduced to the diferrous complex using CoCp2. Even though this diferrous complex is highly reactive, we have successfully isolated and characterized this species using X-ray crystallography and various spectroscopic techniques. Most importantly, upon reacting this diferrous complex with NO gas, we observe quantitative formation of N2O via IR gas headspace analysis, the first demonstration of direct NO reduction by a non-heme diiron model complex. This finding directly supports recent mechanistic proposals for FNORs.

Non-heme High-Spin {FeNO}6-8 Complexes: One Ligand Platform Can Do It All.

Heme and non-heme iron-nitrosyl complexes are important intermediates in biology. While there are numerous examples of low-spin heme iron-nitrosyl complexes in different oxidation states, much less is known about high-spin (hs) non-heme iron-nitrosyls in oxidation states other than the formally ferrous NO adducts ({FeNO}7 in the Enemark-Feltham notation). In this study, we present a complete series of hs-{FeNO}6-8 complexes using the TMG3tren coligand. Redox transformations from the hs-{FeNO}7 complex [Fe(TMG3tren)(NO)]2+ to its {FeNO}6 and {FeNO}8 analogs do not alter the coordination environment of the iron center, allowing for detailed comparisons between these species. Here, we present new MCD, NRVS, XANES/EXAFS, and Mössbauer data, demonstrating that these redox transformations are metal based, which allows us to access hs-Fe(II)-NO-, Fe(III)-NO-, and Fe(IV)-NO- complexes. Vibrational data, analyzed by NCA, directly quantify changes in Fe-NO bonding along this series. Optical data allow for the identification of a "spectator" charge-transfer transition that, together with Mössbauer and XAS data, directly monitors the electronic changes of the Fe center. Using EXAFS, we are also able to provide structural data for all complexes. The magnetic properties of the complexes are further analyzed (from magnetic Mössbauer). The properties of our hs-{FeNO}6-8 complexes are then contrasted to corresponding, low-spin iron-nitrosyl complexes where redox transformations are generally NO centered. The hs-{FeNO}8 complex can further be protonated by weak acids, and the product of this reaction is characterized. Taken together, these results provide unprecedented insight into the properties of biologically relevant non-heme iron-nitrosyl complexes in three relevant oxidation states.

The Semireduced Mechanism for Nitric Oxide Reduction by Non-Heme Diiron Complexes: Modeling Flavodiiron Nitric Oxide Reductases.

Flavodiiron nitric oxide reductases (FNORs) are a subclass of flavodiiron proteins (FDPs) capable of preferential binding and subsequent reduction of NO to N2O. FNORs are found in certain pathogenic bacteria, equipping them with resistance to nitrosative stress, generated as a part of the immune defense in humans, and allowing them to proliferate. Here, we report the spectroscopic characterization and detailed reactivity studies of the diiron dinitrosyl model complex [Fe2(BPMP)(OPr)(NO)2](OTf)2 for the FNOR active site that is capable of reducing NO to N2O [Zheng et al., J. Am. Chem. Soc. 2013, 135, 4902-4905]. Using UV-vis spectroscopy, cyclic voltammetry, and spectro-electrochemistry, we show that one reductive equivalent is in fact sufficient for the quantitative generation of N2O, following a semireduced reaction mechanism. This reaction is very efficient and produces N2O with a first-order rate constant k > 102 s-1. Further isotope labeling studies confirm an intramolecular N-N coupling mechanism, consistent with the rapid time scale of the reduction and a very low barrier for N-N bond formation. Accordingly, the reaction proceeds at -80 °C, allowing for the direct observation of the mixed-valent product of the reaction. At higher temperatures, the initial reaction product is unstable and decays, ultimately generating the diferrous complex [Fe2(BPMP)(OPr)2](OTf) and an unidentified ferric product. These results combined offer deep insight into the mechanism of NO reduction by the relevant model complex [Fe2(BPMP)(OPr)(NO)2]2+ and provide direct evidence that the semireduced mechanism would constitute a highly efficient pathway to accomplish NO reduction to N2O in FNORs and in synthetic catalysts.

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease.

In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds αVß3-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. By contrast, periostin does not stimulate the proliferation of normal human kidney cells. This difference in the response to periostin is due to elevated expression of αVß3-integrins by cystic cells. To determine whether periostin accelerates cyst growth and fibrosis, we generated mice with conditional overexpression of periostin in the collecting ducts (CDs). Ectopic CD expression of periostin was not sufficient to induce cyst formation or fibrosis in wild-type mice. However, periostin overexpression in pcy/pcy ( pcy) kidneys significantly increased mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis; and accelerated the decline in renal function. Moreover, CD-specific overexpression of periostin caused a decrease in the survival of pcy mice. These pathological changes were accompanied by increased renal expression of vimentin, α-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD.

A Structural Model for the Iron-Nitrosyl Adduct of Gentisate Dioxygenase.

We present the synthesis, properties, and characterization of [Fe(T1Et4iPrIP)(NO)(H2O)2](OTf)2 (1) (T1Et4iPrIP = Tris(1-ethyl-4-isopropyl-imidazolyl)phosphine) as a model for the nitrosyl adduct of gentisate 1,2-dioxygenase (GDO). The further characterization of [Fe(T1Et4iPrIP)(THF)(NO)(OTf)](OTf) (2) which was previously communicated (Inorg. Chem. 2014, 53, 5414) is also presented. The weighted average Fe-N-O angle of 162° for 1 is very close to linear (≥ 165°) for these types of complexes. The coordinated water ligands participate in hydrogen bonding interactions. The spectral properties (EPR, UV-vis, FTIR) for 1 are compared with 2 and found to be quite comparable. Complex 1 closely follows the relationship between the Fe-N-O angle and NO vibrational frequency which was previously identified for 6-coordinate {FeNO}7 complexes. Liquid FTIR studies on 2 indicate that the ν(NO) vibration position is sensitive to solvent shifting to lower energy (relative to the solid) in donor solvent THF and shifting to higher energy in dichloromethane. The basis for this behavior is discussed. The K eq for NO binding in 2 was calculated in THF and found to be 470 M-1. Density functional theory (DFT) studies on 1 indicate donation of electron density to the iron center from the π* orbitals of formally NO-. Such a donation accounts for the near linearity of the Fe-N-O bond and the large ν(NO) value of 1791 cm-1.

Is brain response to food rewards related to overeating? A test of the reward surfeit model of overeating in children.

The reward surfeit model of overeating suggests that heightened brain response to rewards contributes to overeating and subsequent weight gain. However, previous studies have not tested whether brain response to reward is associated with food intake, particularly during childhood, a period of dynamic development in reward and inhibitory control neurocircuitry. We conducted functional magnetic resonance imaging (fMRI) with 7-11-year-old children (n = 59; healthy weight, n = 31; overweight, n = 28; 54% female) while they played a modified card-guessing paradigm to examine blood-oxygen-level-dependent (BOLD) response to anticipating and winning rewards (food, money, neutral). Food intake was assessed at three separate meals that measured different facets of eating behavior: 1) typical consumption (baseline), 2) overindulgence (palatable buffet), and 3) eating in the absence of hunger (EAH). A priori regions of interest included regions implicated in both reward processing and inhibitory control. Multiple stepwise regressions were conducted to examine the relationship between intake and BOLD response to rewards. Corrected results showed that a greater BOLD response in the medial prefrontal cortex for anticipating food compared to money positively correlated with how much children ate at the baseline and palatable buffet meals. BOLD response in the dorsolateral prefrontal cortex for winning food compared to money was positively correlated with intake at the palatable buffet meal and EAH. All aforementioned relationships were independent of child weight status. Findings support the reward surfeit model by showing that increased brain response to food compared to money rewards positively correlates with laboratory measures of food intake in children.

Decision mechanisms underlying mood-congruent emotional classification.

There is great interest in understanding whether and how mood influences affective processing. Results in the literature have been mixed: some studies show mood-congruent processing but others do not. One limitation of previous work is that decision components for affective processing and responses biases are not dissociated. The present study explored the roles of affective processing and response biases using a drift-diffusion model (DDM) of simple choice. In two experiments, participants decided if words were emotionally positive or negative while listening to music that induced positive or negative mood. The behavioural results showed weak, inconsistent mood-congruency effects. In contrast, the DDM showed consistent effects that were selectively driven by an a-priori bias in response expectation, suggesting that music-induced mood influences expectations about the emotionality of upcoming stimuli, but not the emotionality of the stimuli themselves. Implications for future studies of emotional classification and mood are subsequently discussed.

Functional Mononitrosyl Diiron(II) Complex Mediates the Reduction of NO to N2O with Relevance for Flavodiiron NO Reductases.

Reaction of [Fe2(N-Et-HPTB)(CH3COS)](BF4)2 (1) with (NO)(BF4) produces a nonheme mononitrosyl diiron(II) complex, [Fe2(N-Et-HPTB)(NO)(DMF)3](BF4)3 (2). Complex 2 is the first example of a [FeII{Fe(NO)}7] species and is also the first example of a mononitrosyl diiron(II) complex that mediates the reduction of NO to N2O. This work describes the selective synthesis, detailed characterization and NO reduction activity of 2 and thus provides new insights regarding the mechanism of flavodiiron nitric oxide reductases.

Electrophysiological correlates of the drift diffusion model in visual word recognition.

This study was designed to explore the electrophysiological correlates of the diffusion models drift rate parameter in cognitive decision making. Eighty-two participants completed a lexical decision task while their stimulus-dependent event-related potentials (ERP) and theta frequency band power were measured. A mass univariate approach was applied to examine the timeline at which correlations were evident. Individual differences in drift rate parameter and condition-wise within-subject differences in drift rates for word emotionality and item repetition were found to be related to amplitude differences in the late positive complex (LPC). No relations to theta frequency band power changes were obtained. The drift rate parameter captures information accumulation of noisy evidence, while LPC amplitudes are discussed to reflect the strength of a memory trace. While these results point to a common underlying cognitive mechanism to explain drift rates and LPC modulation, they also provide a new angle on the timeline of visual word processing following word identification. Further confirmations of the results are needed to approve the LPC as neurophysiological marker of information accumulation. Hum Brain Mapp 38:5616-5627, 2017. © 2017 Wiley Periodicals, Inc.

Drift diffusion model of reward and punishment learning in rare alpha-synuclein gene carriers.

To understand the cognitive effects of alpha-synuclein polymorphism, we employed a drift diffusion model (DDM) to analyze reward- and punishment-guided probabilistic learning task data of participants with the rare alpha-synuclein gene duplication and age- and education-matched controls. Overall, the DDM analysis showed that, relative to controls, asymptomatic alpha-synuclein gene duplication carriers had significantly increased learning from negative feedback, while they tended to show impaired learning from positive feedback. No significant differences were found in response caution, response bias, or motor/encoding time. We here discuss the implications of these computational findings to the understanding of the neural mechanism of alpha-synuclein gene duplication.

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease.

cAMP stimulates cell proliferation and Cl(-)-dependent fluid secretion, promoting the progressive enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Intracellular cAMP levels are determined by the balance of cAMP synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Therefore, PDE isoform expression and activity strongly influence global and compartmentalized cAMP levels. We report here that PDE3 and PDE4 expression levels are lower in human ADPKD tissue and cells compared with those of normal human kidneys (NHKs), whereas PDE1 levels are not significantly different. Inhibition of PDE4 caused a greater increase in basal and vasopressin (AVP)-stimulated cAMP levels and Cl(-) secretion by ADPKD cells than inhibition of PDE1, and inhibition of PDE4 induced cyst-like dilations in cultured mouse Pkd1(-/-) embryonic kidneys. In contrast, inhibition of PDE1 caused greater stimulation of extracellular signal-regulated kinase (ERK) and proliferation of ADPKD cells than inhibition of PDE4, and inhibition of PDE1 enhanced AVP-induced ERK activation. Notably, inhibition of PDE1, the only family of Ca(2+)-regulated PDEs, also induced a mitogenic response to AVP in NHK cells, similar to the effect of restricting intracellular Ca(2+). PDE1 coimmunoprecipitated with B-Raf and A-kinase anchoring protein 79, and AVP increased this interaction in ADPKD but not NHK cells. These data suggest that whereas PDE4 is the major PDE isoform involved in the regulation of global intracellular cAMP and Cl(-) secretion, PDE1 specifically affects the cAMP signal to the B-Raf/MEK/ERK pathway and regulates AVP-induced proliferation of ADPKD cells.

Using Covert Response Activation to Test Latent Assumptions of Formal Decision-Making Models in Humans.

Most decisions that we make build upon multiple streams of sensory evidence and control mechanisms are needed to filter out irrelevant information. Sequential sampling models of perceptual decision making have recently been enriched by attentional mechanisms that weight sensory evidence in a dynamic and goal-directed way. However, the framework retains the longstanding hypothesis that motor activity is engaged only once a decision threshold is reached. To probe latent assumptions of these models, neurophysiological indices are needed. Therefore, we collected behavioral and EMG data in the flanker task, a standard paradigm to investigate decisions about relevance. Although the models captured response time distributions and accuracy data, EMG analyses of response agonist muscles challenged the assumption of independence between decision and motor processes. Those analyses revealed covert incorrect EMG activity ("partial error") in a fraction of trials in which the correct response was finally given, providing intermediate states of evidence accumulation and response activation at the single-trial level. We extended the models by allowing motor activity to occur before a commitment to a choice and demonstrated that the proposed framework captured the rate, latency, and EMG surface of partial errors, along with the speed of the correction process. In return, EMG data provided strong constraints to discriminate between competing models that made similar behavioral predictions. Our study opens new theoretical and methodological avenues for understanding the links among decision making, cognitive control, and motor execution in humans. SIGNIFICANCE STATEMENT: Sequential sampling models of perceptual decision making assume that sensory information is accumulated until a criterion quantity of evidence is obtained, from where the decision terminates in a choice and motor activity is engaged. The very existence of covert incorrect EMG activity ("partial error") during the evidence accumulation process challenges this longstanding assumption. In the present work, we use partial errors to better constrain sequential sampling models at the single-trial level.