Substantial Attenuation Research Articles

Does explaining the origins of misinformation improve the effectiveness of a given correction?

Misinformation often has a continuing influence on event-related reasoning even when it is clearly and credibly corrected; this is referred to as the continued influence effect. The present work investigated whether a correction’s effectiveness can be improved by explaining the origins of the misinformation. In two experiments, we examined whether a correction that explained misinformation as originating either from intentional deception or an unintentional error was more effective than a correction that only identified the misinformation as false. Experiment 2 found no evidence that corrections explaining the reason the misinformation was presented, were more effective than a correction not accompanied by an explanation, and no evidence of a difference in effectiveness between a correction that explained the misinformation as intentional deception and one that explained it as unintentional error. We replicated this in Experiment 2 and found substantial attenuation of the continued influence effect in a novel scenario with the same underlying structure. Overall, the results suggest that informing people of the cause leading to presentation of misinformation, whether deliberate or accidental, may not be an effective correction strategy over and above stating that the misinformation is false.

The impact of the Russian embargo on the development and specialization of agri-food trade between Slovakia and Russia

The paper examines and evaluates the impact of the Russian embargo on the development and specialization of agri-food foreign trade between Slovakia and Russia through the evaluation of the one-factor Lafay and Grubel-Lloyd indexes. As a result of the application of the Russian embargo on imports of agri-food products, based on the calculation of the indexes, we can state that the degree of specialization of Slovak agri-food foreign trade has changed. Although in 2013 Slovakia specialized in exporting a relatively wide range of agri-food products, in 2020, their number decreased. Also, in 2020 there was no overall increase in the volume of mutual trade. In general, Slovakia's exports to Russia decreased compared to 2013. The following factors have contributed to this situation: substantial attenuation, that is, the elimination of Slovak agri-food exports to Russia based on the impact of the Russian embargo with side effects and an increase in imports from Russia but not in absolute but relative terms in the context of its comparison with Slovak exports.

Viral interference with class II function

We have previously demonstrated that classical (exogenous) MHC class II (MHCII)-restricted antigen processing is complemented by a complex endogenous processing network that, in the case of influenza, is a highly efficient source of peptides. Given this picture, it might be expected that some pathogens have adopted strategies to interfere with presentation of endogenously produced peptides. Indeed, this is the case for ectromelia (ECTV), the cause of mousepox. C15, a B22 family member encoded by the largest ECTV open reading frame, is a membrane glycoprotein expressed at the surface of the infected cell. Ablation of C15 results in substantial attenuation of the virus and enhanced ability to present processed antigen via MHCII but not MHC class I (MHCI). Conversely, expression of C15 alone is sufficient to inhibit MHCII-but not MHCI-restricted presentation of processed antigen and synthetic peptide. Imaging analysis suggests that C15 acts by disruption of the immunological synapse. Work toward additional mechanistic insights is ongoing.

Measurement-Based Indoor Millimeter Wave Blockage Models

Blockage is a substantial problem at millimeter wave (mmWave) frequencies, much more so than sub-6 GHz. Blockage events caused by objects such as cars and humans occur quickly and have substantial attenuation; typical attenuations in this work range from 11 to 22 dB, with a maximum of 32 dB. This problem is overcome with spatial diversity. During blockage events, mmWave transceivers can beamform towards an unblocked path. In this paper we explore this idea in depth: if the primary path is blocked, which alternate paths will be available? To answer this question, we have built a measurement system that uses 60 GHz phased arrays to rapidly obtain spatially resolved measurements of the channel. Scans are repeated every 3.2 ms, allowing us to observe blockage events that occur on the different paths in the channel. The design of this system is presented, and a description is given of three human-body blockage measurement campaigns. Paths are assigned states of blocked/unblocked, and each measurement is expressed as a time series of states which specify the status of each path. The evolution between states is described with a Markov model, and the measurement results are used to derive transition probabilities between states.

Wave-induced thermal flux and scattering of P waves in a medium with aligned circular cracks

High temperature affects the seismic properties of cracked and faulted reservoirs and can be an indicator for their detection. To this purpose, the authors study the wave-induced thermal flux (WITF) and develop two exact solutions for the scattering of compressional waves by a circular crack filled with a compressible fluid, in which the approach is based on thermally permeable and impermeable boundary conditions. The authors obtained the phase velocity and attenuation as a function of frequency, which found that there are two loss mechanisms, i.e., thermoelastic dissipation at low frequencies and elastic scattering at high frequencies. Basically, when the crack size is comparable to the thermal and elastic wavelengths, there are substantial dispersion and attenuation (anelasticity) in the WITF and scattering frequency ranges, respectively. This means that the spatial inhomogeneity scale for inducing WITF is much smaller than that of scattering and the two mechanisms can be discriminated. The dependence of the compressional-wave velocity and attenuation on the compressibility and thermal expansion of the crack-filling fluid are different depending on the thermal diffusion rates at the crack interface. The anelasticity is much higher in the fully permeable case. This model has the potential to evaluate thermoelastic properties and heterogeneity at different scales from seismic responses.

Little Contribution of Genome-Wide Gene-Diet Interactions to Cardiometabolic Risk Factors in the UK Biobank

ObjectivesGenome-guided dietary recommendations have long been a goal of precision nutrition and have a substantial evidence base in well-controlled animal experiments. However, it remains unclear how much these gene-diet interactions (GxDs) affect disease risk in human populations. Understanding the contribution of GxDs to variability in disease risk factors is thus critical to guide scientific effort as well as prioritize specific dietary exposures for study. We set out to quantify the genome-wide contribution of GxDs to the heritability of multiple cardiometabolic risk factors across a wide range of dietary traits.MethodsThe study population consisted of unrelated, European-ancestry individuals from the UK Biobank with dietary data available from one or more 24-hour recall questionnaires (N = 122,945). We conducted a genome-wide GxD interaction study for each combination of 12 cardiometabolic risk factors (e.g., lipids and glycemic traits) and 20 dietary exposures (macronutrients, micronutrients, and food groups). We then used the resulting genome-wide summary statistics as input to the regression-based GxEsum method. GxEsum estimates the contribution of genetic main effects or interaction effects to heritability, expressed as a fraction of the outcome trait variability with associated confidence intervals.ResultsNo diet-trait pair passed a Bonferroni significance threshold, though 13 pairs were nominally significant (p < 0.05). The strongest of these was the gene-by-whole grain interaction, explaining 1.1% of the variability in systolic blood pressure (p = 0.002). GxD contributions to heritability (mean of 0.1% variance explained across all diet-trait pairs) were much lower than those from genetic main effects (mean of 16.8% variance explained). Finally, we saw substantial attenuation of heritability estimates when regressions adjusted for GxD terms for the remaining dietary components; this reinforces conclusions from non-dietary studies and indicates the importance of adjusting for “interaction confounders” in nutrigenetic studies.ConclusionsOur results show that it is difficult to find meaningful GxD signal for common traits, even in a large and homogeneous population. This may indicate a true lack of GxD effects or a need for improved (e.g., longitudinal or biomarker-based) dietary behavior estimation.Funding SourcesNHLBI.

Low-frequency vibration control of two flexible appendages using a joint with actively tunable stiffness

Low-frequency and large-amplitude vibration of flexible appendages in space can be induced when a spacecraft performs attitude maneuvers and thermal alternations during orbit operation. In this paper, a novel joint mechanism combined with a semi-active method for variable stiffness control is proposed to suppress the low-frequency vibrations of flexible jointed appendages. The variable stiffness of the joint is derived from the linear relationship between its output torque and rotation angle when direct current (DC) power is applied to the coils. Based on the Lagrange equation and the assumed mode method, the coupling dynamic relationships of the active joint and two flexible appendages are established, and semi-active vibration control simulations are performed. A ground experimental platform is built to simulate the microgravity environment in space. The frequency shift effect of rigid body motion and elastic vibration under impact disturbance are investigated. In addition, the effect of variable stiffness control on the elastic deformation of flexible appendages is studied. The simulation and experimental results indicated that the proposed method can control both the rigid body motion of the system and the elastic vibration of the appendages. It has been found that the major frequency bandwidth of the interference signal is within 0.3–1.0 Hz with a substantial vibration attenuation of 1.82–16.62 dB for the joint and 4.86–11.48 dB for the flexible appendages.

Maternal Serotonergic Antidepressant Use in Pregnancy and Risk of Seizures in Children.

Background and ObjectivesTo evaluate whether children born to women who use serotonergic antidepressants during pregnancy have higher risk of neonatal seizures and epilepsy.MethodsWe used Swedish register-based data to examine associations between maternal reported use of selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) in pregnancy and diagnosis of neonatal seizures or epilepsy in >1.2 million children. To account for systematic differences between exposed and unexposed children, we adjusted for a wide range of measured confounders. After first evaluating the role of maternal indication for SSRI/SNRI use (i.e., depression or anxiety) and parental epilepsy, we adjusted for remaining parental background factors (e.g., age, comorbidities, education, and family socioeconomic indices) and pregnancy-specific characteristics (e.g., maternal use of other psychotropic medications and tobacco smoking in early pregnancy).ResultsCompared with all other children, children of women who reported use of SSRI/SNRI in pregnancy had an elevated risk of neonatal seizures and epilepsy (risk ratio [RR] 1.41, 95% CI 1.03–1.94; hazard ratio [HR] 1.21, 95% CI 1.03–1.43, respectively). The estimates of association were attenuated by adjustment for maternal indications for SSRI/SNRI use (RR 1.30, 95% CI 0.94–1.80; HR 1.13, 95% CI 0.95–1.33), but not by additional adjustment for parental history of epilepsy. Full adjustment for all measured parental and pregnancy-specific factors resulted in substantial attenuation of the remaining associations (RR 1.10, 95% CI 0.79–1.53; HR 0.96, 95% CI 0.81–1.14).DiscussionWe found no support for the concern that maternal SSRI/SNRI use in pregnancy increases children's risk for neonatal seizures or epilepsy.Classification of EvidenceThis study provides Class II evidence that exposure to SSRIs/SNRIs in the first trimester of pregnancy is not associated with an increased incidence of neonatal seizures/epilepsy.

A Note on Increases in Inattentive Online Survey-Takers Since 2020

Lucid, a popular source of online convenience survey samples, has seen a significant increase in inattentive respondents since 2020. Inattentive participants – respondents who incorrectly answer directed query attention check questions – may be introducing substantial measurement error and attenuation bias. Using data from 152,967 survey respondents across multiple studies conducted between January 2020 and June 2021, we find that inattentive respondents report less reliable demographic data, less stable responses, and are systematically different from attentive respondents. We find some evidence of attenuation bias and mixed evidence that data quality has decreased slightly since 2020 even after filtering for inattentive respondents. We conclude that researchers using Lucid should report if they screened on attentiveness and consider replicating any null results. Such an unexpected increase in inattentiveness in a widely-used platform suggests that future researchers relying on online convenience survey samples should continuously assess data quality.

Investigation of Pump Failure-Induced Waterhammer Waves: A Case Study

Abstract This study analyzes the effect of the pipe material type on the transient flow behavior in a pumping system due to an accidental pump shutdown. The material types addressed in this study include steel and high- or low-density polyethylene (HDPE) or (LDPE), involving elastic and plastic rheological pipe-wall behavior. The numerical solution is developed based on the method of characteristics used for the discretization of the extended one-dimensional pressurized-pipe flow model, incorporating the Kelvin-Voigt and Vitkovsky rules. Experimental data from the literature were used to validate the numerical solver. The proposed numerical algorithm is then used to investigate the transient pressure-wave behavior induced by the power failure to a pumping station composed of an inline connection using different pipe material types. The findings show the severity of such a scenario, in terms of the magnitudes of induced up-surge and down-surge pressure waves. Furthermore, this research demonstrates that plastic pipe-wall materials allow for substantial attenuation of surge magnitude in conjunction with the expansion of the period of pressure-wave oscillations. The observed attenuation and expansion effects are also found to be highly dependent on the plastic material type. In this respect, the findings indicate that the (LDPE-steel) piping system's specific layout allows for the best tradeoff between the two last effects.

Cissus quadrangularis extract attenuates diabetic nephropathy by altering SIRT1/DNMT1 axis.

Hyperglycemia-induced SIRT1, DNMT1, SODs, as well as oxidative stress, play a pivotal role in the progression of diabetic nephropathy. Cissus quadrangularis, holds antioxidant and hypoglycemic activity; however, a direct link between its activity and prevention of diabetic nephropathy has not been ascertained yet. Accordingly, we aimed to delineate the protective effect of ethanolic extract of Cissus quadrangularis (EECQ) against high-fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy rats. The control group was fed with a normal chow diet. Rats kept on an HFD for 12 weeks with a single low dose of STZ manifested the features of diabetic nephropathy. The treatment was done by the oral administration of EECQ (200 mg/kg) for six weeks (six rats in each group). Treatment with EECQ demonstrated substantial attenuation of elevated insulin resistance, lipid profile and creatinine level. Additionally, EECQ restored albuminuria, glomerular filtration rate and creatinine clearance in diabetic nephropathy rats. Furthermore, HFD consumption in rats culminated in reduced SIRT1 and enhanced DNMT1 expression, nonetheless, rescued by EECQ. Moreover, EECQ augmented the SOD 1 and 3 levels, thereby safeguarded from oxidative damage and renal inflammation. Besides, treatment protected from renal fibrosis by downregulating TGFβ, Smad2/3 and col1/3 expression in diseased rats. Thus, based on the above findings, we conclude that EECQ shows a protective effect against diabetic nephropathy.

A new continuous integral sliding mode control algorithm for inverted pendulum and 2-DOF helicopter nonlinear systems: Theory and experiment

This paper introduces a new continuous integral sliding mode control algorithm, where the discontinuous function of the super-twisting control law is replaced with a continuous disturbance observer for the substantial chattering attenuation. In the present integral sliding mode control, the discontinuous function generates chattering that is undesirable for several real-time applications. The proposed control strategy decreases the amplitude of the controller gain compared to the existing integral sliding mode controls, and as a consequence of this, the attenuation of chattering is achieved to a great extent. The efficacy of the proposed control algorithm is validated successfully on the single-input single-output Inverted Pendulum and 2-DOF Helicopter nonlinear coupled multi-input multi-output systems. The simulation and experimental results demonstrate the successful application of the proposed control approach to follow reference inputs and acquire robustness and stabilization of the system in the presence of limited matched perturbations and nonlinearities.

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.

Can Managed Realignment Buffer Extreme Surges? The Relationship Between Marsh Width, Vegetation Cover and Surge Attenuation

Managed realignment (MR) involves the landward relocation of sea defences to foster the (re)creation of coastal wetlands and achieve nature-based coastal protection. The wider application of MR is impeded by knowledge gaps related to lacking data on its effectiveness under extreme surges and the role of changes in vegetation cover, for example due to sea-level rise. We employ a calibrated and validated hydrodynamic model to explore relationships between surge attenuation, MR width(/area) and vegetation cover for the MR site of Freiston Shore, UK. We model a range of extreme water levels for four scenarios of variable MR width. We further assess the effects of reduced vegetation cover for the actual MR site and for the scenario of the site with the largest width. We show that surges are amplified for all but the largest two site scenarios, suggesting that increasing MR width results in higher attenuation rates. Substantial surge attenuation (up to 18 cm km−1) is only achieved for the largest site. The greatest contribution to the attenuation in the largest site scenario may come from water being reflected from the breached dike. While vegetation cover has no statistically significant effect on surge attenuations in the original MR site, higher coverage leads to higher attenuation rates in the largest site scenario. We conclude that at the open coast, only large MR sites (> 1148 m width) can attenuate surges with return periods > 10 years, while increased vegetation cover and larger MR widths enable the attenuation of even higher surges.

Assessment of cerebral oxygenation response to hemodialysis using near-infrared spectroscopy (NIRS): Challenges and solutions.

To date, the clinical use of functional near-infrared spectroscopy (NIRS) to detect cerebral ischemia has been largely limited to surgical settings, where motion artifacts are minimal. In this study, we present novel techniques to address the challenges of using NIRS to monitor ambulatory patients with kidney disease during approximately eight hours of hemodialysis (HD) treatment. People with end-stage kidney disease who require HD are at higher risk for cognitive impairment and dementia than age-matched controls. Recent studies have suggested that HD-related declines in cerebral blood flow might explain some of the adverse outcomes of HD treatment. However, there are currently no established paradigms for monitoring cerebral perfusion in real-time during HD treatment. In this study, we used NIRS to assess cerebral hemodynamic responses among 95 prevalent HD patients during two consecutive HD treatments. We observed substantial signal attenuation in our predominantly Black patient cohort that required probe modifications. We also observed consistent motion artifacts that we addressed by developing a novel NIRS methodology, called the HD cerebral oxygen demand algorithm (HD-CODA), to identify episodes when cerebral oxygen demand might be outpacing supply during HD treatment. We then examined the association between a summary measure of time spent in cerebral deoxygenation, derived using the HD-CODA, and hemodynamic and treatment-related variables. We found that this summary measure was associated with intradialytic mean arterial pressure, heart rate, and volume removal. Future studies should use the HD-CODA to implement studies of real-time NIRS monitoring for incident dialysis patients, over longer time frames, and in other dialysis modalities.

Identification and Characterization of Two Transmembrane Proteins Required for Virulence of Ustilago maydis.

Smut fungi comprise a large group of biotrophic phytopathogens infecting important crops such as wheat and corn. Through the secretion of effector proteins, the fungus actively suppresses plant immune reactions and modulates its host’s metabolism. Consequently, how soluble effector proteins contribute to virulence is already characterized in a range of phytopathogens. However, membrane-associated virulence factors have been much less studied to date. Here, we investigated six transmembrane (TM) proteins that show elevated gene expression during biotrophic development of the maize pathogen Ustilago maydis. We show that two of the six proteins, named Vmp1 and Vmp2 (virulence-associated membrane protein), are essential for the full virulence of U. maydis. The deletion of the corresponding genes leads to a substantial attenuation in the virulence of U. maydis. Furthermore, both are conserved in various related smuts and contain no domains of known function. Our biochemical analysis clearly shows that Vmp1 and Vmp2 are membrane-associated proteins, potentially localizing to the U. maydis plasma membrane. Mass photometry and light scattering suggest that Vmp1 mainly occurs as a monomer, while Vmp2 is dimeric. Notably, the large and partially unstructured C-terminal domain of Vmp2 is crucial for virulence while not contributing to dimerization. Taken together, we here provide an initial characterization of two membrane proteins as virulence factors of U. maydis.

ACE2 Knock‐out Mice Show Decreased Blood Pressure Response and Increased Anxiety‐like Behavior to Acute Stress

Stress increases Ang-II production and elevates sympathetic outflow which results in anxiety-related behavior and hypertension. Here, we investigated a potential contribution of Angiotensin Converting Enzyme-2 (ACE2) in the regulation of stress and anxiety-related behavior, in conscious freely moving mice. Previous studies reported that overexpression of ACE2 attenuates HPA axis and decreases anxiety-related behavior (Wang et al., 2018); however, deletion of ACE2 and its implication for such responses are largely unknow. Male mice (30-33 g), 6 ACE2 knock-outs (KO) and 6 wild type (WT) controls were chronically implanted with blood pressure (BP) transducers for continuous recording of BP, heart rate (HR) and locomotor activity. Following a 1-week recovery, mice were subjected to resident-intruder test for 10 min, for the measurement of stress-induced cardiovascular changes. During the dark/active period, a naïve intruder-mouse was suddenly introduced in the experimental mice's cages and their cardiovascular responses were analyzed using the Ponemah software (DSI). In response to intruder-intrusion for 10 min, ACE2 KO mice showed significant (p<0.05) attenuation in BP increases (+15 ±7 mmHg) compared to their WT controls (+39 ±7 mmHg). However, no significant difference was observed in HR increase in ACE2 KO versus WT mice (+166 ±40 and +173±38 bpm, respectively, p=0.45). In contrast, ACE2 KO mice exhibited a significant increase in locomotor activity compared to controls (179 ±19 and 111 ±14 arbitrary units, respectively, p<0.05). These mice were later subjected to the elevated plus maze (EPM) and light-dark box (LDB) tests for 5 min to evaluate anxiety-related behavior. Interestingly ACE2 KO mice were observed to spend more time in closed arms (244 ±19 s) in EPM compared to WT controls (218 ±22 s, p<0.05). However, in the LDB test, ACE2 KO mice showed no difference (286 ±18 s) compared to WT (279 ±19 s, ns). All mice were then chronically implanted subcutaneously with osmotic minipumps filled with an AT1 receptor antagonist (losartan, 10 mg/kg). A week later, mice were again subjected to the intruder test. ACE2 KO mice showed substantial attenuation in BP increase to intruder-intrusion compared to WT mice (+6±3 and +19±6 mmHg respectively, p<0.05); with no significant difference in HR increase in both the groups. Interestingly, pre-treatment with losartan attenuated the intruder-induced locomotor activity in ACE2 KO mice (149±29, p=0.11). In addition, losartan treatment did not attenuate the time ACE2 KO mice spent in closed arms in EPM; but exhibited a decreased time spent in the dark compartment in the LDB test. Surprisingly, our results did not show exacerbated BP responses to acute stress in the absence of ACE2 but instead produced decreased BP responses suggesting other compensatory mechanisms involved. Losartan-mediated attenuation of the increased locomotor activity and anxiety-related behaviors in ACE2 KO mice strongly suggests an Ang-II mediated anxiety-related behaviors. Our experimental findings further extend the current notion that ACE2 potentially contributes to the regulation of stress and anxiety.

Local and CNS-Wide Astrocyte Intracellular Calcium Signaling Attenuation In Vivo with CalExflox Mice.

Astrocytes exist throughout the CNS and affect neural circuits and behavior through intracellular Ca2+ signaling. Studying the function(s) of astrocyte Ca2+ signaling has proven difficult because of the paucity of tools to achieve selective attenuation. Based on recent studies, we generated and used male and female knock-in mice for Cre-dependent expression of mCherry-tagged hPMCA2w/b to attenuate astrocyte Ca2+ signaling in genetically defined cells in vivo (CalExflox mice for Calcium Extrusion). We characterized CalExflox mice following local AAV-Cre microinjections into the striatum and found reduced astrocyte Ca2+ signaling (∼90%) accompanied with repetitive self-grooming behavior. We also crossed CalExflox mice to astrocyte-specific Aldh1l1-Cre/ERT2 mice to achieve inducible global CNS-wide Ca2+ signaling attenuation. Within 6 d of induction in the bigenic mice, we observed significantly altered ambulation in the open field, disrupted motor coordination and gait, and premature lethality. Furthermore, with histologic, imaging, and transcriptomic analyses, we identified cellular and molecular alterations in the cerebellum following mCherry-tagged hPMCA2w/b expression. Our data show that expression of mCherry-tagged hPMCA2w/b with CalExflox mice throughout the CNS resulted in substantial attenuation of astrocyte Ca2+ signaling and significant behavioral alterations in adult mice. We interpreted these findings candidly in relation to the ability of CalEx to attenuate astrocyte Ca2+ signaling, with regards to additional mechanistic interpretations of the data, and their relation to past studies that reduced astrocyte Ca2+ signaling throughout the CNS. The data and resources provide complementary ways to interrogate the function(s) of astrocytes in multiple experimental scenarios.SIGNIFICANCE STATEMENT Astrocytes represent a significant fraction of all brain cells and tile the entire central nervous system. Unlike neurons, astrocytes lack propagated electrical signals. Instead, astrocytes are proposed to use diverse and dynamic intracellular Ca2+ signals to communicate with other cells. An open question concerns if and how astrocyte Ca2+ signaling regulates behavior in adult mice. We approached this problem by generating a new transgenic mouse line to achieve inducible astrocyte Ca2+ signaling attenuation in vivo We report our data with this mouse line and we interpret the findings candidly in relation to past studies and within the framework of different mechanistic interpretations.

NirA Is an Alternative Nitrite Reductase from Pseudomonas aeruginosa with Potential as an Antivirulence Target.

The opportunistic pathogen Pseudomonas aeruginosa produces an arsenal of virulence factors causing a wide range of diseases in multiple hosts and is difficult to eradicate due to its intrinsic resistance to antibiotics. With the antibacterial pipeline drying up, antivirulence therapy has become an attractive alternative strategy to the traditional use of antibiotics to treat P. aeruginosa infections. To identify P. aeruginosa genes required for virulence in multiple hosts, a random library of Tn5 mutants in strain PAO1-L was previously screened in vitro for those showing pleiotropic effects in the production of virulence phenotypes. Using this strategy, we identified a Tn5 mutant with an insertion in PA4130 showing reduced levels of a number of virulence traits in vitro Construction of an isogenic mutant in this gene presented results similar to those for the Tn5 mutant. Furthermore, the PA4130 isogenic mutant showed substantial attenuation in disease models of Drosophila melanogaster and Caenorhabditis elegans as well as reduced toxicity in human cell lines. Mice infected with this mutant demonstrated an 80% increased survival rate in acute and agar bead lung infection models. PA4130 codes for a protein with homology to nitrite and sulfite reductases. Overexpression of PA4130 in the presence of the siroheme synthase CysG enabled its purification as a soluble protein. Methyl viologen oxidation assays with purified PA4130 showed that this enzyme is a nitrite reductase operating in a ferredoxin-dependent manner. The preference for nitrite and production of ammonium revealed that PA4130 is an ammonia:ferredoxin nitrite reductase and hence was named NirA.IMPORTANCE The emergence of widespread antimicrobial resistance has led to the need for development of novel therapeutic interventions. Antivirulence strategies are an attractive alternative to classic antimicrobial therapy; however, they require identification of new specific targets which can be exploited in drug discovery programs. The host-specific nature of P. aeruginosa virulence adds complexity to the discovery of these types of targets. Using a sequence of in vitro assays and phylogenetically diverse in vivo disease models, we have identified a PA4130 mutant with reduced production in a number of virulence traits and severe attenuation across all infection models tested. Characterization of PA4130 revealed that it is a ferredoxin-nitrite reductase and hence was named NirA. These results, together with attenuation of nirA mutants in different clinical isolates, high level conservation of its gene product in P. aeruginosa genomes, and the lack of orthologues in human genomes, make NirA an attractive antivirulence target.

Impact of covariate omission and categorization from the Fine–Gray model in randomized-controlled trials

In this paper, we study the statistical issues related to the omission and categorization of important covariates in the context of the Fine–Gray model in randomized-controlled trials with competing risks. We show that the omission of an important covariate from the Fine–Gray model leads to attenuated estimates for treatment effect and loss of proportionality in general. Our simulation studies reveal substantial attenuation in the estimate for treatment effect and the loss of statistical power, while dichotomizing a continuous covariate leads to similar but less pronounced impact. Our results are illustrated using data from a randomized clinical trial of HIV-infected individuals. The relative merits of conducting an adjusted versus an unadjusted analysis of treatment effect in light of both statistical and practical considerations are discussed.