Microglia phagocytic mechanisms: Development informing disease.

Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.

Kir6.2-K ATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis.

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (K ATP ) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal K ATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K ATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. Highlights: Glycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. With Kir6.2-K ATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. Kir6.2-K ATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions.

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration.

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.

Maternal Caffeine Consumption and Its Impact on the Fetus: A Review.

Maintaining a healthy diet is essential for pregnant women and their developing fetuses, including being mindful of caffeine consumption. While consuming caffeine during pregnancy is generally safe, there is a concern among healthcare practitioners about whether it can adversely impact pregnancy. There is a lack of accurate information about the effects of caffeine on fetal development and inadequate education on the risks of excessive caffeine intake during pregnancy. Therefore, to address this gap, our review provides an overview of the current literature on the impact of caffeine consumption during pregnancy on fetal development. We thoroughly searched databases, including PubMed and Clinicatrial.gov, from September 2022 to January 2023, focusing on relevant clinical studies with a level of clinical evidence II or higher. Our findings reveal that caffeine intake during pregnancy has notable effects on human fetal development. It increases fetal breathing and heart rates but can lead to reduced growth and a lower birth weight. Although it does not affect gestational length or cause hypertension, caffeine increases uterine contractions, potentially resulting in spontaneous abortion. In some cases, it even contributes to the development of pre-eclampsia in the later stages of pregnancy. However, the data on the association between caffeine consumption and the risk of congenital disabilities remains inconclusive. Based on these findings, it is clear that more extensive research is needed to fully understand the impact of caffeine consumption on the development of congenital disabilities in infants born to caffeine-consuming pregnant women. Furthermore, gaining a deeper understanding of how caffeine affects fetal development and pregnancy mechanisms is crucial.

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

Correspondence measures for assessing replication success.

Given recent evidence challenging the replicability of results in the social and behavioral sciences, critical questions have been raised about appropriate measures for determining replication success in comparing effect estimates across studies. At issue is the fact that conclusions about replication success often depend on the measure used for evaluating correspondence in results. Despite the importance of choosing an appropriate measure, there is still no widespread agreement about which measures should be used. This article addresses these questions by describing formally the most commonly used measures for assessing replication success, and by comparing their performance in different contexts according to their replication probabilities-that is, the probability of obtaining replication success given study-specific settings. The measures may be characterized broadly as conclusion-based approaches, which assess the congruence of two independent studies' conclusions about the presence of an effect, and distance-based approaches, which test for a significant difference or equivalence of two effect estimates. We also introduce a new measure for assessing replication success called the correspondence test, which combines a difference and equivalence test in the same framework. To help researchers plan prospective replication efforts, we provide closed formulas for power calculations that can be used to determine the minimum detectable effect size (and thus, sample sizes) for each study so that a predetermined minimum replication probability can be achieved. Finally, we use a replication data set from the Open Science Collaboration (2015) to demonstrate the extent to which conclusions about replication success depend on the correspondence measure selected. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology.

The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.

Factors Predicting the Extent to which STEM Students Value Cross-Disciplinary Skills: A Study across Four Institutions.

Expectancy-value theory of motivation (EVT) suggests that student values influence their likelihood of putting in the effort required to learn, and these values can be shaped by student characteristics, such as their experiences, sociodemographics, and disciplinary norms. To understand the extent to which these characteristics relate to students' values, we surveyed 1162 graduating science, technology, engineering, and mathematics (STEM) students across four universities using the previously developed and validated Survey of Teaching Beliefs and Practices for Undergraduates (STEP-U). The STEP-U survey included Likert questions to capture students' values of 27 cross-disciplinary skills and the frequency with which they experienced 27 instructional methods thought to develop particular skills. Exploratory factor analyses (EFA) showed an understandable factor structure for both students' perceived value of cross-disciplinary skills and frequency of classroom experiences. Using multiple regression, we identified differences in values that were associated with classroom experiences, STEM discipline, participation in undergraduate research, and student sociodemographics. Findings were generalizable across institutions and disciplines. The theoretical framework (EVT), the broad data collection (four institutions with multiple disciplines), and the type of data analyses (e.g., EFA) used provide theoretical, methodological, and practical contributions and suggest additional directions for future research.

Deuterium-enriched water ties planet-forming disks to comets and protostars.

Water is a fundamental molecule in the star and planet formation process, essential for catalysing the growth of solid material and the formation of planetesimals within disks1,2. However, the water snowline and the HDO:H2O ratio within proto-planetary disks have not been well characterized because water only sublimates at roughly 160 K (ref. 3), meaning that most water is frozen out onto dust grains and that the water snowline radii are less than 10 AU (astronomical units)4,5. The sun-like protostar V883 Ori (M* = 1.3 M⊙)6 is undergoing an accretion burst7, increasing its luminosity to roughly 200 L⊙ (ref. 8), and previous observations suggested that its water snowline is 40-120 AU in radius6,9,10. Here we report the direct detection of gas phase water (HDO and [Formula: see text]) from the disk of V883 Ori. We measure a midplane water snowline radius of approximately 80 AU, comparable to the scale of the Kuiper Belt, and detect water out to a radius of roughly 160 AU. We then measure the HDO:H2O ratio of the disk to be (2.26 ± 0.63) × 10-3. This ratio is comparable to those of protostellar envelopes and comets, and exceeds that of Earth's oceans by 3.1σ. We conclude that disks directly inherit water from the star-forming cloud and this water becomes incorporated into large icy bodies, such as comets, without substantial chemical alteration.

The construct of cuteness: A validity study for measuring content and evoked emotions on social media.

Social media users are often exposed to cute content that evokes emotional reactions and influences them to feel or behave certain ways. The cuteness phenomenon in social media has been scarcely studied despite its prevalence and potential to spread quickly and affect large audiences. The main framework for understanding cuteness and emotions related to cuteness outside of social media is baby schema (having juvenile characteristics), which triggers parental instincts. We propose that baby schema is a necessary but not sufficient component of explaining what constitutes cuteness and how people react to it in the social media context. Cute social media content may also have characteristics that evoke approach motivations (a desire to interact with an entity, generally with the expectation of having a positive experience) that can manifest behaviorally in sharing and other prosocial online behaviors. We developed and performed initial validation for measures in social media contexts of: (1) cute attributes that encompass both baby schema and other proposed cuteness characteristics (the Cuteness Attributes Taxonomy, CAT) and (2) the emotional reactions they trigger (Heartwarming Social Media, HSM). We used the Kama Muta Multiplex Scale (KAMMUS Two), as previously validated measure of kama muta (an emotion akin to tenderness; from Sanskrit, "moved by love") as a measure of emotional reaction to cute stimuli and the dimension Cute Content of the Social Media Emotions Annotation Guide (SMEmo-Cute Content) as a developed measure of gestalt cute content to help validate our newly developed measures. Using 1,875 Polish tweets, our results confirmed that cute social media content predicted a kama muta response, but not all KAMMUS Two subscales were sensitive to cute content, and that the HSM measure was a better indicator of the presence of cute content. Further, the CAT measure is an effective means of categorizing cute attributes of social media content. These results suggest potential differences between in-person, online, and social media experiences evoking cute emotional reactions, and the need for metrics that are developed and validated for use in social media contexts.

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients.

Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.

Monitored and Modeled Ambient Air Concentrations of Ethylene Oxide: Contextualizing Health Risk for Potentially Exposed Populations in Georgia.

Recent studies have monitored and modeled long-term ambient air concentrations of ethylene oxide (EO) around emitting facilities in Georgia with the intent of informing risk management of potentially exposed nearby residential populations. Providing health context for these data is challenging because the U.S. Environmental Protection Agency's risk-specific concentrations lack practical utility in distinguishing a health significant increase in exposure. This study analyzes EO data for eight emitting facilities, using a previously published alternative exposure metric, the total equivalent concentration, which is based on U.S. Centers for Disease Control biomarker data for the non-smoking U.S. POPULATION: Mean concentrations for monitoring sites were compared to mean background concentrations to assess whether emissions contribute significantly to environmental concentrations. To assess the health significance of potential exposure at nearby residential locations, the 50th percentile concentration was added to the 50th percentile endogenous equivalent concentration and compared to the total equivalent concentration distribution for the non-smoking U.S. POPULATION: The findings demonstrate that impacts from nearby emission sources are small compared to mean background concentrations at nearby locations, and the total equivalent concentrations for exposed populations are generally indistinguishable from that of the 50th percentile for the non-smoking U.S.

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.

BACKGROUND: Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer's disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. METHODS: We evaluated whether the brain's response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1-21 mice, a model of AD-related ß-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. RESULTS: Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1-21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. CONCLUSIONS: Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.

Ethylene Oxide Exposure in U.S. Populations Residing Near Sterilization and Other Industrial Facilities: Context Based on Endogenous and Total Equivalent Concentration Exposures.

Given ubiquitous human exposure to ethylene oxide (EO), regardless of occupation or geography, the current risk-specific concentrations (RSCs: 0.0001-0.01 ppb) from the U.S. Environmental Protection Agency (EPA) cancer risk assessment for EO are not useful metrics for managing EO exposures to the general U.S. population. The magnitude of the RSCs for EO are so low, relative to typical endogenous equivalent metabolic concentrations (1.1-5.5 ppb) that contribute ~93% of total exposure, that the RSCs provide little utility in identifying excess environmental exposures that might increase cancer risk. EO monitoring data collected in the vicinity of eight EO-emitting facilities and corresponding background locations were used to characterize potential excess exogenous concentrations. Both 50th and 90th percentile exogenous exposure concentrations were combined with the 50th percentile endogenous exposure concentration for the nonsmoking population, and then compared to percentiles of total equivalent concentration for this population. No potential total exposure concentration for these local populations exceeded the normal total equivalent concentration 95th percentile, indicating that excess facility-related exposures are unlikely to require additional management to protect public health.

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice.

Cerebral malaria (CM) is the deadliest form of severe Plasmodium infections. Currently, we have limited understanding of the mechanisms by which Plasmodium parasites induce CM. The mouse model of CM, experimental CM (ECM), induced by infection with the rodent parasite, Plasmodium berghei ANKA (PbANKA) has been extensively used to study the pathophysiology of CM. Recent genomic analyses revealed that the coding regions of PbANKA and the closely related Plasmodium berghei NK65 (PbNK65), that does not cause ECM, differ in only 21 single nucleotide polymorphysims (SNPs). Thus, the SNP-containing genes might contribute to the pathogenesis of ECM. Although the majority of these SNPs are located in genes of unknown function, one SNP is located in the DNA binding site of a member of the Plasmodium ApiAP2 transcription factor family, that we recently showed functions as a virulence factor alternating the host's immune response to the parasite. Here, we investigated the impact of this SNP on the development of ECM. Our results using CRISPR-Cas9 engineered parasites indicate that despite its immune modulatory function, the SNP is neither necessary nor sufficient to induce ECM and thus cannot account for parasite strain-specific differences in ECM phenotypes.

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer's Disease: Where Do We Stand?

Circadian dysfunction has been described in patients with symptomatic Alzheimer's disease (AD), as well as in presymptomatic phases of the disease. Modeling this circadian dysfunction in mouse models would provide an optimal platform for understanding mechanisms and developing therapies. While numerous studies have examined behavioral circadian function, and in some cases clock gene oscillation, in mouse models of AD, the results are variable and inconsistent across models, ages, and conditions. Ultimately, circadian changes observed in APP/PS1 models are inconsistent across studies and do not always replicate circadian phenotypes observed in human AD. Other models, including the 3xTG mouse, tau transgenic lines, and the accelerated aging SAMP8 line, show circadian phenotypes more consistent with human AD, although the literature is either inconsistent or minimal. We summarize these data and provide some recommendations to improve and standardize future studies of circadian function in AD mouse models.

A single-nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor alters the development of host immunity.

The acquisition of malaria immunity is both remarkably slow and unpredictable. At present, we know little about the malaria parasite genes that influence the host's ability to mount a protective immune response. Here, we show that a single-nucleotide polymorphism (SNP) resulting in a single amino acid change (S to F) in an ApiAP2 transcription factor in the rodent malaria parasite Plasmodium berghei (Pb) NK65 allowed infected mice to mount a T helper cell 1 (TH1)-type immune response that controlled subsequent infections. As compared to PbNK65S, PbNK65F parasites differentially expressed 46 genes, most of which are predicted to play roles in immune evasion. PbNK65F infections resulted in an early interferon-γ response and a later expansion of germinal centers, resulting in high levels of infected red blood cell-specific TH1-type immunoglobulin G2b (IgG2b) and IgG2c antibodies. Thus, the Pb ApiAP2 transcription factor functions as a critical parasite virulence factor in malaria infections.