APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.

Evidence for a selective link between cooperation and individual recognition.

The ability to recognize others is a frequent assumption of models of the evolution of cooperation. At the same time, cooperative behavior has been proposed as a selective agent favoring the evolution of individual recognition abilities. Although theory predicts that recognition and cooperation may co-evolve, data linking recognition abilities and cooperative behavior with evidence of selection are elusive. Here, we provide evidence of a selective link between individual recognition and cooperation in the paper wasp Polistes fuscatus through a combination of clinal, common garden, and population genomics analyses. We identified latitudinal clines in both rates of cooperative nesting and color pattern diversity, consistent with a selective link between recognition and cooperation. In behavioral experiments, we replicated previous results demonstrating individual recognition in cooperative and phenotypically diverse P. fuscatus from New York. In contrast, wasps from a less cooperative and phenotypically uniform Louisiana population showed no evidence of individual recognition. In a common garden experiment, groups of wasps from northern populations formed more stable and individually biased associations, indicating that recognition facilitates group stability. The strength of recent positive selection on cognition-associated loci likely to mediate individual recognition is substantially greater in northern compared with southern P. fuscatus populations. Collectively, these data suggest that individual recognition and cooperative nesting behavior have co-evolved in P. fuscatus because recognition helps stabilize social groups. This work provides evidence of a specific cognitive phenotype under selection because of social interactions, supporting the idea that social behavior can be a key driver of cognitive evolution.

Nucleocapsid protein accumulates in renal tubular epithelium of a post-COVID-19 patient.

IMPORTANCE: Even though the coronavirus disease 2019 (COVID-19) pandemic is slowly developing into a conventional infectious disease, the long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection are still not well understood. One of the problems is that many COVID-19 cases develop acute kidney injuries. Still, it is heavily debated whether SARS-CoV-2 virus enters and actively replicates in kidney tissue and if SARS-CoV-2 virus particles can be detected in kidney during or post-infection. Here, we demonstrated that nucleocapsid N protein was detected in kidney tubular epithelium of patients that already recovered form COVID-19. The presence of the abundantly produced N protein without signs of viral replication could have implications for the recurrence of kidney disease and have a continuing effect on the immune system.

Anionic nanoplastic contaminants promote Parkinson's disease-associated α-synuclein aggregation.

Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.

Anionic Nanoplastic Contaminants Promote Parkinson's Disease-Associated α-Synuclein Aggregation.

Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.

Familial Predictors of Alcohol and Drug Use-Related Problems Among Middle-Aged and Older Adults.

This study evaluated whether recent family member alcohol and substance use problems (ASP) and density of family ASP (i.e., number of members with ASP) predict alcohol-related problems and drug use-related problems among middle-aged and older adults. Data were drawn from participants (age 42-93 years, n=2,168) in the longitudinal Midlife in the United States Study (MIDUS). Poisson regression models revealed that adults' alcohol- and drug use-related problems were predicted by similar problems among family members. In particular, parent and partner ASP, but not child ASP, predicted alcohol-related problems in the middle-aged and combined samples, while only partner ASP predicted participants' drug use-related problems. In addition, density of family ASP predicted alcohol-related problems, but not drug use-related problems. There were no gender interactions. Study findings highlight that understanding how adult children, spouses, and aging parents impact each other's substance use should be a priority of future aging and family research.

Within-person associations between alcohol use and memory lapses among middle-aged and older adults.

INTRODUCTION: Alcohol use has been linked to impairment in both short- and long-term measures of objective memory. However, limited research has investigated the association between alcohol use and subjective memory in everyday life. The study purpose was to investigate within- and between-person associations between daily alcohol use and prospective (i.e., forgetting an intended task) and retrospective (i.e., forgetting something learned in the past) memory lapses among middle-aged and older adults. METHODS: Participants (n = 925; Mage = 55.2) were non-abstaining adults from the Midlife in the United States (MIDUS) study or the MIDUS Refresher who participated in an 8-day telephone diary asking about their daily experiences. RESULTS: Multilevel models revealed that within-individuals, heavier-than-usual alcohol use (i.e., having more drinks than one's daily average number of drinks) was associated with greater odds of reporting any memory lapses (odds ratio [OR] 1.06; 95% confidence interval [CI] 1.01, 1.12), while associations at the between-person level were nonsignificant (OR 1.07; 95% CI 0.99, 1.16). When assessing retrospective and prospective lapses separately, alcohol use was only associated with prospective lapses and only at the between-person level (OR 1.10; 95% CI 1.01, 1.19). Finally, alcohol use was unassociated with reported irritation or interference from memory lapses (p > 0.05). DISCUSSION AND CONCLUSIONS: Heavier-than-usual alcohol use may have acute effects on daily memory functioning. Future studies should assess how alcohol use relates to an individual's ability to meet daily cognitive demands, as these findings may have critical implications for harm reduction efforts targeting daily functioning among older adults.

Sex differences in deleterious genetic variants in a haplodiploid social insect.

Deleterious variants are selected against but can linger in populations at low frequencies for long periods of time, decreasing fitness and contributing to disease burden in humans and other species. Deleterious variants occur at low frequency but distinguishing deleterious variants from low-frequency neutral variation is challenging based on population genomics data alone. As a result, we have little sense of the number and identity of deleterious variants in wild populations. For haplodiploid species, it has been hypothesised that deleterious alleles will be directly exposed to selection in haploid males, but selection can be masked in diploid females when deleterious variants are recessive, resulting in more efficient purging of deleterious mutations in males. Therefore, comparisons of the differences between haploid and diploid genomes from the same population may be a useful method for inferring rare deleterious variants. This study provides the first formal test of this hypothesis. Using wild populations of Northern paper wasps (Polistes fuscatus), we find that males have fewer missense and nonsense variants per generation than females from the same population. Allele frequency differences are especially pronounced for rare missense and nonsense variants and these differences lead to a lower mutational load in males than females. Based on these data we infer that many highly deleterious mutations are segregating in the paper wasp population. Stronger selection against deleterious alleles in haploid males may have implications for adaptation in other haplodiploid insects and provides evidence that wild populations harbour abundant deleterious variants.

A latent profile analysis of blackout drinking behavior among young adults.

BACKGROUND: Blackout drinking, or alcohol-induced memory loss during a drinking occasion, is associated with additional negative alcohol-related outcomes. Brief motivational interventions targeting higher-risk alcohol use behavior have largely ignored blackout drinking. Including personalized information on blackout drinking could maximize intervention impact. To move toward incorporating content on blackout drinking in prevention and intervention materials, it is imperative to understand individual-level differences in blackout drinking. The current study aimed to identify latent profiles of young adults based on blackout drinking experiences and to examine person-level predictors and outcomes associated with profile membership. METHOD: Participants were 542 young adults (ages 18-30) who reported 1+ past-year blackout episodes. Fifty-three percent of participants were female and 64% identified as non-Hispanic/Latinx white. RESULTS: Four latent profiles were identified based on blackout drinking frequency, blackout intentions, blackout expectancies, and age of first blackout: Low-Risk Blackout (35% of the sample), Experimental Blackout (23%), At-Risk Blackout (16%), and High-Risk Blackout (26%). Profiles varied by demographic, personality, and cognition- and alcohol-related behaviors. Notably, At-Risk and High-Risk Blackout profiles had the highest alcohol use disorder risk, most memory lapses and cognitive concerns, and highest levels of impulsivity traits. CONCLUSIONS: Findings support the multifaceted nature of blackout drinking experiences and perceptions. Profiles were differentiated across person-level predictors and outcomes, which identify potential intervention targets and individuals at heightened alcohol-related risk. A more comprehensive understanding of the heterogeneity of blackout drinking characteristics may be useful for early detection and intervention of problematic alcohol use predictors and patterns among young adults.

Associations between blackout drinking and self-reported everyday cognition among young adults.

INTRODUCTION: Blackout drinking, or alcohol-induced memory loss during at least some part of a drinking occasion, is common among young adults and associated with negative alcohol-related consequences. One potential unique effect of blackout drinking episodes could be prolonged, general difficulties forming new memories through impairments in encoding, storage, or retrieval. The current study examined preliminary associations between blackout drinking and self-reported everyday cognitive functioning (i.e., memory lapses, non-memory cognitive difficulties, cognitive concerns) among a sample of young adults. We also examined the moderating role of key factors linked to blackout drinking: gender and frequent simultaneous alcohol and cannabis use. METHODS: Participants (N = 479; 53% women) were aged 18-30 who reported past-year blackout drinking. Participants completed an online survey through Qualtrics Panels. RESULTS: More frequent blackout experiences were found to be significantly related to more memory lapses, more non-memory cognitive difficulties, and more cognitive concerns even after controlling for typical alcohol use behavior. Men and individuals reporting frequent simultaneous use indicated stronger relationships between blackout drinking frequency and cognitive outcomes. DISCUSSION AND CONCLUSIONS: Findings add to the growing body of literature supporting the uniquely hazardous effects of blackout drinking and identify individuals at heightened risk of harms. Given that associations between blackout drinking frequency and everyday cognitive functioning were identified even among a young adult sample suggests that blackout drinking may be a risky behavior that links to poorer cognitive functioning.

Sense of control and likelihood of prescription drug misuse 10-years later among middle-aged and older adults.

Objectives: Sense of control (i.e. one's beliefs about their ability to influence life circumstances) has been linked to various psychological outcomes. However, it is unknown if sense of control is protective against prescription drug misuse (PDM). The present study sought to evaluate if sense of control is associated with reduced odds of PDM 9 to 10 years later among a sample of middle-aged and older adults.Methods: Data were evaluated from participants (M = 54 years, SD = 10.86; N = 2,108) of the second and third waves of the Midlife in the United States study. Logistic regression models were used to assess whether baseline sense of control (Wave 2) predicted odds of PDM 9 to 10 years later (Wave 3).Results: Findings revealed that greater sense of control at baseline was related to reduced odds of subsequent PDM (OR = 0.78; 95% CI: 0.64, 0.95), adjusting for baseline PDM, sociodemographic characteristics, health behaviors, psychological factors, number of prescription medications, and health. When assessing the subscales of sense of control separately, constraints (OR = 1.19; 95% CI: 1.00, 1.42), but not mastery (OR = 0.96; 95% CI: 0.80, 1.12), was predictive of odds of subsequent PDM. Further, being female was associated with greater odds of PDM (OR = 1.46; 95% CI: 1.02, 2.09), but did not moderate the association between sense of control and PDM.Conclusions: Sense of control may be a novel and viable target for interventions (e.g. using mobile phone apps) aimed at mitigating prescription drug misuse.

Impulsivity typologies and simultaneous alcohol and cannabis use.

Simultaneous use of alcohol and cannabis or marijuana ("SAM") use is prevalent among young adults and associated with adverse outcomes. Impulsivity is a key construct associated with alcohol and other substance use in this age group, but scant work has considered the role of individual facets of impulsivity on SAM use. The present study compared latent profiles defined by facets of impulsivity (negative urgency, lack of perseverance, lack of premeditation, sensation seeking, and positive urgency) and examined whether profiles were associated with recent SAM use relative to alcohol without cannabis use. Participants were 542 young adults (53% female) recruited through Qualtrics Panels who reported past-year alcohol use and blackout drinking behavior. Participants completed online questionnaires regarding their past-year substance use behavior and typical impulsivity. Regression analysis examining the five impulsivity facets revealed that only sensation seeking predicted the likelihood of recent SAM use relative to alcohol without cannabis use. Using latent profile analysis, four profiles were identified: "low impulsivity," "high sensation seeking/urgency impulsivity," "moderate impulsivity," and "high lack of premeditation/perseverance impulsivity." Individuals in the high sensation seeking/urgency group were more likely to engage in SAM use. Impulsivity may be an important individual difference factor associated with SAM use. Young adults who engage in SAM use may be particularly vulnerable for impulsivity related to sensation seeking and urgency, which may further heighten their risk for hazardous use and related outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Highly Contiguous Genome Assemblies of the Guinea Paper Wasp (Polistes exclamans) and Mischocyttarus mexicanus.

Paper wasps are a model system for the study of social evolution due to a high degree of inter- and intraspecific variation in cooperation, aggression, and visual signals of social status. Increasing the taxonomic coverage of genomic resources for this diverse clade will aid comparative genomic approaches for testing predictions about the molecular basis of social evolution. Here, we provide draft genome assemblies for two well-studied species of paper wasps, Polistes exclamans and Mischocyttarus mexicanus. The P. exclamans genome assembly is 221.5 Mb in length with a scaffold N50 of 4.11 Mb. The M. mexicanus genome assembly is 227 Mb in length with a scaffold N50 of 1.1 Mb. Genomes have low repeat content (9.54-10.75%) and low GC content (32.06-32.4%), typical of other social hymenopteran genomes. The DNA methyltransferase gene, Dnmt3 , was lost early in the evolution of Polistinae. We identified a second independent loss of Dnmt3 within hornets (genus: Vespa).

Rejuvenation of neutrophils and their extracellular vesicles is associated with enhanced aged fracture healing.

Tissue repair is negatively affected by advanced age. Recent evidence indicates that hematopoietic cell-derived extracellular vesicles (EVs) are modulators of regenerative capacity. Here, we report that plasma EVs carrying specific surface markers indicate the degree of age-associated immunosenescence; moreover, this immunosenescence phenotype was accentuated by fracture injury. The number of CD11b+ Ly6Cintermediate Ly6Ghigh neutrophils significantly decreased with age in association with defective tissue regeneration. In response to fracture injury, the frequencies of neutrophils and associated plasma EVs were significantly higher in fracture calluses than in peripheral blood. Exposure of aged mice to youthful circulation through heterochronic parabiosis increased the number of neutrophils and their correlated Ly6G+ plasma EVs, which were associated with improved fracture healing in aged mice of heterochronic parabiosis pairs. Our findings create a foundation for utilizing specific immune cells and EV subsets as potential biomarkers and therapeutic strategies to promote resilience to stressors during aging.

Detection and identification of coronaviruses in human tissues using electron microscopy.

The identification of viral particles within a tissue specimen requires specific knowledge of viral ultrastructure and replication, as well as a thorough familiarity with normal subcellular organelles. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has underscored how challenging the task of identifying coronavirus by electron microscopy (EM) can be. Numerous articles have been published mischaracterizing common subcellular structures, including clathrin- or coatomer- coated vesicles, multivesicular bodies, and rough endoplasmic reticulum, as coronavirus particles in SARS-CoV-2 positive patient tissue specimens. To counter these misinterpretations, we describe the morphological features of coronaviruses that should be used to differentiate coronavirus particles from subcellular structures. Further, as many of the misidentifications of coronavirus particles have stemmed from attempts to attribute tissue damage to direct infection by SARS-CoV-2, we review articles describing ultrastructural changes observed in specimens from SARS-CoV-2-infected individuals that do not necessarily provide EM evidence of direct viral infection. Ultrastructural changes have been observed in respiratory, cardiac, kidney, and intestinal tissues, highlighting the widespread effects that SARS-CoV-2 infection may have on the body, whether through direct viral infection or mediated by SARS-CoV-2 infection-induced inflammatory and immune processes. HIGHLIGHTS: The identification of coronavirus particles in SARS-CoV-2 positive tissues continues to be a challenging task. This review provides examples of coronavirus ultrastructure to aid in the differentiation of the virus from common cellular structures.

Lipid and Nucleocapsid N-Protein Accumulation in COVID-19 Patient Lung and Infected Cells.

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global outbreak and prompted an enormous research effort. Still, the subcellular localization of the coronavirus in lungs of COVID-19 patients is not well understood. Here, the localization of the SARS-CoV-2 proteins is studied in postmortem lung material of COVID-19 patients and in SARS-CoV-2-infected Vero cells, processed identically. Correlative light and electron microscopy on semithick cryo-sections demonstrated induction of electron-lucent, lipid-filled compartments after SARS-CoV-2 infection in both lung and cell cultures. In lung tissue, the nonstructural protein 4 and the stable nucleocapsid N-protein were detected on these novel lipid-filled compartments. The induction of such lipid-filled compartments and the localization of the viral proteins in lung of patients with fatal COVID-19 may explain the extensive inflammatory response and provide a new hallmark for SARS-CoV-2 infection at the final, fatal stage of infection. IMPORTANCE Visualization of the subcellular localization of SARS-CoV-2 proteins in lung patient material of COVID-19 patients is important for the understanding of this new virus. We detected viral proteins in the context of the ultrastructure of infected cells and tissues and discovered that some viral proteins accumulate in novel, lipid-filled compartments. These structures are induced in Vero cells but, more importantly, also in lung of patients with COVID-19. We have characterized these lipid-filled compartments and determined that this is a novel, virus-induced structure. Immunogold labeling demonstrated that cellular markers, such as CD63 and lipid droplet marker PLIN-2, are absent. Colocalization of lipid-filled compartments with the stable N-protein and nonstructural protein 4 in lung of the last stages of COVID-19 indicates that these compartments play a key role in the devastating immune response that SARS-CoV-2 infections provoke.

Within-person methodology to study the addiction recovery process of women.

Women are among the fastest growing populations of those with substance use disorders in the United States. Women face different social barriers than men in their access to treatment and recovery from these disorders. Differentially experienced barriers include greater child caregiving responsibilities, social sigma regarding motherhood and substance use, romantic partners who also use substances, experiences of violence and trauma, and, relatedly, symptoms of post-traumatic stress disorder. These barriers have been studied primarily by employing between-group approaches (e.g. comparing men and women) or between-persons approaches (e.g. cross-sectionally assessing the relationship between person-level PTSD symptoms and relapse). However, there are limited studies on women's gender-specific experiences in recovery with the aim of elucidating within-person effects. Employing within-person designs, such as daily diary or ecological momentary assessments, has many advantages. These advantages include reducing retrospective bias, assessing temporality of processes that occur on a short time scale, and analyzing processes that may occur when individuals deviate from their personally normative experiences. Studying women's experiences in recovery "as they are lived" will enable the development of interventions that are fine-tuned to the specific needs of each woman, and ultimately may help to reduce the suffering of women with substance use disorders.

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

SARS-CoV-2 Immunohistochemistry In Placenta.

Compared to the parental SARS-CoV-2 virus, infections by the now dominant Delta variant of SARS-CoV-2 appear to be more common and more severe in pregnant women. The need for a robust, cheap, and quick method for diagnosing placental infection by SARS-CoV-2 has thus become more acute. Here, we describe a highly sensitive and specific immunohistochemical assay for SARS-CoV-2 nucleocapsid protein for routine use in placental pathology practice.