Pediatric COVID-19 Involving Complicated Sinusitis With Intracranial Extension and Lemierre Syndrome: A Case Report.

Pediatric coronavirus disease 2019 (COVID-19) has been associated with various complications including chronic respiratory disease and multisystem inflammatory syndrome. There are a few reported cases of complicated sinusitis following pediatric COVID-19 infection. We present a patient with recent COVID-19 who developed complicated sinusitis with intracranial extension and Lemierre syndrome. A 16-year-old female with a history of COVID-19 diagnosis 17 days prior presented with worsening head and neck symptoms. Physical examination demonstrated left proptosis, cranial nerve (CN) VI palsy, and limited neck range of motion. Imaging demonstrated bilateral sinus disease, a 3.3 × 2 × 3-centimeter sellar/clival abscess, bilateral cavernous sinus thrombosis, and thrombosis of bilateral internal jugular veins. Urgent endoscopic sinus surgery was performed, and long-term intravenous antibiotics and anticoagulation were initiated with improvement in symptoms over three weeks. Providers caring for patients with COVID-19 should keep complicated sinusitis and Lemierre syndrome in their differential. Further study of COVID-19 pathophysiology in the sinonasal mucosa is needed.

Variants in AQP11 may result in autosomal recessive bilateral cystic renal dysgenesis.

Congenital renal cystic dysplasia is a rare disease that occurs in approximately 1 in 4000 children and is often discovered in the antenatal period by ultrasound. It is commonly associated with oligohydramnios in utero and/or renal insufficiency or failure in the postnatal period. Aquaporins are membrane proteins that serve as transport channels in the transfer of water or small solutes across cell membranes. They play a role in the development of renal cysts. Aquaporin 11 (AQP11) deficient mice develop polycystic kidney disease in utero due to disruption of polycystin-1. Here we describe a case of bilateral cystic kidney disease in a patient with novel compound heterozygous variants in AQP11: c.780G>T (p. Trp260Cys) and c.472C>T (p.Pro158Ser) (NM_173039.2) identified by whole genome sequencing. These findings suggest, for the first time, the potential role of AQP11 in congenital renal cystic dysplasia.

Redox regulation of motile cilia in airway disease.

Motile cilia on airway cells are necessary for clearance of mucus-trapped particles out of the lung. Ciliated airway epithelial cells are uniquely exposed to oxidants through trapping of particles, debris and pathogens in mucus and the direct exposure to inhaled oxidant gases. Dynein ATPases, the motors driving ciliary motility, are sensitive to the local redox environment within each cilium. Several redox-sensitive cilia-localized proteins modulate dynein activity and include Protein Kinase A, Protein Kinase C, and Protein Phosphatase 1. Moreover, cilia are rich in known redox regulatory proteins and thioredoxin domain-containing proteins that are critical in maintaining a balanced redox environment. Importantly, a nonsense mutation in TXNDC3, which contains a thioredoxin motif, has recently been identified as disease-causing in Primary Ciliary Dyskinesia, a hereditary motile cilia disease resulting in impaired mucociliary clearance. Here we review current understanding of the role(s) oxidant species play in modifying airway ciliary function. We focus on oxidants generated in the airways, cilia redox targets that modulate ciliary beating and imbalances in redox state that impact health and disease. Finally, we review disease models such as smoking, asthma, alcohol drinking, and infections as well as the direct application of oxidants that implicate redox balance as a modulator of cilia motility.

Loss of cAMP-dependent stimulation of isolated cilia motility by alcohol exposure is oxidant-dependent.

Alcohol exposure is associated with decreased mucociliary clearance, a key innate defense essential to lung immunity. Previously, we identified that prolonged alcohol exposure results in dysfunction of airway cilia that persists at the organelle level. This dysfunction is characterized by a loss of 3',5'-cyclic adenosine monophosphate (cAMP)-mediated cilia stimulation. However, whether or not ciliary dysfunction develops intrinsically at the organelle level has not been explored. We hypothesized that prolonged alcohol exposure directly to isolated demembranated cilia (axonemes) causes ciliary dysfunction. To test this hypothesis, we exposed isolated axonemes to alcohol (100 mM) for 1-24 h and assessed ciliary beat frequency (CBF) in response to cAMP at 1, 3, 4, 6, and 24 h post-exposure. We found that after 1 h of alcohol exposure, cilia axonemes do not increase CBF in response to cAMP. Importantly, by 6 h after the initial exposure to alcohol, cAMP-mediated CBF was restored to control levels. Additionally, we found that thioredoxin reverses ciliary dysfunction in axonemes exposed to alcohol. Finally, we identified, using a combination of a xanthine oxidase oxidant-generating system, direct application of hydrogen peroxide, and electron paramagnetic resonance, that hydrogen peroxide versus superoxide, is likely the key oxidant species driving alcohol-induced ciliary dysfunction in isolated axonemes. These data highlight the role of alcohol to stimulate local production of oxidants in the axoneme to cause ciliary dysfunction. Additionally, these data specifically add hydrogen peroxide as a potential therapeutic target in the treatment or prevention of alcohol-associated ciliary dysfunction and subsequent pneumonia.

S-nitrosation of protein phosphatase 1 mediates alcohol-induced ciliary dysfunction.

Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to ß-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.

Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

On June 24, 2017, the 22nd annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Research Society on Alcoholism (RSA) Scientific Meeting in Denver, Colorado. The 2017 meeting focused broadly on mechanisms that link alcohol to tissue injury and inflammation, and how this research can be translated to improve human health. Two plenary sessions composed the meeting, which first explored the association between alcohol and trauma/tissue injury, and finished with a discussion of alcohol and mucosal inflammation. The presentations encompassed diverse areas of alcohol research, from effects on the brain, to airway and pulmonary systems, to gut barrier disruption. The discussions also thoughtfully highlighted how current laboratory and clinical research can be used to prevent or treat alcohol-related morbidity and mortality.

Alcohol drives S-nitrosylation and redox activation of protein phosphatase 1, causing bovine airway cilia dysfunction.

Individuals with alcohol (ethanol)-use disorders are at increased risk for lung infections, in part, due to defective mucociliary clearance driven by motile cilia in the airways. We recently reported that isolated, demembranated bovine cilia (axonemes) are capable of producing nitric oxide (∙NO) when exposed to biologically relevant concentrations of alcohol. This increased presence of ∙NO can lead to protein S-nitrosylation, a posttranslational modification signaling mechanism involving reversible adduction of nitrosonium cations or ∙NO to thiolate or thiyl radicals, respectively, of proteins forming S-nitrosothiols (SNOs). We quantified and compared SNO content between isolated, demembranated axonemes extracted from bovine tracheae, with or without in situ alcohol exposure (100 mM × 24 h). We demonstrate that relevant concentrations of alcohol exposure shift the S-nitrosylation status of key cilia regulatory proteins, including 20-fold increases in S-nitrosylation of proteins that include protein phosphatase 1 (PP1). With the use of an ATP-reactivated axoneme motility system, we demonstrate that alcohol-driven S-nitrosylation of PP1 is associated with PP1 activation and dysfunction of axoneme motility. These new data demonstrate that alcohol can shift the S-nitrothiol balance at the level of the cilia organelle and highlight S-nitrosylation as a novel signaling mechanism to regulate PP1 and cilia motility.

Bodily attractiveness and egalitarianism are negatively related in males.

Ancestrally, relatively attractive individuals and relatively formidable males may have had reduced incentives to be egalitarian (i.e., to act in accordance with norms promoting social equality). If selection calibrated one's egalitarianism to one's attractiveness/formidability, then such people may exhibit reduced egalitarianism ("observed egalitarianism") and be perceived by others as less egalitarian ("perceived egalitarianism") in modern environments. To investigate, we created 3D body models of 125 participants to use both as a source of anthropometric measurements and as stimuli to obtain ratings of bodily attractiveness and perceived egalitarianism. We also measured observed egalitarianism (via an economic "dictator" game) and indices of political egalitarianism (preference for socialism over capitalism) and "equity sensitivity." Results indicated higher egalitarianism levels in women than in men, and moderate-to-strong negative relationships between (a) attractiveness and observed egalitarianism among men, (b) attractiveness and perceived egalitarianism among both sexes, and (c) formidability and perceived egalitarianism among men. We did not find support for two previously-reported findings: that observed egalitarianism and formidability are negatively related in men, and that wealth and formidability interact to explain variance in male egalitarianism. However, this lack of support may have been due to differences in variable measurement between our study and previous studies.

Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction.

Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat, and kinase responsiveness and cilia-associated phosphorylation targets when stimulated by ß-agonist or cAMP. Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat and protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, inhibitor-2 (I-2), restoring cAMP-stimulated cilia beat and PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell, and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD.

Why is low waist-to-chest ratio attractive in males? The mediating roles of perceived dominance, fitness, and protection ability.

Past research suggests that a lower waist-to-chest ratio (WCR) in men (i.e., narrower waist and broader chest) is viewed as attractive by women. However, little work has directly examined why low WCRs are preferred. The current work merged insights from theory and past research to develop a model examining perceived dominance, fitness, and protection ability as mediators of to WCR-attractiveness relationship. These mediators and their link to both short-term (sexual) and long-term (relational) attractiveness were simultaneously tested by having 151 women rate one of 15 avatars, created from 3D body scans. Men with lower WCR were perceived as more physically dominant, physically fit, and better able to protect loved ones; these characteristics differentially mediated the effect of WCR on short-term, long-term, and general attractiveness ratings. Greater understanding of the judgments women form regarding WCR may yield insights into motivations by men to manipulate their body image.

Female economic dependence and the morality of promiscuity.

In environments in which female economic dependence on a male mate is higher, male parental investment is more essential. In such environments, therefore, both sexes should value paternity certainty more and thus object more to promiscuity (because promiscuity undermines paternity certainty). We tested this theory of anti-promiscuity morality in two studies (N = 656 and N = 4,626) using U.S. samples. In both, we examined whether opposition to promiscuity was higher among people who perceived greater female economic dependence in their social network. In Study 2, we also tested whether economic indicators of female economic dependence (e.g., female income, welfare availability) predicted anti-promiscuity morality at the state level. Results from both studies supported the proposed theory. At the individual level, perceived female economic dependence explained significant variance in anti-promiscuity morality, even after controlling for variance explained by age, sex, religiosity, political conservatism, and the anti-promiscuity views of geographical neighbors. At the state level, median female income was strongly negatively related to anti-promiscuity morality and this relationship was fully mediated by perceived female economic dependence. These results were consistent with the view that anti-promiscuity beliefs may function to promote paternity certainty in circumstances where male parental investment is particularly important.

The evolution of leader-follower reciprocity: the theory of service-for-prestige.

We describe the service-for-prestige theory of leadership, which proposes that voluntary leader-follower relations evolved in humans via a process of reciprocal exchange that generated adaptive benefits for both leaders and followers. We propose that although leader-follower relations first emerged in the human lineage to solve problems related to information sharing and social coordination, they ultimately evolved into exchange relationships whereby followers could compensate leaders for services which would otherwise have been prohibitively costly for leaders to provide. In this exchange, leaders incur costs to provide followers with public goods, and in return, followers incur costs to provide leaders with prestige (and associated fitness benefits). Because whole groups of followers tend to gain from leader-provided public goods, and because prestige is costly for followers to produce, the provisioning of prestige to leaders requires solutions to the "free rider" problem of disrespectful followers (who benefit from leader services without sharing the costs of producing prestige). Thus service-for-prestige makes the unique prediction that disrespectful followers of beneficial leaders will be targeted by other followers for punitive sentiment and/or social exclusion. Leader-follower relations should be more reciprocal and mutually beneficial when leaders and followers have more equal social bargaining power. However, as leaders gain more relative power, and their high status becomes less dependent on their willingness to pay the costs of benefitting followers, service-for-prestige predicts that leader-follower relations will become based more on leaders' ability to dominate and exploit rather than benefit followers. We review evidential support for a set of predictions made by service-for-prestige, and discuss how service-for-prestige relates to social neuroscience research on leadership.

Body shape preferences: associations with rater body shape and sociosexuality.

There is accumulating evidence of condition-dependent mate choice in many species, that is, individual preferences varying in strength according to the condition of the chooser. In humans, for example, people with more attractive faces/bodies, and who are higher in sociosexuality, exhibit stronger preferences for attractive traits in opposite-sex faces/bodies. However, previous studies have tended to use only relatively simple, isolated measures of rater attractiveness. Here we use 3D body scanning technology to examine associations between strength of rater preferences for attractive traits in opposite-sex bodies, and raters' body shape, self-perceived attractiveness, and sociosexuality. For 118 raters and 80 stimuli models, we used a 3D scanner to extract body measurements associated with attractiveness (male waist-chest ratio [WCR], female waist-hip ratio [WHR], and volume-height index [VHI] in both sexes) and also measured rater self-perceived attractiveness and sociosexuality. As expected, WHR and VHI were important predictors of female body attractiveness, while WCR and VHI were important predictors of male body attractiveness. Results indicated that male rater sociosexuality scores were positively associated with strength of preference for attractive (low) VHI and attractive (low) WHR in female bodies. Moreover, male rater self-perceived attractiveness was positively associated with strength of preference for low VHI in female bodies. The only evidence of condition-dependent preferences in females was a positive association between attractive VHI in female raters and preferences for attractive (low) WCR in male bodies. No other significant associations were observed in either sex between aspects of rater body shape and strength of preferences for attractive opposite-sex body traits. These results suggest that among male raters, rater self-perceived attractiveness and sociosexuality are important predictors of preference strength for attractive opposite-sex body shapes, and that rater body traits -with the exception of VHI in female raters- may not be good predictors of these preferences in either sex.

Revisiting "The evolution of reciprocity in sizable groups": continuous reciprocity in the repeated n-person prisoner's dilemma.

For many years in evolutionary science, the consensus view has been that while reciprocal altruism can evolve in dyadic interactions, it is unlikely to evolve in sizable groups. This view had been based on studies which have assumed cooperation to be discrete rather than continuous (i.e., individuals can either fully cooperate or else fully defect, but they cannot continuously vary their level of cooperation). In real world cooperation, however, cooperation is often continuous. In this paper, we re-examine the evolution of reciprocity in sizable groups by presenting a model of the n-person prisoner's dilemma that assumes continuous rather than discrete cooperation. This model shows that continuous reciprocity has a dramatically wider basin of attraction than discrete reciprocity, and that this basin's size increases with efficiency of cooperation (marginal per capita return). Further, we find that assortative interaction interacts synergistically with continuous reciprocity to a much greater extent than it does with discrete reciprocity. These results suggest that previous models may have underestimated reciprocity's adaptiveness in groups. However, we also find that the invasion of continuous reciprocators into a population of unconditional defectors becomes realistic only within a narrow parameter space in which the efficiency of cooperation is close to its maximum bound. Therefore our model suggests that continuous reciprocity can evolve in large groups more easily than discrete reciprocity only under unusual circumstances.

Fluctuating asymmetry and preferences for sex-typical bodily characteristics.

Body size and shape seem to have been sexually selected in a variety of species, including humans, but little is known about what attractive bodies signal about underlying genotypic or phenotypic quality. A widely used indicator of phenotypic quality in evolutionary analyses is degree of symmetry (i.e., fluctuating asymmetry, FA) because it is a marker of developmental stability, which is defined as an organism's ability to develop toward an adaptive end-point despite perturbations during its ontogeny. Here we sought to establish whether attractive bodies signal low FA to observers, and, if so, which aspects of attractive bodies are most predictive of lower FA. We used a 3D optical body scanner to measure FA and to isolate size and shape characteristics in a sample of 77 individuals (40 males and 37 females). From the 3D body scan data, 360 degrees videos were created that separated body shape from other aspects of visual appearance (e.g., skin color and facial features). These videos then were presented to 87 evaluators for attractiveness ratings. We found strong negative correlations between FA and bodily attractiveness in both sexes. Further, sex-typical body size and shape characteristics were rated as attractive and correlated negatively with FA. Finally, geometric morphometric analysis of joint configurations revealed that sex-typical joint configurations were associated with both perceived attractiveness and lower FA for male but not for female bodies. In sum, body size and shape seem to show evidence of sexual selection and indicate important information about the phenotypic quality of individuals.

Do human parents face a quantity-quality tradeoff?: evidence from a Shuar community.

A number of evolutionary theories of human life history assume a quantity-quality tradeoff for offspring production: parents with fewer offspring can have higher biological fitness than those with more. Direct evidence for such a tradeoff, however, is mixed. We tested this assumption in a community of Ecuadorian Shuar hunter-horticulturalists, using child anthropometry as a proxy for fitness. We measured the impact of household consumer/producer (CP) ratio on height, weight, skinfold thicknesses, and arm and calf circumferences of 85 children and young adults. To control for possible "phenotypic" correlates that might mask the effect of CP ratio on anthropometry, we also measured household garden productivity, wealth, and social status. Regression models of the age-standardized variables indicated a significant negative impact of CP ratio on child growth and nutrition. The age-standardized height and weight of children in households with the largest CP ratio (10) were 1.38 and 1.44 standard deviations, respectively, below those of children in households with the smallest CP ratio (2). Surprisingly, garden productivity, wealth, and status had little to no effect on the fitness proxies. There was, however, an interesting and unexpected interaction between status and sex: for females, but not males, higher father status correlated significantly with higher values on the proxies.

Cognitive Adaptations for n-person Exchange: The Evolutionary Roots of Organizational Behavior.

Organizations are composed of stable, predominantly cooperative interactions or n-person exchanges. Humans have been engaging in n-person exchanges for a great enough period of evolutionary time that we appear to have evolved a distinct constellation of species-typical mechanisms specialized to solve the adaptive problems posed by this form of social interaction. These mechanisms appear to have been evolutionarily elaborated out of the cognitive infrastructure that initially evolved for dyadic exchange. Key adaptive problems that these mechanisms are designed to solve include coordination among individuals, and defense against exploitation by free riders. Multi-individual cooperation could not have been maintained over evolutionary time if free riders reliably benefited more than contributors to collective enterprises, and so outcompeted them. As a result, humans evolved mechanisms that implement an aversion to exploitation by free riding, and a strategy of conditional cooperation, supplemented by punitive sentiment towards free riders. Because of the design of these mechanisms, how free riding is treated is a central determinant of the survival and health of cooperative organizations. The mapping of the evolved psychology of n-party exchange cooperation may contribute to the construction of a principled theoretical foundation for the understanding of human behavior in organizations.

Pro-community altruism and social status in a Shuar village.

Reciprocity theory (RT) and costly signaling theory (CST) provide different explanations for the high status of pro-community altruists: RT proposes that altruists are positively and negatively sanctioned by others, whereas CST proposes that altruists are attractive to others. Only RT, however, is beset by first- and higher-order free rider problems, which must be solved in order for RT to explain status allocations. In this paper, several solutions to RT's free rider problems are proposed, and data about status allocations to Ecuadorian Shuar pro-community altruists are analyzed in light of RT and CST. These data confirm that perceived pro-community altruists are indeed high status and suggest that (1) community residents skillfully monitor the altruism of coresidents, (2) residents who engage in opportunities to broadcast desirable qualities are high status only to the extent that they are considered altruistic, and (3) individuals who sanction coresidents based on coresidents' contributions to the community are themselves relatively high status. To a greater extent than CST, RT straightforwardly predicts all of these results.