APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Human Brainstem and Cerebellum Atlas: Chemoarchitecture and Cytoarchitecture Paired to MRI.

Lesion localization is the basis for understanding neurologic disease, which is predicated on neuroanatomical knowledge carefully cataloged from histology and imaging atlases. However, it is often difficult to correlate clinical images of brainstem injury obtained by MRI scans with the details of human brainstem neuroanatomy represented in atlases, which are mostly based on cytoarchitecture using Nissl stain or a single histochemical stain, and usually do not include the cerebellum. Here, we report a high-resolution (200 µm) 7T MRI of a cadaveric male human brainstem and cerebellum paired with detailed, coregistered histology (at 2 µm single-cell resolution) of the immunohistochemically stained cholinergic, serotonergic, and catecholaminergic (dopaminergic, noradrenergic, and adrenergic) neurons, in relationship to each other and to the cerebellum. These immunohistochemical findings provide novel insights into the spatial relationships of brainstem cell types and nuclei, including subpopulations of melanin and TH+ neurons, and allows for more informed structural annotation of cell groups. Moreover, the coregistered MRI-paired histology helps validate imaging findings. This is useful for interpreting both scans and histology, and to understand the cell types affected by lesions. Our detailed chemoarchitecture and cytoarchitecture with corresponding high-resolution MRI builds on previous atlases of the human brainstem and cerebellum, and makes precise identification of brainstem and cerebellar cell groups involved in clinical lesions accessible for both laboratory scientists and clinicians alike.SIGNIFICANCE STATEMENT Clinicians and neuroscientists frequently use cross-sectional anatomy of the human brainstem from MRI scans for both clinical and laboratory investigations, but they must rely on brain atlases to neuroanatomical structures. Such atlases generally lack both detail of brainstem chemical cell types, and the cerebellum, which provides an important spatial reference. Our current atlas maps the distribution of key brainstem cell types (cholinergic, serotonergic, and catecholaminergic neurons) in relationship to each other and the cerebellum, and pairs this histology with 7T MR images from the identical brain. This atlas allows correlation of the chemoarchitecture with corresponding MRI, and makes the identification of cell groups that are often discussed, but rarely identifiable on MRI scan, accessible to clinicians and clinical researchers.

Roles of mast cells and their interactions with the trigeminal nerve in migraine headache.

Migraine pain is characterized by an intense, throbbing pain in the head area and possesses complex pathological and physiological origins. Among the various factors believed to contribute to migraine are mast cells (MCs), resident tissue immune cells that are closely associated with pain afferents in the meninges. In this review, we aim to examine and discuss recent findings on the individual roles of MCs and the trigeminal nerve in migraine, as well as the various connections between their mechanisms with an emphasis on the contributions those relationships make to migraine. This is seen through MC release of histamine, among other compounds, and trigeminal nerve release of calcitonin-gene-related-peptide (CGRP) and pituitary adenylate cyclase activating peptide-38 (PACAP-38), which are peptides that are thought to contribute to migraine. Secondly, we illustrate the bi-directional relationship of neurogenic inflammation as well as highlight the role of MCs and their effect on the trigeminal nerve in migraine mechanisms. Lastly, we discuss potential new targets for clinical interventions of MC- and trigeminal nerve-mediated migraine, and present future perspectives of mechanistic and translational research.

Psychosocial Functioning of Parents of Youth Receiving Intensive Interdisciplinary Pain Treatment.

OBJECTIVE: Parents of youth with chronic pain report psychosocial difficulties, yet treatment often focuses on improving their child's functioning and pain. This study evaluated changes in parents' social and emotional functioning and explored predictors of change, as they completed a parent-focused intervention while their child was enrolled in an intensive interdisciplinary pain treatment (IIPT) program. METHODS: Parents (n = 69) completed questionnaires at baseline and weekly (average duration of 4 weeks) during their child's participation in IIPT. Parents engaged in 3 groups per week providing education, therapeutic art, and psychotherapy (3 hr/week total). RESULTS: At baseline, 38% of parents reported scores in the clinically elevated range for at least 1 psychosocial variable. Linear mixed modeling for the full sample indicated reduced parent anxiety (t = -2.72, p <.01) and depression (t = -3.59, p <.001), but not increased emotional support (t = 1.86, p >. 05) or reduced social isolation (t = -1.20, p >.05). For parents with at least moderately elevated psychosocial concerns, statistically significant improvements were observed for all 4 outcomes (all p's<.01). Psychological flexibility, cognitive reappraisal, and emotional suppression were found to be related to changes in parent outcomes (anxiety, depression, isolation, and support). CONCLUSIONS: Findings support the benefit of parent-focused interventions in addition to child-focused interventions. Many parents of youth participating in IIPT had elevated scores for at least 1 psychosocial concern at baseline. Brief, parent-focused intervention including psychoeducation, therapeutic art, and psychotherapy targeting mindfulness, acceptance, and values had a significant impact on these parents, particularly those with greater struggles at baseline.

Partisan bias in false memories for misinformation about the 2021 U.S. Capitol riot.

ABSTRACTMemory for events can be biased. For example, people tend to recall more events that support than oppose their current worldview. The present study examined partisan bias in memory for events related to the January 6, 2021, Capitol riot in the United States. Participants rated their memory for true and false events that were either favourable to their political party or the other major political party in the United States. For both true and false events, participants remembered more events that favoured their political party. Regression analyses showed that the number of false memories that participants reported was positively associated with their tendency to support conspiracy beliefs and with their self-reported engagement with the Capitol riot. These results suggest that Democrats and Republicans remember the Capitol Riot differently and that certain individual difference factors can predict the formation of false memories in this context. Misinformation played an influential role in the Capitol riot and understanding differences in memory for this event is beneficial to avoiding similar tragedies in the future.

Emergency Medical Services Traumatic Brain Injury Protocols Do Not Reflect Brain Trauma Foundation Guidelines.

OBJECTIVES: Implementation of traumatic brain injury (TBI) guideline recommendations for prehospital care is associated with improved outcomes, but prehospital guideline uptake is frequently delayed. Our objective was to estimate how well TBI guidelines are reflected in a national sample of prehospital TBI protocols in 2012 and 2018, 5 and 11 years after guideline publication. Methods: A purposeful sample of publicly accessible prehospital protocols were obtained in 2012, and updates of those protocols were obtained in 2018. Guideline recommendations were codified into a 23-item tool that was used to dual-abstract each prehospital protocol set. Descriptive statistics and chi-square testing were used to compare differences. Fifty-three sets of protocols representing 25 states and multiple administrative structures were identified. Results: None of the protocols contained all twenty-three elements of the guidelines, and more than one-third (19/53, 35%) did not have a TBI-specific protocol. While some individual items appeared more frequently in 2018 than 2012, more than half of the reviewed protocols do not contain guidance on ventilation or definitions of hypoxemia, hypotension, or pupil asymmetry. Conclusions: Evaluation of a diverse sample of EMS protocols demonstrates a significant deficit in the adoption of TBI guidelines more than a decade after publication.

Engineering DNA recognition and allosteric response properties of TetR family proteins by using a module-swapping strategy.

The development of synthetic biological systems requires modular biomolecular components to flexibly alter response pathways. In previous studies, we have established a module-swapping design principle to engineer allosteric response and DNA recognition properties among regulators in the LacI family, in which the engineered regulators served as effective components for implementing new cellular behavior. Here we introduced this protein engineering strategy to two regulators in the TetR family: TetR (UniProt Accession ID: P04483) and MphR (Q9EVJ6). The TetR DNA-binding module and the MphR ligand-binding module were used to create the TetR-MphR. This resulting hybrid regulator possesses DNA-binding properties of TetR and ligand response properties of MphR, which is able to control gene expression in response to a molecular signal in cells. Furthermore, we studied molecular interactions between the TetR DNA-binding module and MphR ligand-binding module by using mutant analysis. Together, we demonstrated that TetR family regulators contain discrete and functional modules that can be used to build biological components with novel properties. This work highlights the utility of rational design as a means of creating modular parts for cell engineering and introduces new possibilities in rewiring cellular response pathways.

Neuropsychological Functioning of Youth Receiving Intensive Interdisciplinary Pain Treatment.

Objective: Chronic pain is associated with school difficulties; however, there is limited published evidence on the cognitive or neuropsychological functioning of youth with chronic pain. Method: When beginning intensive interdisciplinary pain treatment, 94 youth (age = 10-18) with chronic pain completed neuropsychological assessment (e.g., intelligence, academic skills, learning and recall, and attention) and clinical questionnaires (e.g., pain and physical and psychological functioning). We compared neuropsychological scores with test norms and with clinical questionnaires. Results: Youth with chronic pain had higher verbal comprehension and full scale IQ scores than expected, below-average nondominant hand dexterity, and difficulty with visual recall. Self-reported difficulties with executive functioning were associated with small-to-moderate difficulties with objectively measured attention. Performance on neuropsychological measures was generally not associated with pain, impairment, anxiety, or depression, though catastrophizing was negatively correlated with perceptual reasoning. An expected number of these youth had learning disorders (14%); however, more than expected had an autism spectrum disorder (9%) or attention deficit hyperactivity disorder (18%), and nearly a quarter demonstrated characteristics of nonverbal learning disability (22%). Conclusions: Some of these cognitive findings may be a consequence of chronic pain, and others may reflect subtle neurodevelopmental differences that may predate or be comorbid with pain. Regardless of etiology, with more than half the current sample experiencing some type of learning challenge, often undiagnosed, pediatric psychologists evaluating youth with chronic pain may wish to screen for comorbid learning difficulties.

The Relationship Between Pain Characteristics, Peer Difficulties, and Emotional Functioning Among Adolescents Seeking Treatment for Chronic Pain: A Test of Mediational Models.

Objective: To evaluate patterns of relationships between pain characteristics, peer difficulties, and emotional functioning in a sample of adolescents seeking treatment for chronic pain. Methods: Participants were 172 adolescents (age M = 14.88 years; 76% female, 88% White) with heterogeneous chronic pain disorders who completed measures of pain characteristics, peer difficulties, and emotional functioning before their new patient appointment in a pain management clinic. Direct and indirect relationships between variables were tested using path analysis. Results: Adequate model fit was found for models that specified emotional functioning (anxiety and depression) as a mediator of the relationship between pain interference and peer difficulties. Conversely, poor fit was found for all models specifying peer difficulties as a mediator of the relationship between pain characteristics and emotional functioning. Conclusions: Assessing and targeting depression and anxiety among youth with high pain interference may help prevent or improve peer difficulties.

Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms.

Nerve growth factor (NGF) is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans, but the actual mechanisms underlying the persistent effects of NGF remain incompletely understood. We developed a rat model of NGF-induced persistent thermal hyperalgesia and mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of NGF. Persistent thermal hypersensitivity and mechanical allodynia require de novo protein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar) injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal hypersensitivity via peripheral and spinal sites of action and mechanical allodynia via only a spinal site of action. Therefore, NGF-evoked thermal and mechanical allodynia are mediated by spatially distinct mechanisms. NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased capsaicin-evoked nocifensive responses, increased calcitonin gene-related peptide release from hindpaw skin biopsies, and increased capsaicin-evoked inward current and membrane expression of TRPV1 protein in dorsal root ganglia neurons. Finally, we showed that NGF treatment increased concentrations of linoleic and arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active lipids were reduced by peripheral and spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized lipid TRPV1 agonists.

Adaptation of the State-Trait Inventory for Cognitive and Somatic Anxiety for Use in Children: A Preliminary Analysis.

OBJECTIVE: Anxiety has both state/trait and cognitive/somatic dimensions, and these distinctions may be particularly relevant for children with medical problems. This two-part study adapted the State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA) and confirmed its factor structure in a sample of children in a primary care clinic. METHODS: STICSA items were adapted for reading level and piloted in a small group of children. Next, 250 children (12.3 ± 2.7 years) completed the adapted version, the STICSA-C. RESULTS: Separate confirmatory factor analyses conducted on the State and Trait forms of the STICSA-C confirmed the two-factor structure of the original measure (i.e., cognitive and somatic anxiety) and suggested an improved parsimonious model. CONCLUSIONS: Support was found for use of the STICSA-C as a reasonably good internally consistent measure for assessing cognitive and somatic anxiety in pediatric samples. Further investigation of its reliability and validity with replication in pediatric populations is warranted.

The misinformation effect is unrelated to the DRM effect with and without a DRM warning.

The misinformation and Deese-Roediger-McDermott (DRM) paradigms are used to study forms of false memories. Despite the abundance of research using these two paradigms, few studies have examined the relationship between the errors that arise from them. In the present study, 160 participants completed a misinformation task and two DRM tasks, receiving a warning about the effect before the second DRM task. Participants demonstrated misinformation and DRM effects (with and without the warning), but susceptibility to these forms of false memory were not significantly related across individuals. The DRM warning reduced the DRM effect, and signal detection analysis revealed that the DRM warning reduced a liberal response bias in this task. Sensitivity and response bias in both DRM tasks were not significantly related to these measures in the misinformation task. These findings suggest that these two forms of false memories are not interchangeable and they appear to be the result of different cognitive processes.

Use of Dehydrated Agar to Estimate Microbial Water Quality for Horticulture Irrigation.

Petrifilms are dehydrated agar culture plates that have been used to quantify colony forming units (CFU) mL of either aerobic bacteria (Petrifilm-AC) or fungus (Petrifilm-YM), depending on substrate composition. Microbes in irrigation systems can indicate biofilm risk and potential clogging of irrigation emitters. The research objective was to compare counts on Petrifilms versus traditional, hydrated-agar plates using samples collected from recirculated irrigation waters and cultures of isolated known species. The estimated count (in CFU mL) from a recirculated irrigation sample after 7 d of incubation on Petrifilm-YM was only 5.5% of the count quantified using sabouraud dextrose agar (SDA) with chloramphenicol after 14 d. In a separate experiment with a known species, Petrifilm-YM did not successfully culture zoospores of . Isolates of viable zoospores were cultured successfully on potato-dextrose agar (PDA), with comparable counts with a vegetable juice medium supplemented with the antibiotics pimaricin, ampicillin, rifamycin, pentochloronitrobenzene and hymexazol (PARP-H). The quantification of pv. Begoniaceae on Petrifilm-AC was not significantly different ( < 0.05) than on PDA, but was lower than on Reasoner and Goldrich agar (R2A) or with a hemocytometer. The current formulation of Petrifilm-YM is unlikely to be a useful monitoring method for plant pathogens in irrigation water because of the inability to successfully culture oomycetes. However, Petrifilm-AC was an effective method to quantify bacteria and can provide an easy-to-use on-farm tool to monitor biofilm risk and microbial density.

Design of a VLP-nanovehicle for CYP450 enzymatic activity delivery.

BACKGROUND: The intracellular delivery of enzymes for therapeutic use has a promising future for the treatment of several diseases such as genetic disorders and cancer. Virus-like particles offer an interesting platform for enzymatic delivery to targeted cells because of their great cargo capacity and the enhancement of the biocatalyst stability towards several factors important in the practical application of these nanoparticles. RESULTS: We have designed a nano-bioreactor based on the encapsulation of a cytochrome P450 (CYP) inside the capsid derived from the bacteriophage P22. An enhanced peroxigenase, CYPBM3, was selected as a model enzyme because of its potential in enzyme prodrug therapy. A total of 109 enzymes per capsid were encapsulated with a 70 % retention of activity for cytochromes with the correct incorporation of the heme cofactor. Upon encapsulation, the stability of the enzyme towards protease degradation and acidic pH was increased. Cytochrome P450 activity was delivered into Human cervix carcinoma cells via transfecting P22-CYP nanoparticles with lipofectamine. CONCLUSION: This work provides a clear demonstration of the potential of biocatalytic virus-like particles as medical relevant enzymatic delivery vehicles for clinical applications.

A longitudinal study examining the effects of a season of American football on lipids and lipoproteins.

BACKGROUND: Dyslipidemia is one factor cited for increased risk of cardiovascular disease (CVD) in American football players. However, American football players undergo physical conditioning which is known to influence lipids. This study examined if the physical activity of an American football season is associated with changes in lipids and if a relationship exists between lipids and body composition. METHODS: Fourteen division I freshmen American football players had blood drawn prior to summer training (T1), end of competition (T2), and end of spring training (T3). Samples were analyzed for total cholesterol (TCHL), HDL-C, LDL-C, and triglycerides (TG). Body composition was assessed via dual-x-ray absorptiometry. National Cholesterol Education Program (NCEP) lipid categorization was used to characterize participants. Pearson correlations were computed to determine relationships. RESULTS: Body mass increased T2 (p=0.008) as a result of increase in fat mass (p=0.005) and remained high despite a decrease T3. Lean mass did not differ significantly at any time. No significant time effects were observed for lipids measured. The number of participants presenting with risk factors attributed to dyslipidemia varied. By T3, no participant was categorized as "low" for HDL-C. TCHL was moderately correlated (r=0.60) with fat mass at T1; whereas a moderate correlation (r=-0.57) was observed between BMI and HDL-C at T2. TG was strongly correlated with fat mass at each time point (T1, r=0.83; T2, r=0.94; T3, r=0.70). CONCLUSION: The physical activity associated with a season of football results in little change in blood lipids and CVD risk. Further, TG are strongly related to fat mass. Future research should focus on examining the cause of dyslipidemia in American football players.

Amplified pain syndromes in children: treatment and new insights into disease pathogenesis.

PURPOSE OF REVIEW: Although many diagnostic terms are used for pediatric chronic pain, evidence suggests a common thread of signal amplification, leading to the unifying term 'amplified pain syndromes'. Ongoing research provides new insights into biopsychosocial contributors and treatments for pediatric amplified pain syndromes. RECENT FINDINGS: Basic science indicates a complex interplay of genetic, epigenetic, neurochemical, endocrine, and inflammatory contributors, along with environmental and psychological factors. Although medications and interventions remain common approaches to children with chronic pain, their evidence is limited. Preliminary evidence exists for mindfulness-based therapies, yoga, and other complementary/alternative medicine approaches. The strongest evidence is for exercise-based and cognitive-behavioral treatments, in particular, when combined in a multidisciplinary format. Intensive approaches (pain rehabilitation) have the potential to effectively and efficiently treat those most disabled by amplified pain syndromes, and lead to sustained improvement in pain, functioning, and medical utilization. SUMMARY: Although understanding of the mechanisms underlying pediatric amplified pain syndromes evolves, standard of care is multidisciplinary emphasizing exercise therapy, cognitive-behavioral treatment, and self-regulation. Treatment should target full return to physical function, which leads to subsequent improvement or resolution of pain. Multidisciplinary care can be coordinated by a rheumatologist or other physician with appropriate referrals, or through a multidisciplinary team.

RNA-protein binding interface in the telomerase ribonucleoprotein.

Telomerase is a specialized reverse transcriptase containing an intrinsic telomerase RNA (TR) which provides the template for telomeric DNA synthesis. Distinct from conventional reverse transcriptases, telomerase has evolved a unique TR-binding domain (TRBD) in the catalytic telomerase reverse transcriptase (TERT) protein, integral for ribonucleoprotein assembly. Two structural elements in the vertebrate TR, the pseudoknot and CR4/5, bind TERT independently and are essential for telomerase enzymatic activity. However, the details of the TR-TERT interaction have remained elusive. In this study, we employed a photoaffinity cross-linking approach to map the CR4/5-TRBD RNA-protein binding interface by identifying RNA and protein residues in close proximity. Photoreactive 5-iodouridines were incorporated into the medaka CR4/5 RNA fragment and UV cross-linked to the medaka TRBD protein fragment. The cross-linking RNA residues were identified by alkaline partial hydrolysis and cross-linked protein residues were identified by mass spectrometry. Three CR4/5 RNA residues (U182, U187, and U205) were found cross-linking to TRBD amino acids Tyr503, Phe355, and Trp477, respectively. This CR4/5 binding pocket is distinct and separate from the previously proposed T pocket in the Tetrahymena TRBD. Based on homologous structural models, our cross-linking data position the essential loop L6.1 adjacent to the TERT C-terminal extension domain. We thus propose that stem-loop 6.1 facilitates proper TERT folding by interacting with both TRBD and C-terminal extension. Revealing the telomerase CR4/5-TRBD binding interface with single-residue resolution provides important insights into telomerase ribonucleoprotein architecture and the function of the essential CR4/5 domain.

Running Shoes of the Postmodern Footwear Era: A Narrative Overview of Advanced Footwear Technology.

The modern era of running shoes began in the 1960s with the introduction of simple polymer midsole foams, and it ended in the late 2010s with the introduction of advanced footwear technology (AFT). AFT is characterized by highly compliant, resilient, and lightweight foams with embedded, rigid, longitudinal architecture. This footwear complex improves a runner's efficiency, and it introduced a step change in running performance. Purpose: This review serves to examine the current state of knowledge around AFT-what it is and what we know about its ingredients, what benefits it confers to runners, and what may or may not mediate that benefit. We also discuss the emerging science around AFT being introduced to track-racing spikes and how it is currently regulated in sporting contexts. Conclusions: AFT has changed running as a sport. The construction of AFT is grossly understood, but the nature of the interacting elements is not. The magnitude of the enhancement of a runner's economy and performance has been characterized and modeled, but the nuanced factors that mediate those responses have not. With these knowns and unknowns, we conclude the review by providing a collection of best practices for footwear researchers, advice for runners interested in AFT, and a list of pertinent items for further investigation.

Personality and misinformation.

Misinformation poses a significant concern, promoting false beliefs and eroding trust in media. People differ in their susceptibility to believe and to share misinformation. In this article, we reviewed recent research on relationships between personality traits and belief in and sharing of misinformation. Findings show that more extroverted and less conscientious and agreeable people tend to be more susceptible to believing in and sharing misinformation. Additionally, the Dark Triad personality traits of narcissism, psychopathy, and Machiavellianism tend to be positively associated with sharing of misinformation, and narcissism and psychopathy are associated with greater belief in misinformation. Understanding these individual differences can inform interventions to reduce the effects of misinformation.