Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.

STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome.

While originally identified as an antiviral pathway, recent work has implicated that cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling is playing a critical role in the neuroinflammatory response to traumatic brain injury (TBI). STING activation results in a robust inflammatory response characterized by the production of inflammatory cytokines called interferons, as well as hundreds of interferon stimulated genes (ISGs). Global knock-out (KO) mice inhibiting this pathway display neuroprotection with evidence that this pathway is active days after injury; yet, the early neuroinflammatory events stimulated by STING signaling remain understudied. Furthermore, the source of STING signaling during brain injury is unknown. Using a murine controlled cortical impact (CCI) model of TBI, we investigated the peripheral immune and microglial response to injury utilizing male chimeric and conditional STING KO animals, respectively. We demonstrate that peripheral and microglial STING signaling contribute to negative outcomes in cortical lesion volume, cell death, and functional outcomes postinjury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 h. Transcriptomic analysis at 2 h, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-ß (IL-1ß), which is lost in conditional knock-out mice. The upregulation of alternative innate immune pathways also occurs after injury in these animals, which supports a complex relationship between brain-resident and peripheral immune cells to coordinate the proinflammatory response and immune cell influx to damaged tissue after injury.

Design Strategies for Luminescent Titanocenes: Improving the Photoluminescence and Photostability of Arylethynyltitanocenes.

Complexes that undergo ligand-to-metal charge transfer (LMCT) to d0 metals are of interest as possible photocatalysts. Cp2Ti(C2Ph)2 (where C2Ph = phenylethynyl) was reported to be weakly emissive in room-temperature (RT) fluid solution from its phenylethynyl-to-Ti 3LMCT state but readily photodecomposes. Coordination of CuX between the alkyne ligands to give Cp2Ti(C2Ph)2CuX (X = Cl, Br) has been shown to significantly increase the photostability, but such complexes are not emissive in RT solution. Herein, we investigate whether inhibition of alkyne-Ti-alkyne bond compression might be responsible for the increased photostability of the CuX complexes by investigating the decomposition of a structurally constrained analogue, Cp2Ti(OBET) (OBET = o-bis(ethynyl)tolane). To investigate the mechanism of nonradiative decay from the 3LMCT states in Cp2Ti(C2Ph)2CuX, the photophysical properties were investigated both upon deuteration and upon rigidifying in a poly(methyl methacrylate) film. These investigations suggested that inhibition of structural rearrangement may play a dominant role in increasing emission lifetimes and quantum yields. The bulkier Cp*2Ti(C2Ph)2CuBr was prepared and is emissive at 693 nm in RT THF solution with a photoluminescent quantum yield of 1.3 × 10-3 (τ = 0.18 µs). Time-dependent density functional theory (TDDFT) calculations suggest that emission occurs from a 3LMCT state dominated by Cp*-to-Ti charge transfer.

Activating hidden signals by mimicking cryptic sites in a synthetic extracellular matrix.

Cryptic sites are short signaling peptides buried within the native extracellular matrix (ECM). Enzymatic cleavage of an ECM protein reveals these hidden peptide sequences, which interact with surface receptors to control cell behavior. Materials that mimic this dynamic interplay between cells and their surroundings via cryptic sites could enable application of this endogenous signaling phenomenon in synthetic ECM hydrogels. We demonstrate that depsipeptides ("switch peptides") can undergo enzyme-triggered changes in their primary sequence, with proof-of-principle studies showing how trypsin-triggered primary sequence rearrangement forms the bioadhesive pentapeptide YIGSR. We then engineered cryptic site-mimetic synthetic ECM hydrogels that experienced a cell-initiated gain of bioactivity. Responding to the endothelial cell surface enzyme aminopeptidase N, the inert matrix transformed into an adhesive synthetic ECM capable of supporting endothelial cell growth. This modular system enables dynamic reciprocity in synthetic ECMs, reproducing the natural symbiosis between cells and their matrix through inclusion of tunable hidden signals.

The role of political devotion in sharing partisan misinformation and resistance to fact-checking.

Online misinformation is disproportionality created and spread by people with extreme political attitudes, especially among the far-right. There is a debate in the literature about why people spread misinformation and what should be done about it. According to the purely cognitive account, people largely spread misinformation because they are lazy, not biased. According to a motivational account, people are also motivated to believe and spread misinformation for ideological and partisan reasons. To better understand the psychological and neurocognitive processes that underlie misinformation sharing among the far-right, we conducted a cross-cultural experiment with conservatives and far-right partisans in the Unites States and Spain (N = 1,609) and a neuroimaging study with far-right partisans in Spain (N = 36). Far-right partisans in Spain and U.S. Republicans who highly identify with Trump were more likely to share misinformation than center-right voters and other Republicans, especially when the misinformation was related to sacred values (e.g., immigration). Sacred values predicted misinformation sharing above and beyond familiarity, attitude strength, and salience of the issue. Moreover, far-right partisans were unresponsive to fact-checking and accuracy nudges. At a neural level, this group showed increased activity in brain regions implicated in mentalizing and norm compliance in response to posts with sacred values. These results suggest that the two components of political devotion-identity fusion and sacred values-play a key role in misinformation sharing, highlighting the identity-affirming dimension of misinformation sharing. We discuss the need for motivational and identity-based interventions to help curb misinformation for high-risk partisan groups. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy.

BACKGROUND: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus-a structure that is highly susceptible to injury-has been implicated in the evolution of seizure development. METHODS: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis. RESULTS: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. CONCLUSIONS: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

Risk perception and conspiracy theory endorsement predict compliance with COVID-19 public health measures.

Public health measures such as spatial distancing and physical hygiene have been found effective in mitigating the spread of the coronavirus. However, there is considerable variability in individual compliance with such public health measures and factors contributing to these interindividual differences are currently still understudied. The present study set out to determine the role of risk perception and conspiracy theory endorsement on compliance with COVID-19 public health measures and explored variations in these associations across participant age and the developmental status of a country, leveraging a large multi-national data set (N = 45,772) across 66 countries/territories, collected via online survey during the early phase of the COVID-19 pandemic (between April and May 2020). Human Development Index (HDI), developed by the United Nations Development Program, was used as a proxy of a country's achievement in key dimensions of human development. Overall, higher risk perception was associated with greater compliance, particularly in individuals with greater conspiracy theory endorsement. Specifically, people from more developed countries who perceived themselves less at risk but showed stronger conspiracy theory endorsement reported the lowest compliance with COVID-19 public health measures. Findings from this study advance understanding of the interplay between risk perception and conspiracy theory endorsement in their effect on compliance with COVID-19 public health measures, under consideration of both individual-level and country-level demographic variables and have potential to inform the design of tailored interventions to fight the current and future global pandemics.

How social identity shapes conspiratorial belief.

While conspiracy theories may offer benefits to those who believe in them, they can also foster intergroup conflict, threaten democracy, and undercut public health. We argue that the motivations behind conspiracy theory belief are often related to social identity. Conspiracy theories are well-positioned to fulfill social identity needs such as belongingness goals, the need to think highly of one's in-group, and the need to feel secure in one's group status. Understanding the social motives that attract people to conspiracy theories should be a focus of future research, and may be key to creating more successful interventions to reduce socially harmful conspiracy theories.

The role of generalizability in moral and political psychology.

The aim of the social and behavioral sciences is to understand human behavior across a wide array of contexts. Our theories often make sweeping claims about human nature, assuming that our ancestors or offspring will be prone to the same biases and preferences. Yet we gloss over the fact that our research is often based in a single temporal context with a limited set of stimuli. Political and moral psychology are domains in which the context and stimuli are likely to matter a great deal (Van Bavel, Mende-Siedlecki, Brady, & Reinero, 2016). In response to Yarkoni (see BBS issue), we delve into topics related to political and moral psychology that likely depend on features of the research. These topics include understanding differences between liberals and conservatives, when people are willing to sacrifice someone to save others, the behavior of political leaders, and the dynamics of intergroup conflict.

A multi-national test on self-reported compliance with COVID-19 public health measures: The role of individual age and gender demographics and countries' developmental status.

RATIONALE/OBJECTIVE: The COVID-19 pandemic has brought far-reaching consequences on individual and societal levels. Social distancing and physical hygiene constitute effective public health measures to limit the spread of the virus. This study investigated age and gender demographics, in tandem with national levels of human development, as crucial factors influencing self-reported compliance with COVID-19-related public health measures. METHODS: The present study leveraged a large multi-national sample that ranged across the adult lifespan (18-100 years) and comprised 45,772 women and men from 66 countries/territories. Data were collected in Spring (2020) during the earlier phase of the COVID-19 pandemic. Self-reports of compliance with two public health measures (spatial distancing and physical hygiene) were assessed via online survey. Human Development Index (HDI), developed by the United Nations Development Program, was used as a proxy of a country's achievement in key dimensions of human development. RESULTS: Older age, female gender, and lower HDI were independently associated with greater self-reported compliance. A significant three-way interaction further revealed that self-reported compliance was lowest in young males from well-developed countries, while highest among females across all ages from less-developed countries. CONCLUSION: The study offers an integration of individual-level and country-level demographic predictors of self-reported compliance and allows for robust testing in a large multi-national adult lifespan sample for enhanced generalizability. The results highlight the potential of data-driven, tailored (i.e., towards specific demographics, countries) health campaigns and public policies in the fight against a global pandemic.

Preregistered Replication of "Feeling Superior Is a Bipartisan Issue: Extremity (Not Direction) of Political Views Predicts Perceived Belief Superiority".

There is currently a debate in political psychology about whether dogmatism and belief superiority are symmetric or asymmetric across the ideological spectrum. Toner, Leary, Asher, and Jongman-Sereno (2013) found that dogmatism was higher among conservatives than liberals, but both conservatives and liberals with extreme attitudes reported higher perceived superiority of beliefs. In the current study, we conducted a preregistered direct and conceptual replication of this previous research using a large nationally representative sample. Consistent with Toner et al.'s findings, our results showed that conservatives had higher dogmatism scores than liberals, whereas both conservative and liberal extreme attitudes were associated with higher belief superiority compared with more moderate attitudes. As in their study, we also found that whether conservative or liberal attitudes were associated with higher belief superiority was topic dependent. Contrasting Toner et al.'s findings, our results also showed that ideologically extreme individuals had higher dogmatism. We discuss implications of these results for theoretical debates in political psychology.

Cardiac Arrhythmia Following an Epileptic Seizure.

Sudden unexplained death in epilepsy (SUDEP) refers to a death in a patient with epilepsy that is not due to trauma, drowning, status epilepticus, or another apparent cause. Although the pathophysiology of SUDEP is incompletely understood, growing evidence supports the role of seizure-associated arrhythmias as a potential etiology. We present a unique case of a patient presenting with ventricular tachycardia shortly following a seizure, along with corresponding laboratory data. Awareness of high risk arrhythmias in seizure patients could lead to advances in understanding pathophysiology and treatment of this complication of seizure disorder and ultimately prevention of SUDEP.

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer's Disease.

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer's disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aß), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aß production, Aß clearance, and hyperphosphorylation of tau proteins. Aß itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aß is produced as an AMP in response to HSV-1 and other brain infections, leading to Aß deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

A Simple Model to Identify Risk of Sarcopenia and Physical Disability in HIV-Infected Patients.

Farinatti, P, Paes, L, Harris, EA, Lopes, GO, and Borges, JP. A simple model to identify risk of sarcopenia and physical disability in HIV-infected patients. J Strength Cond Res 31(9): 2542-2551, 2017-Early detection of sarcopenia might help preventing muscle loss and disability in HIV-infected patients. This study proposed a model for estimating appendicular skeletal muscle mass (ASM) to calculate indices to identify "sarcopenia" (SA) and "risk for disability due to sarcopenia" (RSA) in patients with HIV. An equation to estimate ASM was developed in 56 patients (47.2 ± 6.9 years), with a cross-validation sample of 24 patients (48.1 ± 6.6 years). The model validity was determined by calculating, in both samples: (a) Concordance between actual vs. estimated ASM; (b) Correlations between actual/estimated ASM vs. peak torque (PT) and total work (TW) during isokinetic knee extension/flexion; (c) Agreement of patients classified with SA and RSA. The predictive equation was ASM (kg) = 7.77 (sex; F = 0/M = 1) + 0.26 (arm circumference; cm) + 0.38 (thigh circumference; cm) + 0.03 (Body Mass Index; kg·m) - 8.94 (R = 0.74; Radj = 0.72; SEE = 3.13 kg). Agreement between actual vs. estimated ASM was confirmed in validation (t = 0.081/p = 0.94; R = 0.86/p < 0.0001) and cross-validation (t = 0.12/p = 0.92; R = 0.87/p < 0.0001) samples. Regression characteristics in cross-validation sample (Radj = 0.80; SEE = 3.65) and PRESS (RPRESS = 0.69; SEEPRESS = 3.35) were compatible with the original model. Percent agreements for the classification of SA and RSA from indices calculated using actual and estimated ASM were of 87.5% and 77.2% (gamma correlations 0.72-1.0; p < 0.04) in validation, and 95.8% and 75.0% (gamma correlations 0.98-0.97; p < 0.001) in cross-validation sample, respectively. Correlations between actual/estimated ASM vs. PT (range 0.50-0.73, p ≤ 0.05) and TW (range 0.59-0.74, p ≤ 0.05) were similar in both samples. In conclusion, our model correctly estimated ASM to determine indices for identifying SA and RSA in HIV-infected patients.

Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer's Disease.

This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer's disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-ß (Aß) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aß damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials.

Experiences of Veterans With Diabetes From Shared Medical Appointments.

Camaraderie and shared narratives, coupled with clinical guidance, may help motivate veterans to better manage their diabetes.

Epithelial cell tumors of the hen reproductive tract.

There is a paucity of preclinical models that simulate the development of ovarian tumors in humans. At present, the egg-laying hen appears to be the most promising model to study the spontaneous occurrence of ovarian tumors in the clinical setting. Although gross classification and histologic grade of tumors have been used prognostically in women with ovarian tumors, there is currently no single system that is universally used to classify reproductive tumors in the hen. Four hundred and one 192-wk-old egg-laying hens were necropsied to determine the incidence of reproductive tumors using both gross pathology and histologic classification. Gross pathologic classifications were designated as follows: birds presenting with ovarian tumors only (class 1), those presenting with oviductal and ovarian tumors (class 2), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract (class 3), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract and other distant organs (class 4), those with oviductal tumors only (class 5), those with oviductal tumors that metastasized to other organs with no ovarian involvement (class 6), and those with ovarian tumors that metastasized to other organs with no oviductal involvement (class 7), including birds with gastrointestinal tumors and no reproductive involvement (GI only) and those with no tumors (normal). Histopathologic classifications range from grades 1 to 3 and are based on mitotic developments and cellular differentiation. An updated gross pathology and histologic classification systems for the hen reproductive malignancies provides a method to report the range of reproductive tumors revealed in a flock of aged laying hens.

Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice.

It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.