A bacterial TIR-based immune system senses viral capsids to initiate defense.

Toll/interleukin-1 receptor (TIR) domains are present in immune systems that protect prokaryotes from viral (phage) attack. In response to infection, TIRs can produce a cyclic adenosine diphosphate-ribose (ADPR) signaling molecule, which activates an effector that depletes the host of the essential metabolite NAD+ to limit phage propagation. How bacterial TIRs recognize phage infection is not known. Here we describe the sensing mechanism for the staphylococcal Thoeris defense system, which consists of two TIR domain sensors, ThsB1 and ThsB2, and the effector ThsA. We show that the major capsid protein of phage Φ80α forms a complex with ThsB1 and ThsB2, which is sufficient for the synthesis of 1"-3' glycocyclic ADPR (gcADPR) and subsequent activation of NAD+ cleavage by ThsA. Consistent with this, phages that escape Thoeris immunity harbor mutations in the capsid that prevent complex formation. We show that capsid proteins from staphylococcal Siphoviridae belonging to the capsid serogroup B, but not A, are recognized by ThsB1/B2, a result that suggests that capsid recognition by Sau-Thoeris and other anti-phage defense systems may be an important evolutionary force behind the structural diversity of prokaryotic viruses. More broadly, since mammalian toll-like receptors harboring TIR domains can also recognize viral structural components to produce an inflammatory response against infection, our findings reveal a conserved mechanism for the activation of innate antiviral defense pathways.

Immune response and intergroup bias: Vaccine-induced increases in cytokine activity are associated with worse evaluations of resume for Latina job applicant.

Situational factors can increase people's vulnerability to intergroup bias, including prejudicial attitudes, negative stereotyping, and discrimination. We proposed that increases in inflammatory activity that coincide with acute illness may represent a hitherto unstudied situational factor that increases intergroup bias. The current study experimentally manipulated increases in inflammatory activity by administering the seasonal influenza vaccine or a saline placebo. We quantified inflammatory activity by assessing change in salivary pro-inflammatory cytokines and assessed intergroup bias using a resume evaluation task and self-reported ethnocentrism. Primary analyses focused on a subsample of 117 participants who provided high quality data; robustness analyses included various permutations of lower quality participants. Findings revealed that changes in the cytokine interleukin-1ß (IL-1ß) in response to the vaccine were associated with greater intergroup bias. Among participants who received the vaccine, IL-1ß change was negatively associated with evaluation of a Latina (but not a White woman) applicant's competency and recommended starting salary. Moreover, IL-1ß change was positively associated with ethnocentrism. Overall, results provide support for the hypothesis that acute illness, via the mechanistic role of inflammatory cytokines, affects social cognition in ways that can increase intergroup bias.

Bacterial cGAS senses a viral RNA to initiate immunity.

Cyclic oligonucleotide-based antiphage signalling systems (CBASS) protect prokaryotes from viral (phage) attack through the production of cyclic oligonucleotides, which activate effector proteins that trigger the death of the infected host1,2. How bacterial cyclases recognize phage infection is not known. Here we show that staphylococcal phages produce a structured RNA transcribed from the terminase subunit genes, termed CBASS-activating bacteriophage RNA (cabRNA), which binds to a positively charged surface of the CdnE03 cyclase and promotes the synthesis of the cyclic dinucleotide cGAMP to activate the CBASS immune response. Phages that escape the CBASS defence harbour mutations that lead to the generation of a longer form of the cabRNA that cannot activate CdnE03. As the mammalian cyclase OAS1 also binds viral double-stranded RNA during the interferon response, our results reveal a conserved mechanism for the activation of innate antiviral defence pathways.

Trends in antenatal depression and suicidal ideation diagnoses among commercially insured childbearing individuals in the United States, 2008-2018.

INTRODUCTION: Antenatal depression and suicidal ideation represent serious pregnancy-related complications, yet comprehensive estimates of the prevalence and predictors of these diagnoses among birthing people remain unclear. OBJECTIVE: This study aimed to characterize trends in the prevalence of depression and suicidal ideation diagnoses identified among pregnant individuals prior to giving birth. METHODS: This study included 536,647 individuals aged 15-44 years continuously enrolled in a single commercial health insurance plan for one year before childbirth from 2008 to 2018. The primary outcomes included depression or suicidal ideation based on identification of the relevant ICD-9 and ICD-10 diagnosis codes during pregnancy. RESULTS: Rates (95 % CIs) of depression increased by 39 % from 540 (520-560) per 10,000 individuals in 2008 to 750 (730-770) per 10,000 individuals in 2018. Suicidal ideation increased by 100 % from 15 (12-18) per 10,000 individuals in 2008 to 44 (39-50) per 10,000 individuals in 2018. Black birthing people experiencing the sharpest proportional increases. CONCLUSIONS: The prevalence of depression and suicidal ideation occurring during pregnancy substantially increased over a ten-year period. Further, suicidal ideation diagnosis increased the most for among Black birthing people compared to all groups, resulting in a need for future studies in this area to determine the reasons for an increase in diagnosis and any change in resulting treatment of follow up.

Type III-A CRISPR immunity promotes mutagenesis of staphylococci.

Horizontal gene transfer and mutation are the two major drivers of microbial evolution that enable bacteria to adapt to fluctuating environmental stressors1. Clustered, regularly interspaced, short palindromic repeats (CRISPR) systems use RNA-guided nucleases to direct sequence-specific destruction of the genomes of mobile genetic elements that mediate horizontal gene transfer, such as conjugative plasmids2 and bacteriophages3, thus limiting the extent to which bacteria can evolve by this mechanism. A subset of CRISPR systems also exhibit non-specific degradation of DNA4,5; however, whether and how this feature affects the host has not yet been examined. Here we show that the non-specific DNase activity of the staphylococcal type III-A CRISPR-Cas system increases mutations in the host and accelerates the generation of antibiotic resistance in Staphylococcus aureus and Staphylococcus epidermidis. These mutations require the induction of the SOS response to DNA damage and display a distinct pattern. Our results demonstrate that by differentially affecting both mechanisms that generate genetic diversity, type III-A CRISPR systems can modulate the evolution of the bacterial host.

Bioactive Peptides and Hydrolysates from Egg Proteins as a New Tool for Protection Against Cardiovascular Problems.

The aim of the present work is to review the potential beneficial effects of dietary supplementation with bioactive egg protein hydrolysates or peptides on cardiometabolic changes associated with oxidative stress. The development of nutritionally improved food products designed to address specific health concerns is of particular interest because many bioactive food compounds can be potentially useful in various physiological functions such as for reducing oxidative stress. The results presented suggest that egg hydrolysates or derived peptides could be included in the diet to prevent and/or reduce some cardiometabolic complications associated with oxidative stress-related diseases.

Deleterious effects of chronic mercury exposure on in vitro LTP, memory process, and oxidative stress.

Heavy metal contamination in aquatic environments plays an important role in the exposure of humans to these toxicants. Among these pollutants, mercury (Hg) is one main concern due to its high neurotoxicity and environmental persistence. Even in low concentrations, Hg bioaccumulation is a major threat to human health, with higher impact on populations whose diet has fish as chief consumption. Mercury compounds have high affinity for neuronal receptors and proteins, which gives Hg its cumulative feature and have the ability to cross cell membranes and blood-brain barrier to show their neurotoxicity. Intoxication with Hg increases levels of reactive oxygen species (ROS), thus depleting faster the resource of antioxidant proteins. To evaluate Hg-induced hippocampal ROS production, synaptic plasticity, anxiety, and memory, a total of 11 male Wistar rats were exposed to HgCl2 (Hg30 group) to produce a residual concentration of 8 ng/mL at the end of 30 days. Behavioral tests (plus-maze discriminative avoidance task), in vitro electrophysiology, and ROS assays were performed. Western blot assay showed decreased levels of antioxidant proteins GPx and SOD in Hg30 group. Increased ROS production was observed in the CA1 and CA3 regions in the Hg-exposed group. Plus-maze task detected long-term memory impairment in Hg30 group, linked to poorer in vitro long-term potentiation as compared to control group. Hg intoxication also promoted higher anxiety-like behavior in the exposed animals. In conclusion, our data suggests that low doses of HgCl2 resulted in impaired long-term memory and unbalance between decreased antioxidant protein expression and increased ROS production in the hippocampus.

Endothelium: A Target for Harmful Actions of Metals.

The use of heavy metals is closely linked to the history of mankind. They have been used as important materials in a wide variety of human activities such as manufacturing utensils and tools. Such extended use has significantly increased professional and environmental exposure to mercury, lead and cadmium. These metals are known to produce hypertension in humans and animals and, among other effects, they can also affect endothelial function. Results described here suggest that mercury, lead and cadmium affect vascular reactivity, even at low doses or concentrations. Several vascular actions are mediated by the endothelium via increasing the production of free radicals and angiotensin II by local ACE stimulation. These results provide further evidence that these toxic metals, even at low doses, are an environmental risk factor to the exposed population. These results also suggest that continuous exposure to these metals, followed by their absorption and progressive accumulation in the body, may be hazardous to cardiovascular function. Therefore, the current reference values, which are considered safe, need to be reduced.

Mercury leads to features of polycystic ovary syndrome in rats.

Mercury (Hg) is a heavy metal and Hg exposure is associated with various neural, immune, and cardiovascular abnormalities. However, few studies have evaluated Hg's toxicologic effect on reproductive and metabolic functions. In this study, we assessed whether Hg exposure results in reproductive and metabolic abnormalities. Hg was administered to adult female Wistar rats, mimicking the Hg levels found in exposed human blood, and their reproductive and metabolic function was assessed. Rats exposed to Hg displayed abnormal estrous cyclicity and ovarian follicular development, with a reduction in ovarian antral follicles and an increase in atretic and cystic ovarian follicles. Uterine atrophy with the presence of inflammatory cells was observed in Hg-exposed rats. The presence of abnormal ovarian fat accumulation, as well as increased ovarian lipid drops accumulation, was observed in Hg-exposed rats. Ovarian oxidative stress was also present in the Hg-exposed rats. High fasting glucose levels, glucose, and insulin intolerance were observed in Hg-exposed rats. Thus, these data suggest that Hg exposure led to abnormal reproductive and metabolic features similar to those found in the polycystic ovary syndrome (PCOS) rat models.

Immunization with Components of the Viral Fusion Apparatus Elicits Antibodies That Neutralize Epstein-Barr Virus in B Cells and Epithelial Cells.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.

Impaired participation of potassium channels and Na+ /K+ -ATPase in vasodilatation due to reduced nitric oxide bioavailability in rats exposed to mercury.

Mercury intoxication is a public health risk factor due to its hazardous effect to several organs, including the cardiovascular system. There is evidence of endothelial dysfunction after exposure to mercury, but the effects on endothelium-dependent vasodilatation are still unknown. In the present study, we aimed to evaluate the chronic effects of high HgCl2 doses on the mechanisms of vasodilatation. Wistar rats were injected with HgCl2 (1st dose 10.86 µg/kg, and daily doses 0.014 µg/kg for 30 days i.m.), and saline was used as control. Mercury exposure reduced the acetylcholine-induced vasodilatation in aortic rings, which was restored by incubation with antioxidant tiron. Inhibition of the NO synthase, Na+ /K+ -ATPase and K+ channels indicates reduced participation of these factors. In the mercury group, there were an increased local anion superoxide and a reduced NO. The vasodilatation to exogenous NO was partially inhibited by co-incubation with TEA plus tiron, suggesting that reduced NO bioavailability is the responsible to that decreased the participation of K+ channels. Moreover, there was an increased participation of the Na+ /K+ -ATPase associated with an up-regulation of its alpha-1 subunit. In conclusion, reduced NO bioavailability plays a major role in the impaired participation of K+ channels and Na+ /K+ -ATPase in the acetylcholine-mediated relaxation, although sodium pump is up-regulated probably as a compensatory mechanism.

Solitonic Dispersive Hydrodynamics: Theory and Observation.

Ubiquitous nonlinear waves in dispersive media include localized solitons and extended hydrodynamic states such as dispersive shock waves. Despite their physical prominence and the development of thorough theoretical and experimental investigations of each separately, experiments and a unified theory of solitons and dispersive hydrodynamics are lacking. Here, a general soliton-mean field theory is introduced and used to describe the propagation of solitons in macroscopic hydrodynamic flows. Two universal adiabatic invariants of motion are identified that predict trapping or transmission of solitons by hydrodynamic states. The result of solitons incident upon smooth expansion waves or compressive, rapidly oscillating dispersive shock waves is the same, an effect termed hydrodynamic reciprocity. Experiments on viscous fluid conduits quantitatively confirm the soliton-mean field theory with broader implications for nonlinear optics, superfluids, geophysical fluids, and other dispersive hydrodynamic media.

Mercury-induced vascular dysfunction is mediated by angiotensin II AT-1 receptor upregulation.

Low doses of mercury (Hg) promote deleterious effects on cardiovascular system, but the mechanisms implicated remain unclear. This study analyzed whether angiotensin II AT-1 receptors are involved in the vascular dysfunction caused by chronic exposure to low HgCl2 doses. For this, rats were divided into four groups and untreated (saline by im injections and tap water by gavage) or treated for 30 days as follows: Mercury (HgCl2im, first dose of 4.6 µg kg-1 and subsequent doses of 0.07 µg kg-1 day-1, and tap water by gavage); Losartan (saline im and losartan, 15 mg kg-1 day-1, by gavage); Losartan-Mercury (HgCl2im and Losartan by gavage). Systolic blood pressure was measured by tail plethysmography, vascular reactivity in aorta by isolated organ bath, oxidative stress by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and antioxidant capacity (FRAP) and protein expression of AT-1 receptors by Western Blot. As results, co-treatment with losartan prevented the increased aortic vasoconstrictor responses to phenylephrine (Phe), the involvement of ROS and prostanoids on the response to Phe and the reduced negative endothelial modulation by nitric oxide on these responses. Moreover, this co-treatment avoided the increase in plasmatic and vascular oxidative stress and AT-1 protein expression in aorta. In conclusion, these results suggest that AT-1 receptors upregulation might play a key role in the vascular damage induced by Hg exposure by increasing oxidative stress and probably by reducing NO bioavailability.

Preliminary Studies of Acute Cadmium Administration Effects on the Calcium-Activated Potassium (SKCa and BKCa) Channels and Na+/K+-ATPase Activity in Isolated Aortic Rings of Rats.

Cadmium is an environmental pollutant closely linked with cardiovascular diseases that seems to involve endothelium dysfunction and reduced nitric oxide (NO) bioavailability. Knowing that NO causes dilatation through the activation of potassium channels and Na+/K+-ATPase, we aimed to determine whether acute cadmium administration (10 µM) alters the participation of K+ channels, voltage-activated calcium channel, and Na+/K+-ATPase activity in vascular function of isolated aortic rings of rats. Cadmium did not modify the acetylcholine-induced relaxation. After L-NAME addition, the relaxation induced by acetylcholine was abolished in presence or absence of cadmium, suggesting that acutely, this metal did not change NO release. However, tetraethylammonium (a nonselective K+ channels blocker) reduced acetylcholine-induced relaxation but this effect was lower in the preparations with cadmium, suggesting a decrease of K+ channels function in acetylcholine response after cadmium incubation. Apamin (a selective blocker of small Ca2+-activated K+ channels-SKCa), iberiotoxin (a selective blocker of large-conductance Ca2+-activated K+ channels-BKCa), and verapamil (a blocker of calcium channel) reduced the endothelium-dependent relaxation only in the absence of cadmium. Finally, cadmium decreases Na+/K+-ATPase activity. Our results provide evidence that the cadmium acute incubation unaffected the calcium-activated potassium channels (SKCa and BKCa) and voltage-calcium channels on the acetylcholine vasodilatation. In addition, acute cadmium incubation seems to reduce the Na+/K+-ATPase activity.

Aluminum Exposure at Human Dietary Levels for 60 Days Reaches a Threshold Sufficient to Promote Memory Impairment in Rats.

Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control-received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control-received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal.

Reproductive dysfunction after mercury exposure at low levels: evidence for a role of glutathione peroxidase (GPx) 1 and GPx4 in male rats.

Mercury is a ubiquitous environmental pollutant and mercury contamination and toxicity are serious hazards to human health. Some studies have shown that mercury impairs male reproductive function, but less is known about its effects following exposure at low doses and the possible mechanisms underlying its toxicity. Herein we show that exposure of rats to mercury chloride for 30 days (first dose 4.6µgkg-1, subsequent doses 0.07µgkg-1day-1) resulted in mean (±s.e.m.) blood mercury concentrations of 6.8±0.3ngmL-1, similar to that found in human blood after occupational exposure or released from removal of amalgam fillings. Even at these low concentrations, mercury was deposited in reproductive organs (testis, epididymis and prostate), impaired sperm membrane integrity, reduced the number of mature spermatozoa and, in the testes, promoted disorganisation, empty spaces and loss of germinal epithelium. Mercury increased levels of reactive oxygen species and the expression of glutathione peroxidase (GPx) 1 and GPx4. These results suggest that the toxic effects of mercury on the male reproductive system are due to its accumulation in reproductive organs and that the glutathione system is its potential target. The data also suggest, for the first time, a possible role of the selenoproteins GPx1 and GPx4 in the reproductive toxicity of mercury chloride.

Spironolactone Prevents Endothelial Nitric Oxide Synthase Uncoupling and Vascular Dysfunction Induced by ß-Adrenergic Overstimulation: Role of Perivascular Adipose Tissue.

Sustained stimulation of ß-adrenoceptors (ß-ARs) and activation of renin-angiotensin-aldosterone system are common features of cardiovascular diseases with rising sympathetic activation, including essential hypertension, myocardial infarction, and heart failure. In this study, we investigated the role of AT1 receptor and mineralocorticoid receptor (MR) in the vascular alterations caused by ß-AR overstimulation. ß-AR overstimulation with associated cardiac hypertrophy and increased vasoconstrictor response to phenylephrine in aorta were modeled in rats by 7-day isoproterenol treatment. The increased vasoconstrictor response to phenylephrine in this model was blunted by the MR antagonist spironolactone, but not by the AT1 receptor antagonist losartan, despite the blunting of cardiac hypertrophy with both drugs. Spironolactone, but not losartan, restored NO bioavailability in association with lower endothelial nitric oxide synthase-derived superoxide production, increased endothelial nitric oxide synthase dimerization, and aortic HSP90 upregulation. MR genomic and nongenomic functions were activated in aortas from isoproterenol-treated rats. Isoproterenol did not modify plasma levels of MR ligands aldosterone and corticosterone but rather increased perivascular adipose tissue-derived corticosterone in association with increased expression of 11ß-hydroxysteroid dehydrogenase type 1. The anticontractile effect of aortic perivascular adipose tissue was impaired by ß-AR overstimulation and restored by MR blockade. These results suggest that activation of vascular MR signaling contributes to the vascular dysfunction induced by ß-AR overstimulation associated with endothelial nitric oxide synthase uncoupling. These findings reveal an additional explanation for the protective effects of MR antagonists in cardiovascular disorders with sympathetic activation.

Observation of Dispersive Shock Waves, Solitons, and Their Interactions in Viscous Fluid Conduits.

Dispersive shock waves and solitons are fundamental nonlinear excitations in dispersive media, but dispersive shock wave studies to date have been severely constrained. Here, we report on a novel dispersive hydrodynamic test bed: the effectively frictionless dynamics of interfacial waves between two high viscosity contrast, miscible, low Reynolds number Stokes fluids. This scenario is realized by injecting from below a lighter, viscous fluid into a column filled with high viscosity fluid. The injected fluid forms a deformable pipe whose diameter is proportional to the injection rate, enabling precise control over the generation of symmetric interfacial waves. Buoyancy drives nonlinear interfacial self-steepening, while normal stresses give rise to the dispersion of interfacial waves. Extremely slow mass diffusion and mass conservation imply that the interfacial waves are effectively dissipationless. This enables high fidelity observations of large amplitude dispersive shock waves in this spatially extended system, found to agree quantitatively with a nonlinear wave averaging theory. Furthermore, several highly coherent phenomena are investigated including dispersive shock wave backflow, the refraction or absorption of solitons by dispersive shock waves, and the multiphase merging of two dispersive shock waves. The complex, coherent, nonlinear mixing of dispersive shock waves and solitons observed here are universal features of dissipationless, dispersive hydrodynamic flows.

Cardiovascular effects of Sp-CTx, a cytolysin from the scorpionfish (Scorpaena plumieri) venom.

Fish venom cytolysins are multifunctional proteins that in addition to their cytolytic/hemolytic effects display neurotoxic, cardiotoxic and inflammatory activities, being described as "protein lethal factors". A pore-forming cytolysin called Sp-CTx (Scorpaena plumieriCytolytic Toxin) has been recently purified from the venom of the scorpionfish Scorpaena plumieri. It is a glycoprotein with dimeric constitution, comprising subunits of approximately 65 kDa. Previous studies have revealed that this toxin has a vasorelaxant activity that appears to involve the L-arginine-nitric oxide synthase pathway; however its cardiovascular effects have not been fully comprehended. The present study examined the cardiovascular effects of Sp-CTx in vivo and in vitro. In anesthetized rats Sp-CTx (70 µg/kg i.v) produced a biphasic response which consisted of an initial systolic and diastolic pressure increase followed by a sustained decrease of these parameters and the heart rate. In isolated rats hearts Sp-CTx (10(-9) to 5 × 10(-6) M) produced concentration-dependent and transient ventricular positive inotropic effect and vasoconstriction response on coronary bed. In papillary muscle, Sp-CTx (10(-7) M) also produced an increase in contractile isometric force, which was attenuated by the catecholamine releasing agent tyramine (100 µM) and the ß-adrenergic antagonist propranolol (10 µM). On isolated ventricular cardiomyocytes Sp-CTx (1 nM) increased the L-type Ca(2+) current density. The results show that Sp-CTx induces disorders in the cardiovascular system through increase of sarcolemmal calcium influx, which in turn is partially caused by the release of endogenous noradrenaline.