Antagonistic Responses Research Articles

Response Systems, Antagonistic Responses, and the Behavioral Repertoire.

While response systems are often mentioned in the behavioral and physiological literature, an explicit discussion of what response systems are is lacking. Here we argue that response systems can be understood as an interaction between anatomically constrained behavioral topographies occasioned by currently present stimuli and a history of reinforcement. “New” response systems can develop during the lifetime as the organism gains instrumental control of new fine-grained topographies. Within this framework, antagonistic responses compete within each response system based on environmental stimulation, and competition is resolved at the striatum-thalamo-cortical loops level. While response systems can be by definition independent from one another, separate systems are often recruited at the same time to engage in complex responses, which themselves may be selected by reinforcement as functional units.

Abstract P023: Achieving synergism in combination chemotherapy for gastric cancer treatment

Abstract Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of deaths from cancer. Although the combination of conventional chemotherapeutics with molecular targeted agents targeting tumor-specific biomarkers has increased the treatment efficacy in certain types of cancer such as breast cancer, similar success could not be achieved in GC treatment. Therefore, there is an urgent need for combination protocols that can increase the therapeutic success in GC therapy. Synergism is the most important requirement for the success of drug combinations in cancer therapy. Besides the choice of anti-cancer agents included in combination protocols, the order of application and the time interval between drug applications, are important determinants of synergism. In this study, we aim to test whether sequential application of conventional chemotherapeutic-molecular targeted agent pairs can transform antagonistic response into synergistic response in GC. To achieve the goals of this study, we have screened dual combinations of five different chemotherapeutics from anthracyclins, platinium derivatives, taxanes, fluoropyrimidines and topoisomerase inhibitors, and three different molecular-targeted agents targeting EGFR, mTOR or c-Met in four different GC cell models to identify synergistic and antagonistic drug pairs. The most antagonistic drug pairs are selected to test whether sequential application schedules can transform antagonism into synergism for these drug pairs. Drug pairs that display strongest synergism in concomitant applications are also further analyzed in detail to investigate their potential in GC treatment. The degree of synergism is measured with Chou-Talalay Method, and apoptosis, autophagy and cell cycle responses were investigated to identify possible molecular mechanisms of synergism. Our data shows that sequential application schedules can transform antagonism into synergism. We believe that the treatment schedules that will be defined in this study can increase the success of chemotherapeutic-molecular targeted agent combinations in GC. Citation Format: Ozen Leylek, Gulnihal Ozcan. Achieving synergism in combination chemotherapy for gastric cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P023.

Interactions among Escovopsis, Antagonistic Microfungi Associated with the Fungus-Growing Ant Symbiosis

Fungi in the genus Escovopsis (Ascomycota: Hypocreales) are prevalent associates of the complex symbiosis between fungus-growing ants (Tribe Attini), the ants’ cultivated basidiomycete fungi and a consortium of both beneficial and harmful microbes found within the ants’ garden communities. Some Escovopsis spp. have been shown to attack the ants’ cultivated fungi, and co-infections by multiple Escovopsis spp. are common in gardens in nature. Yet, little is known about how Escovopsis strains impact each other. Since microbe–microbe interactions play a central role in microbial ecology and evolution, we conducted experiments to assay the types of interactions that govern Escovopsis–Escovopsis relationships. We isolated Escovopsis strains from the gardens of 10 attine ant genera representing basal (lower) and derived groups in the attine ant phylogeny. We conducted in vitro experiments to determine the outcome of both intraclonal and interclonal Escovopsis confrontations. When paired with self (intraclonal interactions), Escovopsis isolated from lower attine colonies exhibited antagonistic (inhibitory) responses, while strains isolated from derived attine colonies exhibited neutral or mutualistic interactions, leading to a clear phylogenetic pattern of interaction outcome. Interclonal interactions were more varied, exhibiting less phylogenetic signal. These results can serve as the basis for future studies on the costs and benefits of Escovopsis coinfection, and on the genetic and chemical mechanisms that regulate the compatibility and incompatibility observed here.

A size and space structured model of tumor growth describes a key role for protumor immune cells in breaking equilibrium states in tumorigenesis.

Switching from the healthy stage to the uncontrolled development of tumors relies on complicated mechanisms and the activation of antagonistic immune responses, that can ultimately favor the tumor growth. We introduce here a mathematical model intended to describe the interactions between the immune system and tumors. The model is based on partial differential equations, describing the displacement of immune cells subjected to both diffusion and chemotactic mechanisms, the strength of which is driven by the development of the tumors. The model takes into account the dual nature of the immune response, with the activation of both antitumor and protumor mechanisms. The competition between these antagonistic effects leads to either equilibrium or escape phases, which reproduces features of tumor development observed in experimental and clinical settings. Next, we consider on numerical grounds the efficacy of treatments: the numerical study brings out interesting hints on immunotherapy strategies, concerning the role of the administered dose, the role of the administration time and the interest in combining treatments acting on different aspects of the immune response. Such mathematical model can shed light on the conditions where the tumor can be maintained in a viable state and also provide useful hints for personalized, efficient, therapeutic strategies, boosting the antitumor immune response, and reducing the protumor actions.

Characterization of a new type of neuronal 5-HT G- protein coupled receptor in the cestode nervous system.

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected diseases. Neurotransmitter signaling is of critical importance for these parasites which lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode motility, development and reproduction. In previous work, we deorphanized a group of 5-HT7 type GPCRs from cestodes. However, little is known about another type of 5-HT GPCR, the 5-HT1 clade, which has been studied in several invertebrate phyla but not in platyhelminthes. Three putative 5-HT GPCRs from Echinococcus canadensis, Mesocestoides vogae (syn. M. corti) and Hymenolepis microstoma were cloned, sequenced and bioinformatically analyzed. Evidence grouped these new sequences within the 5-HT1 clade of GPCRs but differences in highly conserved GPCR motifs were observed. Transcriptomic analysis, heterologous expression and immunolocalization studies were performed to characterize the E. canadensis receptor, called Eca-5-HT1a. Functional heterologous expression studies showed that Eca-5-HT1a is highly specific for serotonin. 5-Methoxytryptamine and α-methylserotonin, both known 5-HT GPCR agonists, give stimulatory responses whereas methysergide, a known 5-HT GPCR ligand, give an antagonist response in Eca-5-HT1a. Mutants obtained by the substitution of key predicted residues resulted in severe impairment of receptor activity, confirming that indeed, these residues have important roles in receptor function. Immunolocalization studies on the protoscolex stage from E. canadensis, showed that Eca-5-HT1a is localized in branched fibers which correspond to the nervous system of the parasite. The patterns of immunoreactive fibers for Eca-5-HT1a and for serotonin were intimately intertwined but not identical, suggesting that they are two separate groups of fibers. These data provide the first functional, pharmacological and localization report of a serotonergic receptor that putatively belongs to the 5-HT1 type of GPCRs in cestodes. The serotonergic GPCR characterized here may represent a new target for antiparasitic intervention.

Wheat transcriptome profiling reveals abscisic and gibberellic acid treatments regulate early-stage phytohormone defense signaling, cell wall fortification, and metabolic switches following Fusarium graminearum-challenge

BackgroundTreatment of wheat with the phytohormones abscisic acid (ABA) and gibberellic acid (GA) has been shown to affect Fusarium head blight (FHB) disease severity. However, the molecular mechanisms underlying the elicited phenotypes remain unclear. Toward addressing this gap in our knowledge, global transcriptomic profiling was applied to the FHB-susceptible wheat cultivar ‘Fielder’ to map the regulatory responses effected upon treatment with ABA, an ABA receptor antagonist (AS6), or GA in the presence or absence of Fusarium graminearum (Fg) challenge.ResultsSpike treatments resulted in a total of 30,876 differentially expressed genes (DEGs) identified in ‘Fielder’ (26,004) and the Fg (4872) pathogen. Topology overlap and correlation analyses defined 9689 wheat DEGs as Fg-related across the treatments. Further enrichment analyses demonstrated that these included expression changes within ‘Fielder’ defense responses, cell structural metabolism, molecular transport, and membrane/lipid metabolism. Dysregulation of ABA and GA crosstalk arising from repression of ‘Fielder’ FUS3 was noted. As well, expression of a putative Fg ABA-biosynthetic cytochrome P450 was detected. The co-applied condition of Fg + ABA elicited further up-regulation of phytohormone biosynthesis, as well as SA and ET signaling pathways and cell wall/polyphenolic metabolism. In contrast, co-applied Fg + GA mainly suppressed phytohormone biosynthesis and signaling, while modulating primary and secondary metabolism and flowering. Unexpectedly, co-applied Fg + AS6 did not affect ABA biosynthesis or signaling, but rather elicited antagonistic responses tied to stress, phytohormone transport, and FHB disease-related genes.ConclusionsObserved exacerbation (misregulation) of classical defense mechanisms and cell wall fortifications upon ABA treatment are consistent with its ability to promote FHB severity and its proposed role as a fungal effector. In contrast, GA was found to modulate primary and secondary metabolism, suggesting a general metabolic shift underlying its reduction in FHB severity. While AS6 did not antagonize traditional ABA pathways, its impact on host defense and Fg responses imply potential for future investigation. Overall, by comparing these findings to those previously reported for four additional plant genotypes, an additive model of the wheat-Fg interaction is proposed in the context of phytohormone responses.

Acaricidal activity of Shirazian thyme and rosemary methanolic extracts in combination with spirodiclofen and propargite on Tetranychus urticae (Acari: Tetranychidae)

The two-spotted spider mite, Tetranychus urticae Koch is one of the polyphagous pests that attack a wide range of crops. In recent decades, excessive application of synthetic acaricides has led to its resistance to pesticides and environmental pollution. However, considering the importance of the role of pesticides in controlling plant pests, it is impossible to cease using these compounds. In recent decades, new methods such as the use of plant extracts have been proposed that not only control pests but also have no residues and harmful environmental effects. Also, the use of plant extracts in combination with synthetic pesticides while controlling the pest, reduces the amount of pesticide usage. In this study, the efficacy of methanolic extracts of Zataria multiflora and Rosmarinus officinalis was investigated individually and in combination with spirodiclofen and propargite to control two-spotted spider mites. Bioassay tests were performed using the leaf dipping method. Each treatment was performed in three independent biological replications and the mortality was recorded 24 h after exposure. The 50% lethal dose (LC50) of spirodiclofen and propargite as well as methanolic extracts of Z. multiflora and R. officinalis were estimated to 1.89, 12.76, 1934.13, and 4382.07 mg/l, respectively. In addition, results of experiments related to mixing plant extracts with acaricides showed that the combination of Z. multiflora extract with spirodiclofen and propargite caused a synergistic effect with a co-toxicity coefficient of 66.66 and 55.55, respectively. However, the combination of R. officinalis extract with spirodiclofen and propargite caused an antagonistic response with −77.78 and −80.56, respectively.

Sub-lethal effects of soil multiple contamination on the avoidance behaviour of Eisenia fetida

Natural ecosystems are frequently exposed to complex mixtures of different chemicals. However, the environmental risk assessment is mainly based on data from individual substances. In this study, the individual and combined effects on the terrestrial earthworm E. fetida exposed to the anionic surfactant sodium lauryl ether sulphate (SLES) and the pesticides chlorpyrifos (CPF) and imidacloprid (IMI) were investigated, by using the avoidance behaviour as endpoint. Earthworms were exposed to a soil artificially contaminated with five sub-lethal concentrations of each contaminant, both as single substances and in combination of binary and ternary mixtures. Overall results showed that IMI provoked the highest avoidance effect on earthworms, with a concentration value that induced an avoidance rate of 50% of treated organisms (AC50) of 1.30 mg/kg, followed by CPF (AC50 75.26 mg/kg) and SLES (AC50 139.67 mg/kg). The application of the Combination Index (CI) method, indicated that a deviation from the additive response occurred for most of the tested chemical mixtures, leading to synergistic or antagonistic avoidance responses. Synergistic effects were produced by the exposure to the two lowest concentrations of the CPF+IMI mixture, and by the highest concentrations of SLES+CPF and SLES+CPF+IMI mixtures. On the contrary, antagonistic effects were observed at the lowest concentrations of the binary mixtures containing the SLES and at almost all the tested concentrations of the SLES+CPF+IMI mixture (with the exception of the highest tested concentration). These results show that the avoidance test is suitable to assess the detrimental effects exerted on earthworms by chemical mixtures in soil ecosystems and the use of behavioural endpoints can increase the ecological significance of environmental risk assessment procedures.

Hormonal crosstalk in regulating salinity stress tolerance in graminaceous crops.

Soil salinity is one of the major threats that pose challenges to global cereal productivity and food security. Cereals have evolved sophisticated mechanisms to circumvent stress at morpho-physiological, biochemical, and molecular levels. Salt stress cues are perceived by the roots, which trigger the underlying signaling pathways that involve phytohormones. Each phytohormone triggers a specific signaling pathway integrated in a complex manner to produce antagonistic, synergistic, and additive responses. Phytohormones induce salt-responsive signaling pathways to modulate various physiological and anatomical mechanisms, including cell wall repair, apoplastic pH regulation, ion homeostasis, root hair formation, chlorophyll content, and leaf morphology. Exogenous applications of phytohormones moderate the adverse effects of salinity and improve growth. Understanding the complex hormonal crosstalk in cereals under salt stress will advance the knowledge about cooperation or antagonistic mechanisms among hormones and their role in developing salt-tolerant cereals to enhance the productivity of saline agricultural land. In this context, the present review focuses on the mechanisms of hormonal crosstalk that mediate the salt stress response and adaptation in graminaceous crops.

Leaf size modulation by cytokinins in sesame plants

Phytohormones play important roles in controlling leaf size and in the modulation of various stress responses, including drought. In this study, hormone profiling analyses by ultra high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (UHPLC-MS/MS) was performed in leaves collected at three stages of active leaf growth to unravel which phytohormones modulate leaf size in sesame (Sesamum indicum L.) plants, an important oil-rich crop. Furthermore, endogenous contents of phytohormones were measured in parallel to various stress markers in sesame plants exposed to mild water deficit conditions by withholding water in potted plants for one week. Results revealed a major role of cytokinins and auxin in the modulation of leaf growth in sesame plants (which increased by 21.5 and 2.1-fold, respectively, with leaf growth), as well as a putative antagonistic response between jasmonic acid and salicylic acid during leaf development. Furthermore, growth arrest during water deficit stress appeared to be modulated by cytokinins, the endogenous contents of which decreased (by 48%) in parallel with ABA increases (by 59%). Reductions in the contents of the active cytokinin trans-zeatin occurred in parallel with increases in isopentenyladenine contents under drought, which suggests a partial metabolic limitation in cytokinin biosynthesis in leaves upon water deficit stress. These results provide useful information for the hormonal modulation of leaf size and the improvement of leaf growth and production in sesame plants through manipulation of the levels of key regulatory phytohormones.

Trinseo and ETB Global to create biobased 1,3-butadiene for green tyres

Air pollution is considered as a major public health issue worldwide. It consists of a complex mixture of pollutants including nanoparticles to which we are increasingly exposed to due to the dramatic development of the nanotechnologies and their incidental or intentional release in the environment. Consequently, some concerns have raised about the combined toxicity of air particulates and other air pollutants on human health. However, the interactions between the contaminants and their resulting combined toxicity are often overlooked. Indeed, the biological effects triggered by nanoparticles are usually assessed focusing on individual nanoparticles, while their interaction with co-contaminants can deeply impact, either positively or negatively, their biodistribution, fate in the organism and toxicological profile (additive, synergistic or antagonistic responses). This paper presents a bibliographic review on the combined toxicity of nanoparticles and co-pollutants and discusses the underlying mechanisms. It also highlights the scarcity of data in the current literature, arguing for an urgent need to take into account the mixture effects to be more representative of real-life conditions for a better and accurate human health risk assessment and management.

Assessing Aerated Vermicompost Tea Combined with Microbial Biological Control Agents for Suppression of Fusarium and Rhizoctonia.

Biological control of plant diseases is important in organic greenhouse vegetable production, where fungicide use is limited. Organic producers use microbially diverse substrates, including composts, as media for plant growth. Previous research into the impact of vermicompost on the efficacy of applied biocontrol agents is limited. An invitro assay was developed to test the efficacy of two biological control agents in a competitive microbial background. Suppression of the pathogen Fusarium oxysporum f. sp. radicis-cucumerinum by Clonostachys rosea f. catenulata (Gliocladium catenulatum strain J1446 [Prestop]) and Bacillus subtilis strain QST 713 (Rhapsody), was assessed on agar media amended with aerated vermicompost tea (ACT). Pathogen growth was reduced more by C. rosea than ACT alone, and C. rosea was equally effective when combined with ACT. In contrast, B. subtilis reduced pathogen growth less than ACT and, when combined, reduced pathogen growth no more than ACT alone. Both biocontrol agents were similarly tested with ACT against F. oxysporum f. sp. radicis-cucumerinum and Rhizoctonia solani on cucumber and radish. Additive, neutral, and antagonistic responses, depending on host, pathogen, and biocontrol agent, were observed. ACT alone provided more consistent disease suppression on cucumber compared with B. subtilis or C. rosea. In combination, disease suppression was most often better than each biocontrol alone but not better than ACT alone. ACT had antagonistic or additive interactions with C. rosea in the radish/R. solani pathosystem, depending on the experiment. The specific and general suppression of plant diseases by biological control agents in microbially rich environments is variable and warrants further study.

Osmotic stress and vesiculation as key mechanisms controlling bacterial sensitivity and resistance to TiO2 nanoparticles

Toxicity mechanisms of metal oxide nanoparticles towards bacteria and underlying roles of membrane composition are still debated. Herein, the response of lipopolysaccharide-truncated Escherichia coli K12 mutants to TiO2 nanoparticles (TiO2NPs, exposure in dark) is addressed at the molecular, single cell, and population levels by transcriptomics, fluorescence assays, cell nanomechanics and electrohydrodynamics. We show that outer core-free lipopolysaccharides featuring intact inner core increase cell sensitivity to TiO2NPs. TiO2NPs operate as membrane strippers, which induce osmotic stress, inactivate cell osmoregulation and initiate lipid peroxidation, which ultimately leads to genesis of membrane vesicles. In itself, truncation of lipopolysaccharide inner core triggers membrane permeabilization/depolarization, lipid peroxidation and hypervesiculation. In turn, it favors the regulation of TiO2NP-mediated changes in cell Turgor stress and leads to efficient vesicle-facilitated release of damaged membrane components. Remarkably, vesicles further act as electrostatic baits for TiO2NPs, thereby mitigating TiO2NPs toxicity. Altogether, we highlight antagonistic lipopolysaccharide-dependent bacterial responses to nanoparticles and we show that the destabilized membrane can generate unexpected resistance phenotype.

Neutrophils: fast and furious-the nucleotide pathway.

Nucleotide signaling is a key element of the neutrophil activation pathway. Neutrophil recruitment and migration to injured tissues is guided by purinergic receptor sensitization, mostly induced by extracellular adenosine triphosphate (ATP) and its hydrolysis product, adenosine (ADO), which is primarily produced by the CD39-CD73 axis located at the neutrophil cell surface. In inflammation unrelated to cancer, neutrophil activation via purinergic signaling aims to eliminate antigens and promote an immune response with minimal damage to healthy tissues; however, an antagonistic response may be expected in tumors. Indeed, alterations in purinergic signaling favor the accumulation of extracellular ATP and ADO in the microenvironment of solid tumors, which promote tumor progression by inducing cell proliferation, angiogenesis, and escape from immune surveillance. Since neutrophils and their N1/N2 polarization spectrum are being considered new components of cancer-related inflammation, the participation of purinergic signaling in pro-tumor activities of neutrophils should also be considered. However, there is a lack of studies investigating purinergic signaling in human neutrophil polarization and in tumor-associated neutrophils. In this review, we discussed the human neutrophil response elicited by nucleotides in inflammation and extrapolated its behavior in the context of cancer. Understanding these mechanisms in cancerous conditions may help to identify new biological targets and therapeutic strategies, particularly regarding tumors that are refractory to traditional chemo- and immunotherapy.

Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge.

Diverse organic compounds, many derived from consumer products, are found in sewage sludge worldwide. Understanding which of these poses the most significant environmental threat following land application can be investigated through a variety of predictive and cell-based toxicological techniques. Nontargeted analysis using high-resolution mass spectrometry with predictive estrogenic activity modeling was performed on sewage sludge samples from 12 wastewater treatment plants in California. Diisobutyl phthalate and dextrorphan were predicted to exhibit estrogenic activity and identified in >75% of sludge samples, signifying their universal presence and persistence. Additionally, the application of an estrogen-responsive cell bioassay revealed reductions in agonistic activity during mesophilic and thermophilic treatment but significant increases in antagonism during thermophilic treatment, which warrants further research. Ten nontarget features were identified (metoprolol, fenofibric acid, erythrohydrobupropion, oleic acid, mestranol, 4'-chlorobiphenyl-2,3-diol, medrysone, scillarenin, sudan I, and N,O-didesmethyltramadol) in treatment set samples and are considered to have influenced the in vitro estrogenic activity observed. The combination of predictive and in vitro estrogenicity with nontargeted analysis has led to confirmation of 12 estrogen-active contaminants in California sewage sludge and has highlighted the importance of evaluating both agonistic and antagonistic responses when evaluating the bioactivity of complex samples.

Democratising South African universities: From activism to advocacy

The segregation enforced during apartheid has not only ensured widely disparate South African university landscapes, but also framed constructions of activism in historical discourses of racial disenfranchisement and marginalisation. As a result, activism is implicitly and explicitly associated with disadvantaged universities; with black students; and specifically directed at an apartheid government. If there were expectations – certainly on the side of government – that the transition to a democratic state would allay student activism, this was not the case. Instead, student activism – still manifested in a critical mass of black students – has not only intensified but has degenerated into disturbing displays of destruction and violence. The recent spate of student protests, which centred on matters of access, free education and decolonisation, and more recently, gender-based violence, has provoked defensive, and at times, antagonistic and discouraging responses from universities – placing students firmly in an opposing discourse. Seemingly, while the political climate has shifted, universities have yet to reconceptualise their institutional, academic and spatial environments into contexts conducive to open and mutual deliberation. Current impressions from university responses suggest that activism, as symbolised through student protests, is out of place in democratic spaces. In considering the relational positioning of universities to activism and, hence, to students, the interest of this article resides, firstly, in how notions of activism might be reimagined within democratic contexts and, secondly, in how universities might reposition themselves from being sites of activism, to being advocates of social, economic and ethical reform.

Synergistic, antagonistic, and additive effects of heavy metals (copper and cadmium) and polycyclic aromatic hydrocarbons (PAHs) under binary and tertiary combinations in key habitat-forming kelp species of Chile.

Heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) are persistent toxicants in coastal environments. Notably, in comparison to individual metal toxicity, knowledge about the effects of HMs and PAHs mixtures on kelps remains scarce. Accordingly, we performed in vitro experiments to determine the individual and combined effects of Cu, Cd, and PAHs on spore release, settlement, and germination on Macrocystis pyrifera and Lessonia spicata, two key-habitat forming kelp species of the coast of the Valparaíso Region in Chile. This region concentrates highly polluting industries, mainly due to unrestrained mining and fossil-fuel energy production. Single Cu, Cd, and PAHs treatments included concentrations in the ranges 5-200, 0.125-2000, and 0.05-100 μg/L, respectively, and a toxic-free treatment. Cu, Cd, and PAHs concentrations causing 20-50% (IC20, IC50) arrested spore release, settlement, and germination were determined, and the results shown in both species that single Cu, Cd, and PAHs IC20 values were generally lower on spore release than on spore settlement and germination, probably due to the absence of a cell wall in spores compared to later stages. Binary equitoxic IC20s mixture treatments changed from an antagonistic response to another with a greater inhibitory effect on spore release, from hour 1 to 7, whereas in IC50 treatments, the response was always antagonistic. The tertiary IC20 mixture of Cu+Cd+PAHs produced generally an antagonistic effect. Remarkably, all IC20 equitoxic mixture treatments showed a synergistic response on spore settlement in both kelps, suggesting that these toxicants are extremely harmful to kelp population persistence near highly polluted sites.

Cytokine Profile in Children with Severe Multisystem Inflammatory Syndrome Related to the Coronavirus Disease 2019.

The multisystem inflammatory syndrome in children (MIS-C) is a novel and concerning entity related to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Although MIS-C has been the subject of intensive research efforts, its pathophysiology and optimal treatment remain elusive. We studied the clinical features, laboratory findings, and immunoinflammatory profiles of seven children prospectively admitted to a pediatric intensive care unit (PICU) during the first wave of the pandemic. All patients had immunoglobulin (Ig)-G against SARS-CoV-2, four of seven patients had both IgM and IgG, and in one of the 7 SARS-CoV-2 was detected in a respiratory sample. All patients received intravenous fluid boluses (median: 15 mL/kg) and norepinephrine. The most common form of respiratory support was supplemental oxygen via nasal cannula. None of the patients needed mechanical ventilation. The cardiovascular system was frequently involved. All patients had an elevated troponin-I (median: 107.3 ng/L). Four out of seven patients had coronary artery abnormalities, and two of seven had both abnormal electrocardiogram (EKG) findings and evidence of left ventricular dysfunction on echocardiogram. Ig levels and complement function were normal. Peripheral blood phenotyping with flow cytometry showed decreased T-cell numbers at the expense of CD8+ T-cells. Cytokine profiling showed a heterogeneous increase in interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-18, IL-2Ra, IL-10, and IL-1Ra that tended to normalize after treatment. Our study shows that children with MIS-C have elevated plasma levels of pro- and anti-inflammatory cytokines in the acute phase of the disease without other relevant immunologic disturbances. These findings suggest the presence of a mixed antagonist response syndrome (MARS) similar to that present in pediatric sepsis. Combining a meticulous differential diagnosis with cautiously coordinated immunomodulatory therapy and high-quality supportive care can help clinicians avoid causing iatrogenic harm in patients with MIS-C.

Anti-Cholinesterase Combination Drug Therapy as a Potential Treatment for Alzheimer's Disease.

Alzheimer’s disease (AD) is a burgeoning social and healthcare problem. Cholinesterase inhibitors (ChEIs) are employed for symptomatic treatment of AD, but often elicit adverse drug reactions (ADRs). Herein, the potency of the ChEIs, donepezil, tacrine, berberine, and galantamine to inhibit human or Torpedo californica acetylcholinesterase (tcAChE) proteins were evaluated. The efficacy of dual-drug combinations to inhibit human AChE directly and within differentiated neurons was also quantified. ChEI potency was in the order: donepezil > tacrine > berberine > galantamine for both AChEs. Dual-drug combinations of berberine and tacrine (BerTac), berberine and galantamine (BerGal), and tacrine and donepezil (TacDon) all produced synergistic outcomes for AChE inhibition. Donepezil and berberine (DonBer) and tacrine and galantamine (TacGal) elicited antagonistic responses. Donepezil and galantamine (DonGal) was synergistic for human AChE but antagonistic for tcAChE. After application of dual-drug combinations to neuronal cells, BerTac, BerGal, DonGal, and DonBer all showed synergistic inhibition of AChE, TacDon additive, and TacGal antagonistic effects. BerGal produced the most potent synergism and reduced total drug dose by 72%. Individual ChEIs or dual-drug combinations were relatively non-toxic to neuronal cells, and only reduced cell viability at concentrations two–three orders of magnitude greater than that required to inhibit AChE. In summary, dual-drug combinations of ChEIs potentially represent a novel means of AD patient treatment, with reduced and more cost-effective drug dosing, and lowered likelihood of ADRs.

Endocrine Disruptors Acting on Estrogen and Androgen Pathways Cause Reproductive Disorders through Multiple Mechanisms: A Review.

Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERβ) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.