Altered Reactivity Research Articles

The impact of cannabidiol placebo on amygdala-based neural responses to an acute stressor.

Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress. Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA. CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC (p = 0.042), but did not systematically alter amygdala-AI rsFC (p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context. CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.

Methamphetamine-Induced Blood Pressure Sensitization Correlates with Morphological Alterations within A1/C1 Catecholamine Neurons

Methamphetamine (METH) is a drug of abuse, which induces behavioral sensitization following repeated doses. Since METH alters blood pressure, in the present study we assessed whether systolic and diastolic blood pressure (SBP and DBP, respectively) are sensitized as well. In this context, we investigated whether alterations develop within A1/C1 neurons in the vasomotor center. C57Bl/6J male mice were administered METH (5 mg/kg, daily for 5 consecutive days). Blood pressure was measured by tail-cuff plethysmography. We found a sensitized response both to SBP and DBP, along with a significant decrease of catecholamine neurons within A1/C1 (both in the rostral and caudal ventrolateral medulla), while no changes were detected in glutamic acid decarboxylase. The decrease of catecholamine neurons was neither associated with the appearance of degeneration-related marker Fluoro-Jade B nor with altered expression of α-synuclein. Rather, it was associated with reduced free radicals and phospho-cJun and increased heat shock protein-70 and p62/sequestosome within A1/C1 cells. Blood pressure sensitization was not associated with altered arterial reactivity. These data indicate that reiterated METH administration may increase blood pressure persistently and may predispose to an increased cardiovascular response to METH. These data may be relevant to explain cardiovascular events following METH administration and stressful conditions.

Altered Brain Reactivity to Food Cues in Undergraduate Students with Disordered Eating Behaviors.

A growing body of evidence has shown that electroencephalography (EEG) is an interesting method of assessing the underlying brain physiology associated with disordered eating. Using EEG, we sought to evaluate brain reactivity to hyper-palatable food cues in undergraduate students with disordered eating behavior (DEB). After assessing the eating behaviors of twenty-six undergraduate students using the Eating Attitudes Test (EAT-26), electroencephalographic signals were recorded while the participants were presented with pictures of hyper-palatable food. The current study used a temporospatial principal component analysis (PCA) approach to identify event-related potential (ERP) responses that differed between DEB and non-DEB individuals. A temporospatial PCA applied to the ERPs identified a positivity with a maximum amplitude at 347 ms at the occipital-temporal electrodes in response to pictures of hyper-palatable food. This positivity was correlated with the EAT-26 scores. Participants with DEB showed reduced positivities in this component compared with those without DEB. Our findings may reflect greater motivated attention toward hyper-palatable food cues in undergraduate students with DEB. These results are an important step toward obtaining a more refined understanding of specific abnormalities related to reactivity to food cues in this population.

Feasibility of an Online Acute Stressor in Preschool Children of Mothers with Depression.

Maternal depression is a risk factor for future mental health problems in offspring, with stress-system function as a candidate vulnerability factor. Here we present initial validation of an online matching-task (MT) paradigm in young children exposed to maternal depression (N=40), a first in stressor-paradigm research for this age group. Investigations of stress-system reactivity that can be conducted online are an innovative assessment approach, accelerated by the COVID-19 pandemic. Results indicate high feasibility, with a >75% data collection success rate across measures, similar-to or better-than in-person success rates in young children. Overall, the online MT elicited significant heart rate but not cortisol reactivity. Individual differences in child mental health symptoms were a moderator of reactivity to the stressor such that children with lower, but not higher, behavioral problems exhibited the typical pattern of cortisol reactivity to the online MT. Results are aligned with allostatic load models, which suggest downregulation of stress-system reactivity as a result of experiencing adversity and mental health vulnerability. Consistent with in-person research, this suggests that an early phenotype for the emergence of behavior problems may be linked to altered stress-system reactivity. Results hold potential clinical implications for intervention development and the future of online stress-system research. Trial Registration: Clinical Trial Registration: NCT04639557; (Building Regulation in Dual Generations-Telehealth Model [BRIDGE]).

Quality of human-animal interactions during beef cattle auctions in Panama

This study aimed to determine the quality of human-animal interactions during cattle auctions in Panama and to assess the relationship between cattle reactivity, value paid, and time spent on commercialization. Data were recorded by watching video records of 4531 individual cattle sold in the main Panamanian auctions. Cattle reactivity was assessed by one previously trained observer when the animals entered the box where they were exposed for sale, assigning one of three scores: 1 = calm, 2 = reactive, and 3 = very reactive. Human-animal interactions were assessed using a binary score to assess the occurrence of hitting (1) or not (0) during commercialization. When cattle were hit to stimulate movement, their reactivity was assessed again to determine whether hitting altered their behavior. The value paid (USD/kg of live weight), and the time spent on commercialization (s) of each animal were also recorded in a subsample of 704 animals. Cattle reactivity, genetic group, animal category, auction location and phase of commercialization influenced the occurrence of hits (p<0.05). Hitting altered cattle reactivity (p<0.001); 95 % of the animals scored calm when they entered the auction box, dropped to 85 % after being hit. There was a significant effect of the reactivity score (p<0.05), genetic group (p=0.01), location (p<0.001) and auction phase (p=0.002) on the number of hits received by the cattle when inside the auction box. The median value paid for very reactive cattle tended to be higher than for calm cattle (1.85 vs 1.82 USD/kg; respectively; p=0.06). There were no differences in the time spent on commercialization according to cattle reactivity (p>0.05). In conclusion, cattle reactivity, and auction phase, in addition to other factors such as genetic group, animal category, and auction location, affected the frequency of negative human-animal interactions during commercialization. Cattle reactivity tended to affect the price paid per head of cattle but not the time spent in marketing.

Gamma activity in Autism Spectrum Disorder: Enhanced response to visual input

IntroductionAutism spectrum disorder (ASD) is a childhood onset neurodevelopmental condition, that leads to permanent disability in a high proportion of cases. ASD is associated with a heterogeneous symptom presentation, which - besides social interaction and communication difficulties - encompasses altered sensory reactivity, including excessive hyper-sensitivity to stimuli, especially in the visual domain. Meta-analyses of fMRI studies revealed increased reactivity in visual task conditions in the temporal and occipital brain regions. Neural oscillations in the EEG gamma band are viewed as a candidate neurobiological marker for higher order sensory and perceptual processes, and social interactions.ObjectivesWe investigated changes in gamma activity in the EEG in the eyes open (EO) vs. eyes closed (EC) condition in order to identify the neurobiological underpinning of the enhanced sensitivity to visual input in ASD as compared to typically developing (TD) subjects.MethodsEEGs were obtained in EC and EO condition in ASD (N=23) and TD subjects (N=24) in an ongoing study. For EEG recording we used a high-density 128-channel BioSemi system, with 0.5 Hz frequency resolution. The spectral power in the gamma band (30-100Hz) was quantified by the power spectral density. To investigate whether changes in the gamma band were linked to changes in arousal instead of enhanced visual processing, we also examined alterations in the alpha band (8-13Hz) in the EO condition. Spectral power changes were determined for each EEG channel by computing the difference between the EC and EO conditions (EO-EC).ResultsSpectral power in the gamma band showed changes in the opposite direction in the two study groups: ASD subjects manifested significant (p&lt;0.05) increase, while TD subjects had a decrease in the EO vs. EC condition in the temporal and occipital brain regions. By contrast, the changes in the alpha band were similar, with both groups exhibiting a spectral power decrease in the EO compared to the EC condition.ConclusionsIn ASD, an enhancement of gamma activity is present in the EO as compared to the EC condition in the posterior brain areas. These brain areas are involved in the processing of visual information, and gamma activity is considered as a measure of perceptual processes. Thus, the gamma alterations in the EO vs. EC condition may underlie the hyper-sensitivity symptoms to visual stimuli in ASD, and EEG can offer a simple to use tool to delineate the neurobiological foundation of the symptom presentation.Funding statement: Hungarian Brain Research program,#NAP2022-I-4/2022Disclosure of InterestNone Declared

A Case of Lymphoplasmacytic Cell Lymphoma Characterized by Marked Nuclear Fission and Brain Gyrus Nuclei of Lymphocytes

A 67-year-old male was admitted to the hospital due to fatigue and thrombocytopenia. Peripheral blood cells analysis showed the white blood cells count of 2.99 × 109 /L, red blood cell (RBC) count of 2.08 × 1012/L, platelet count of 15 × 109 /L. β2- microglobulin of serum was 5.50 mg/L. Whole-body positron emission tomography-computed tomography suggested altered reactivity in the lymph nodes of the bilateral neck. Morphological examination of bone marrow (BM) indicated the presence of abnormal smaller lymphocytes, accounting for 12.5% of the total nucleated cells. Strikingly, nuclear fission or brain gyrus nuclei were prominently observed in all abnormal lymphocytes (Figure 1, original magnification 1000×; Wright–Giemsa stain). The proportion of plasma cells was 0.5%, and no morphological abnormalities were observed. Additionally, some RBCs were exhibited a rouleaux arrangement. Flow cytometry analysis of BM identified 16.12% of κ-restricted B lymphocytes expressing CD5- , CD10- , CD19+ , CD20+ . A minimal proportion of 0.03% plasma cells with κ/λ ratio of 1.07. Consistent results were confirmed by immunohistochemistry in the BM biopsy. Immunofixation electrophoresis revealed abnormal monoclonal bands in the IgM and κ lanes. Furthermore, mutations of MYD88 (L265P), CXCR4 (T318fs), and TP53 (R306X) were identified through next-generation sequencing analysis. A diagnosis of lymphoplasmic cell lymphoma/waldenström macroglobulinemia (LPL/WM) was established.

Feasibility and comparability of different platelet function tests in acute stroke with or without prior antiplatelet therapy.

The clinical course of ischemic and hemorrhagic strokes can be influenced by the coagulation status of individual patients. The prior use of antiplatelet therapy (APT) such as acetylsalicylic acid (ASA) or P2Y12-antagonists has been inconsistently described as possibly increasing the risk of hemorrhagic transformation or expansion. Since clinical studies describing prior use of antiplatelet medication are overwhelmingly lacking specific functional tests, we aimed to implement testing in routine stroke care. We used fluorescence-activated cell sorting (FACS) with antibodies against CD61 for thrombocyte identification and CD62p or platelet activation complex-1 (PAC-1) to determine platelet activation. Aggregometry and automated platelet functioning analyzer (PFA-200) were employed to test thrombocyte reactivity. FACS and aggregometry samples were stimulated in vitro with arachidonic acid (AA) and adenosine diphosphate (ADP) to measure increase in CD62p-/PAC-1-expression or aggregation, respectively. Between February and July 2023, 20 blood samples (n = 11 ischemic strokes; n = 7 hemorrhagic strokes; n = 2 controls) were acquired and analyzed within 24 h of symptom onset. N = 11 patients had taken ASA, n = 8 patients no APT and n = 1 ASA+clopidogrel. ASA intake compared to no APT was associated with lower CD62p expression after stimulation with AA on FACS analysis (median 15.8% [interquartile range {IQR} 12.6-37.2%] vs. 40.1% [IQR 20.3-56.3%]; p = 0.020), lower platelet aggregation (9.0% [IQR 7.0-12.0%] vs. 88.5% [IQR 11.8-92.0%]; p = 0.015) and longer time to plug formation with PFA-200 (248.0 s [IQR 157.0-297] vs. 121.5 s [IQR 99.8-174.3]; p = 0.027). Significant correlations were noted between AA-induced CD62p expression and aggregometry analysis (n = 18; ρ = 0.714; p < 0.001) as well as a negative correlation between CD62p increase and PFA clot formation time (n = 18; ρ = -0.613; p = 0.007). Sensitivity for ASA intake was highest for PFA (81.8% for values ≥155.5 s). The combination of ASA + clopidogrel also affected ADP-induced CD62p and PAC-1 expression. In the clinical setting it is feasible to use differentiated platelet analytics to determine alterations caused by antiplatelet therapy. Among the tests under investigation, PFA-200 showed the highest sensitivity for the intake of ASA in stroke patients. FACS analysis on the other hand might be able to provide a more nuanced approach to altered platelet reactivity.

P145 Phagocyte responses to gut-derived C. albicans are modified in inflammatory bowel disease

Abstract Background Fungi are a key component of the human gut microbiota and have been strongly implicated in the pathogenesis of inflammatory bowel disease (IBD). Candida albicans typically exists as a commensal yeast within healthy hosts but can form tissue-invasive filaments that secrete Candidalysin (CLYS) toxin to disrupt epithelial barriers. Dynamics of this morphological switch are influenced by genotypic and phenotypic variation of gut-resident C. albicans strains, which may impact host response and extent of mucosal inflammation. Methods C. albicans isolates were derived from healthy control (HC) and IBD gut biopsies. Phenotypic, genomic, and proteomic analyses were conducted on these isolates. To further understand host interplay with intestinal C. albicans under physiologically relevant conditions, a human ‘gut-on-a-chip’ system was developed to assess tissue invasion potential in vitro. Results IBD-derived isolates were more readily able to form filaments, displayed altered cell wall composition, and modulated expression of adhesion-associated genes including IHD1. Subsequent innate leukocyte responses to these strain-dependent profiles were investigated to understand impact on host immunity. When exposed to IBD-derived C. albicans strains, blood neutrophils from healthy donors displayed increased swarming behaviour and NETosis induction, whereas monocyte-derived macrophages released greater amounts of pro-inflammatory IL-1b. These responses were substantially diminished in neutrophils and macrophages from IBD patients, suggesting altered reactivity to fungal stimuli in disease settings. The gut-on-a-chip model system confirmed that IBD-derived strains display increased adhesion and translocation in a dynamic human gut environment. Conclusion Gut-adapted C. albicans strains from HC and IBD donors exhibit distinct biological profiles that impact on host immune responses and shape interactions with the gut barrier in a novel organ chip model.

Rumination and altered reactivity to sensory input as vulnerability factors for developing post-traumatic stress symptoms among adults with autistic traits.

Recent literature has suggested that individuals with autism spectrum disorder (ASD) or autistic traits (ATs) would be more likely to encounter traumatic events in their lifetime and to develop post-traumatic stress disorder (PTSD). However, the nature of this relationship has not yet been fully elucidated. The aims of this study were to evaluate the relationship between AT and PTSD and to investigate which specific autistic dimension was more associated with trauma and stress-related symptoms. A total of 68 subjects with ASD and 64 healthy controls (HCs) were assessed with the Adult Autism Subthreshold Spectrum (AdAS Spectrum) and the Trauma and Loss Spectrum (TALS) questionnaires. Statistical analyses included Mann-Whitney U test, chi-square test, calculation of Spearman's coefficients, and logistic regression analysis. Patients with significant AT reported a 30% rate of PTSD and higher TALS total and domain scores than HCs, among whom no PTSD was found instead. Significant positive correlations were reported between AdAS Spectrum and TALS-SR scores in the whole sample. AdAS Spectrum total scores were statistically predictive of the presence of PTSD. High scores at AdAS Spectrum Inflexibility and adherence to routine and Restrictive interest and rumination domains were identified as positive predictors of a probable PTSD. Compared to HCs, subjects with significant AT are more likely to present symptoms of PTSD. In particular, AT related to ruminative thinking, narrow interests, and sensorial reactivity would seem to predict the presence of post-traumatic stress symptomatology.

A Non-Functional Carbon Dioxide-Mediated Post-Translational Modification on Nucleoside Diphosphate Kinase of Arabidopsis thaliana.

The carbamate post-translational modification (PTM), formed by the nucleophilic attack of carbon dioxide by a dissociated lysine epsilon-amino group, is proposed as a widespread mechanism for sensing this biologically important bioactive gas. Here, we demonstrate the discovery and in vitro characterization of a carbamate PTM on K9 of Arabidopsis nucleoside diphosphate kinase (AtNDK1). We demonstrate that altered side chain reactivity at K9 is deleterious for AtNDK1 structure and catalytic function, but that CO2 does not impact catalysis. We show that nucleotide substrate removes CO2 from AtNDK1, and the carbamate PTM is functionless within the detection limits of our experiments. The AtNDK1 K9 PTM is the first demonstration of a functionless carbamate. In light of this finding, we speculate that non-functionality is a possible feature of the many newly identified carbamate PTMs.

Influence of molecular structure on the coupling strength to a plasmonic nanoparticle and hot carrier generation.

Strong coupling between metal nanoparticles and molecules mixes their excitations, creating new eigenstates with modified properties such as altered chemical reactivity, different relaxation pathways or modified phase transitions. Here, we explore excited state plasmon-molecule coupling and discuss how strong coupling together with a changed orientation and number of an asymmetric molecule affects the generation of hot carriers in the system. We used a promising plasmonic material, magnesium, for the nanoparticle and coupled it with CPDT molecules, which are used in organic optoelectronic materials for organic electronic applications due to their facile modification, electron-rich structure, low band gap, high electrical conductivity and good charge transport properties. By employing computational quantum electronic tools we demonstrate the existence of a strong coupling mediated charge transfer plasmon whose direction, magnitude, and spectral position can be tuned. We find that the orientation of CPDT changes the nanoparticle-molecule gap for which maximum charge separation occurs, while larger gaps result in trapping hot carriers within the moieties due to weaker interactions. This research highlights the potential for tuning hot carrier generation in strongly coupled plasmon-molecule systems for enhanced energy generation or excited state chemistry.

Generation and reactivity of the fragment ion [B12I8S(CN)]- in the gas phase and on surfaces.

Gaseous fragment ions generated in mass spectrometers may be employed as "building blocks" for the synthesis of novel molecules on surfaces using ion soft-landing. A fundamental understanding of the reactivity of the fragment ions is required to control bond formation of deposited fragments in surface layers. The fragment ion [B12X11]- (X = halogen) is formed by collision-induced dissociation (CID) from the precursor [B12X12]2- dianion. [B12X11]- is highly reactive and ion soft-landing experiments have shown that this ion binds to the alkyl chains of organic molecules on surfaces. In this work we investigate whether specific modifications of the precursor ion affect the chemical properties of the fragment ions to such an extent that attachment to functional groups of organic molecules on surfaces occurs and binding of alkyl chains is prevented. Therefore, a halogen substituent was replaced by a thiocyanate substituent. CID of the precursor [B12I11(SCN)]2- ion preferentially yields the fragment ion [B12I8S(CN)]-, which shows significantly altered reactivity compared to the fragment ions of [B12I12]2-. [B12I8S(CN)]- has a previously unknown structural element, wherein a sulfur atom bridges three boron atoms. Gas-phase reactions with different neutral reactants (cyclohexane, dimethyl sulfide, and dimethyl amine) accompanied by theoretical studies indicate that [B12I8S(CN)]- binds with higher selectivity to functional groups of organic molecules than fragment ions of [B12I12]2- (e.g., [B12I11]- and [B12I9]-). These findings were further confirmed by ion soft-landing experiments, which showed that [B12I8S(CN)]- ions attacked ester groups of adipates and phthalates, whereas [B12I11]- ions only bound to alkyl chains of the same reagents.

Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change

AbstractBackgroundQuantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.MethodsTREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.Results31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.ConclusionsThis clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.

Association of GAB2 genotype with EEG characteristics and vascular reactivity to hyperventilation in nondemented adults during aging

AbstractBackgroundGAB2 rs2373115 genotype increases the risk of Alzheimer’s (AD) and vascular (VD) diseases (Reiman et al., 2007; Lambert et al., 2013; Kondreddy et al., 2021). EEG reactivity to hyperventilation (HV) depends on hypocapnia‐induced cerebral vasoconstriction, which may be impaired in subjects with preclinical AD and VD. EEG differences in the carriers of GAB2 genotype in nondemented adults remain unknown. The study was aimed to determine the possible effect of GAB2 rs2373115 genotype on resting EEG and EEG reactivity to HV in non‐demented adults during aging.MethodThe enrolled cohort included 151 healthy volunteers, age range 20‐80 years, stratified by GAB2 rs2373115 genotype. Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening. The significance of the differences between the EEG in different subgroups was estimated using ANOVA in the general linear model. APOE and sex was included in the analysis as covariates.ResultIn the entire sample the presence of GAB2 C allele was associated with higher alpha2 relative power in resting EEG, with more pronounced differences in the right parietal area.EEG reactivity to HV decreased with aging, and the decrease was more pronounced in the carriers of GAB2 C allele. Under HV the older GAB2 AC&amp;CC carriers as compared with the older GAB2 AA carriers had lower theta power. The HV reactivity of blood pressure and heart rate was decreased in aging to a greater extend in the GAB2 C allele carriers than in the homozygous GAB2 AA individuals.ConclusionThe results show that GAB2 genotype is associated with alpha2 relative power difference in non‐demented adults. Reduced EEG and vascular reactivity to HV in the older GAB2 C allele carriers indicates altered cerebrovascular reactivity to hypocapnia and suggests that vascular factors can mediate GAB2‐related AD susceptibility.The study was supported by Russian Science Foundation (Project N 22‐15‐00448, Project N 19‐75‐30039 genotyping) and the National Institutes of Health, United States (grant R01AG054712 to ER statistical analysis).

Abnormalities of reactivity of posterior resting‐state electroencephalographic alpha rhythms during eyes opening in patients with dementia due to Alzheimer’s disease and Parkinson’s disease

AbstractBackgroundPatients with dementia due to Alzheimer’s disease (ADD) and Parkinson’s disease (PDD) suffer from vigilance dysregulation. We hypothesized that such dysregulation may be reflected by altered reactivity of posterior resting‐state electroencephalographic (rsEEG) alpha rhythms during the vigilance transition from eyes‐closed to ‐open condition.MethodA Eurasian database provided clinical, demographic, and rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.ResultResults showed substantial (&gt; ‐10%) reduction (reactivity) in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients (Figure 1). In these alpha‐reactive participants, there were lower reductions in the posterior alpha activities in the ADD and PDD groups than in the Healthy group. That reduction in the parietal region was lower in the PDD than in the ADD group (Figure 2).ConclusionThese results suggest that ADD and PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in the quiet wakefulness in ADD and PDD patients. Such biomarkers may provide endpoints targets for pharmacological intervention and brain electromagnetic stimulations to improve the ADD and PDD patients’ general ability to regulate vigilance and visual primary consciousness in the activities of daily living.

A role for astrocytic insulin-like growth factor I receptors in the response to ischemic insult

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults using tamoxifen-regulated Cre deletion of IGF-IR in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 (Iba 1) microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

Blood Coagulation and Platelet Function Are Impaired By the ARP2 p.R258G Variant in Mice

Introduction: Venous thromboembolism (VTE) displays significant heritability, yet the genes explaining this heritability are not completely characterized. We previously identified that tissue factor pathway inhibitor heterozygosity ( Tfpi+/−) on the homozygous F5L background ( F5L/L) produces a lethal perinatal thrombotic phenotype. Using a sensitized ENU mutagenesis screen, we discovered an autosomal dominant missense mutation in the Actr2 gene (p.R258G, Actr2G) that suppresses thrombosis and restores survival to F5L/LTfpi+/− mice. Inheritance of the Actr2Gmutation is associated with nearly complete suppression of the lethal F5L/LTfpi+/- phenotype. Actr2 codes for the ARP2 protein, an essential component of the ARP2/3 complex, which mediates actin cytoskeletal rearrangements during platelet activation. We hypothesized that the Actr2G variant affects blood coagulation and platelet function to reduce thrombosis. Methods: To investigate potential effects of the Actr2G mutation on the coagulation cascade, prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma-dependent thrombin generation assays (TGA) were used to evaluate clot formation. A mouse tail clip assay was used to measure bleeding time and quantify blood loss. Finally, platelets were assessed for functional defects using platelet spreading and aggregometry assays. Results: Actr2 +/Gplasma had significantly prolonged PT and aPTT compared to wild type controls (N&amp;gt;17, p&amp;lt;0.03). There was also a significant reduction in Actr2+/G thrombin peak height compared to wildtypes (N=10; p=0.03). Despite the delayed time to clot formation, Actr2+/G mice did not exhibit a bleeding phenotype and showed no significant differences in blood loss from tail clip assays. Activated Actr2+/G platelets exhibited reduced surface area and adhesion (N=5; p&amp;lt;0.02), as well as significant defects in collagen induced whole blood aggregation (N=10; p&amp;lt;0.02). Discussion: The results of the PT, aPTT and TGA indicate reduced thrombin generation potential, suggesting a defect in the common pathway of coagulation. This hypocoaguability may be due to a decrease in circulating procoagulant factors, or an increase in endogenous thrombin inhibitors. Both the significantly decreased aggregation and defective platelet spreading in the Actr2+/G mice indicate that Actr2+/G platelets are less responsive to agonists, a protective mechanism that contributes to overall thrombosis suppression. Conclusion: In summary, our studies demonstrate the pleiotropic effects that the Actr2G mutation exerts in suppressing thrombosis. The combination of altered plasma coagulation and platelet reactivity likely contribute to suppression of the F5L/LTfpi+/− phenotype. Defects in these actin-mediated processes precipitated by Actr2+/G are the likely root of the F5L/LTfpi+/- phenotype rescue, demonstrating the power of this gene in maintaining hemostatic balance. However, the combination of these thrombosis suppressing phenotypes is not significant enough to prolong the bleeding time in mice with the Actr2G mutation. Thus, our results suggest that targeting actin proteins such as ARP2 for novel antithrombotic drug therapies may have clinical applicability with limited effects on bleeding.

Quantity and Functional Exhaustion of Mucosal-Associated Invariant T Cells in Acute Myeloid Leukemia: Friends or Foes?

Abstract Introduction Acute Myeloid Leukemia (AML) is a hematological malignancy affecting hematopoietic progenitor cell differentiation, proliferation, and cell cycle progression, possibly involving disturbances in host immune function. Comprehensive understanding of the immune system composition and function in AML patients is crucial for developing novel immunotherapeutic strategies. Mucosa-Associated Invariant T cells (MAITs), as a subset of unconventional T cells, bridge innate and adaptive immunity and have been predominantly studied in the context of mucosa-related cancers. However, their role in AML remains largely unexplored. Investigating the association between MAITs and AML is of significant importance for understanding the immune escape mechanisms in AML, developing novel immunotherapeutic approaches, and predicting patient prognosis. Methods This study aimed to delineate the longitudinal immune profile of MAITs during AML pathogenesis and treatment, which may contribute to understanding immunological changes of MAITs in AML and predicting patient prognosis. In this prospective study, we collected peripheral blood or bone marrow samples from 131 AML patients, including 99 newly diagnosed cases, 18 in remission, and 14 in relapse, as well as 69 healthy controls. We performed multi-parameter flow cytometry for phenotypic and functional analysis of MAITs and explored their relationship with disease features, progression, and prognosis. Results We initially demonstrated that MAITs reflected immunological defects in AML patients. MAITs showed signs of depletion in both frequency and absolute count at initial diagnosis (p&amp;lt;0.0001) (Fig. 1A), especially in the CD8 + MAITs subset. The frequency of MAITs reflected AML cell genetics, tumor burden, disease status, and treatment responsiveness (Fig. 1B). AML patients exhibited reduced frequency of effector memory MAITs (p&amp;lt;0.0001) and increased frequency of terminal differentiated MAITs (p&amp;lt;0.0001) in peripheral blood (Fig. 1C), indicating altered reactivity of MAIT cells to antigen stimulation. MAITs displayed a state of high activation and even exhaustion, as evidenced by upregulated PD-1 expression. Impaired secretion of Th1-type cytokines and increased secretion of Th17-type cytokines (Fig. 1D), granzyme B, and perforin were observed in MAITs, while MAITs also shifted towards secreting tumor-promoting cytokines such as IL-8. Lower frequency of MAITs was correlated with inferior Overall Survival (OS) and Progression-Free Survival (PFS) (Fig. 1E). Multivariate analysis identified MAITs frequency &amp;lt;2.12% as an independent prognostic factor affecting OS. Conclusion Our study highlights the role of MAITs in immunological defects in Acute Myeloid Leukemia and reveals their functional impairment and enhanced tumor-promoting effects. The frequency of MAITs in peripheral blood reflects the genetic features, tumor burden, disease status, and treatment responsiveness of AML patients. Lower frequency of MAITs is associated with inferior OS and PFS, serving as a prognostic indicator for AML.

Adverse Life Experiences and Brain Function

Adverse life experiences have been proposed to contribute to diverse mental health problems through an association with corticolimbic functioning. Despite compelling evidence from animal models, findings from studies in humans have been mixed; activation likelihood estimation (ALE) meta-analyses have failed to identify a consistent association of adverse events with brain function. To investigate the association of adversity exposure with altered brain reactivity using multilevel kernel density analyses (MKDA), a meta-analytic approach considered more robust than ALE to small sample sizes and methodological differences between studies. Searches were conducted using PsycInfo, Medline, EMBASE, and Web of Science from inception through May 4, 2022. The following search term combinations were used for each database: trauma, posttraumatic stress disorder (PTSD), abuse, maltreatment, poverty, adversity, or stress; and functional magnetic resonance imaging (fMRI) or neuroimaging; and emotion, emotion regulation, memory, memory processing, inhibitory control, executive functioning, reward, or reward processing. Task-based fMRI studies within 4 domains (emotion processing, memory processing, inhibitory control, and reward processing) that included a measure of adverse life experiences and whole-brain coordinate results reported in Talairach or Montreal Neurological Institute space were included. Conference abstracts, books, reviews, meta-analyses, opinions, animal studies, articles not in English, and studies with fewer than 5 participants were excluded. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline, 2 independent reviewers assessed abstracts and full-text articles for entry criteria. A third reviewer resolved conflicts and errors in data extraction. Data were pooled using a random-effects model and data analysis occurred from August to November 2022. Peak activation x-axis (left-right), y-axis (posterior-anterior), and z-axis (inferior-superior) coordinates were extracted from all studies and submitted to MKDA meta-analyses. A total of 83 fMRI studies were included in the meta-analysis, yielding a combined sample of 5242 participants and 801 coordinates. Adversity exposure was associated with higher amygdala reactivity (familywise error rate corrected at P < .001; x-axis = 22; y-axis = -4; z-axis = -17) and lower prefrontal cortical reactivity (familywise error rate corrected at P < .001; x-axis = 10; y-axis = 60; z-axis = 10) across a range of task domains. These altered responses were only observed in studies that used adult participants and were clearest among those who had been exposed to severe threat and trauma. In this meta-analysis of fMRI studies of adversity exposure and brain function, prior adversity exposure was associated with altered adult brain reactivity to diverse challenges. These results might better identify how adversity diminishes the ability to cope with later stressors and produces enduring susceptibility to mental health problems.