Pathological Behavior Research Articles

Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease

BackgroundAdult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD).MethodsIn vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation.ResultsRestoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.ConclusionsCPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.

On the heart rhythm analysis using a nonlinear dynamics perspective: analytical study and electronic simulation

Biological systems are highly complex, so understanding them requires extensive analysis. Cardiac rhythms are one such analysis. These rhythms are linked to a complex dynamic system defined on the basis of the electrical activity of cardiac cells. This electrical activity is essential to human physiology, defining numerous behaviours that include normal or pathological rhythms, generally measured by the electrocardiogram (ECG). This article presents a mathematical model to describe the electrical activity of the heart, using a nonlinear dynamics perspective. The stability analysis of this model in its autonomous state, uni-directionally coupled, shows a very rich dynamical behaviour characterized by periodical regions of stability and unstability. The model studied makes it possible to construct synthetic ECGs. These ECGs demonstrate a variety of responses, including normal and pathological rhythms: ventricular flutter, ventricular fibrillation, ventricular tachycardia and ventricular extrasystole. A quantitative analysis of the model is also carried out using bifurcation diagrams and the corresponding maximum Lyapunov exponents. In addition, variations in sinus rhythm are described by a time-dependent frequency (a dynamic variable varying in a disordered manner or following a given law), representing transient disturbances. This type of situation can represent transitions between different pathological behaviours or between normal and pathological physiologies. In this respect, the perspective of nonlinear dynamics is used to describe cardiac rhythms, which makes it possible to represent normal or pathological behaviours. An electronic simulation performed with the OrCAD-Pspice software for a real implementation of the cardiac system is carried out. The results obtained are in agreement with those obtained numerically.

Predictors of pathological gambling behaviours in parents population in Nigeria

Predictors of pathological gambling behaviours in parents population in Nigeria

Exercised-enriched blood plasma rescues hippocampal impairments and cognitive deficits in an Alzheimer's disease model

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and moderate exercise holds promise in ameliorating the ongoing neurodegeneration and cognitive decline. Here, we investigated whether exercise-enriched blood plasm could yield a beneficial therapeutic effect on AD pathologies and cognitive decline in transgenic AD (P301S) mice. In this investigation, a cohort of 2-month-old C57BL/6 mice were granted continuous access to either a running wheel or a fixed wheel for 6 weeks. After that, their plasmas were extracted and subsequently injected intravenously into 4.5-month-old P301S mice biweekly over a 6-week period. A comprehensive methodology was then employed, integrating behavioral tests, pathology assessments, and biochemical analyses to unveil the potential anti-dementia implications of exercise-enriched blood plasma in P301S mice. Upon systemic administration, the findings revealed a noteworthy attenuation of hippocampus-dependent behavioral impairments in P301S mice. Conversely, blood plasma from sedentary counterparts exhibited no discernible impact. These effects were intricately associated with the mitigation of neuroinflammation, the augmentation of hippocampal adult neurogenesis, and a reduction of synaptic impairments following the administration of exercise-enriched blood plasma. These findings advance the proposition that administering exercise-enriched blood plasma may serve as an effective prophylactic measure against AD, opening avenues for further exploration and potential therapeutic interventions.

The contribution of periaqueductal gray in the regulation of physiological and pathological behaviors.

Periaqueductal gray (PAG), an integration center for neuronal signals, is located in the midbrain and regulates multiple physiological and pathological behaviors, including pain, defensive and aggressive behaviors, anxiety and depression, cardiovascular response, respiration, and sleep-wake behaviors. Due to the different neuroanatomical connections and functional characteristics of the four functional columns of PAG, different subregions of PAG synergistically regulate various instinctual behaviors. In the current review, we summarized the role and possible neurobiological mechanism of different subregions of PAG in the regulation of pain, defensive and aggressive behaviors, anxiety, and depression from the perspective of the up-down neuronal circuits of PAG. Furthermore, we proposed the potential clinical applications of PAG. Knowledge of these aspects will give us a better understanding of the key role of PAG in physiological and pathological behaviors and provide directions for future clinical treatments.

The 2012 Briganti nomogram predicts disease progression after surgery in high-risk prostate cancer patients

ABSTRACT Objectives We tested whether the 2012 Briganti nomogram for the risk of pelvic lymph node invasion (PLNI) may represent a predictor of disease progression after surgical management in high-risk (HR) prostate cancer (PCa) patients according to the European Association of Urology. Methods Between January 2013 and December 2021, HR PCa patients treated with robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND) were identified. The 2012 Briganti nomogram was evaluated as a continuous and categorical variable, which was dichotomized using the median. The risk of disease progression, defined as the event of biochemical recurrence and/or local recurrence/distant metastases was assessed by Cox regression models. Results Overall, 204 patients were identified. The median 2012 Briganti nomogram score resulted 12.0% (IQR: 6.0–22.0%). PLNI was detected in 57 (27.9%) cases. Compared to patients who had preoperatively a 2012 Briganti nomogram score ≤12%, those with a score >12% were more likely to present with higher percentage of biopsy positive cores, palpable tumors at digital rectal examination, high-grade cancers at prostate biopsies, and unfavorable pathology in the surgical specimen. At multivariable Cox regression analyses, disease progression, which occurred in 85 (41.7%) patients, was predicted by the 2012 Briganti nomogram score (HR: 1.02; 95%CI: 1.00–1.03; p = 0.012), independently by tumors presenting as palpable (HR: 1.78; 95%CI: 1.10.2.88; p = 0.020) or the presence of PLNI in the surgical specimen (HR: 3.73; 95%CI: 2.10–5.13; p = 0.012). Conclusions The 2012 Briganti nomogram represented an independent predictor of adverse prognosis in HR PCa patients treated with RARP and ePLND. As the score increased, so patients were more likely to experience disease progression, independently by the occurrence of PLNI. The association between the nomogram, unfavorable pathology and tumor behavior might turn out to be useful for selecting a subset of patients needing different treatment paradigms in HR disease.

Non-canonical IKB kinases regulate YAP/TAZ and pathological vascular remodeling behaviors in pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) causes pulmonary vascular remodeling, increasing pulmonary vascular resistance (PVR) and leading to right heart failure and death. Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell-specific approach. Our previous work demonstrated that targeting non-canonical IKB kinase TBK1 reduced YAP/TAZ activation in human lung fibroblasts. Here, we investigate non-canonical IKB kinases TBK1 and IKKε in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP/TAZ. We show that TBK1 and IKKε are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1/IKKε expression/activity significantly reduces PAH-associated PASMC remodeling, with longer-lasting effects on YAP/TAZ than treprostinil, an approved PAH therapy. These results show that non-canonical IKB kinases regulate YAP/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.

Exploring the neurofunctional impairments and cognitive biases concerning food and body related stimuli in anorexia nervosa: An integrated EEG and eye-tracking study protocol.

Patients with Anorexia Nervosa (AN) exhibit significant cognitive and neural disturbances compared to healthy individuals when processing food and body-related stimuli. These disturbances not only contribute to the manifestation and chronification of their pathological eating behaviour but also underscore the complex interplay of cognitive, emotional, and neurobiological factors in AN. However, the precise underlying cognitive and neural mechanisms of these disturbances remain a compelling area of investigation. This study presents a protocol developed for conducting a cross-sectional quasi-experimental study using a mixed model ANOVA approach with a crossover design. Our participants will consist of 20 patients with an active diagnosis of AN, 20 Overweight/obese individuals, and 20 Healthy Controls (HCs) with a normal BMI. An integrated eye-tracking and EEG methodology will be used in conjunction, with the primary aim of assessing participants' cognitive and neural processing towards high and low-calorie food stimuli. On an exploratory level, by utilizing the same methods, the present study will also investigate AN patients' responses towards high weight, normal weight, low weight, and self-body pictures, as well as towards images from the International Affective Picture System (IAPS) characterized by elevated valence and arousal levels. Additionally, behavioural methods such as yes or no questions, and self-reported questionnaires will be administered. The EEG and eye-tracking data will be analysed at early (50-300 ms) and late (350-500 ms) time intervals. The investigation of the underlying cognitive and neural processes employed by patients with AN during the processing of food and body-related stimuli can help us develop a better understanding of the cognitive and neural mechanisms that contribute to the manifestation and maintenance of the disorder and assist in the development of more effective screening methods. Ethical approval for the study has been obtained by the Cyprus National Bioethics Committee on 27.04.2023 (ΕΕΒΚ/ΕΠ/2023/19), and by the University of Cyprus (20.02.2023). Written informed consent will be obtained from all participants.

Trauma plays an important role in acral melanoma: A retrospective study of 303 patients.

Acral melanoma (AM) is the most common subtype of malignant melanoma in China, with a very poor prognosis. Despite the frequent reporting of trauma events in AM cases, the precise etiology of AM remains elusive. A retrospective analysis was conducted on a cohort of 303 AM patients at Nanjing Drum Tower Hospital. The patients were categorized into four distinct groups based on different patterns of disease onset: trauma type (Type 1), pigmented nevus type (Type 2), pigmented nevi with trauma (Type 3), and pigmented nevi with natural ulceration (Type 4). Differences in clinicopathological features, genetic alterations, and tumor immune microenvironment (TIME) were analyzed. Traumatic events accounted for a large proportion of AM cases. Among these categories, Type 1 patients displayed the least favorable pathological traits and an immunosuppressive TIME. Common copy number variations (CNVs) were observed in CCND1, RB1, FGF19, and IL7R, while CNVs in CDK4 and TERT occurred less frequently in patients with a history of trauma (Type 1 and Type 3). Type 2 patients exhibited the most favorable pathological characteristics and genetic profiles, and demonstrated the lowest incidence of CCDN1 and RB1 CNVs but had the highest CDK4 CNVs. In contrast, the pathological behavior of Type 3 and Type 4 patients was in between Type 1 and Type 2. And patients in Type 3 and Type 4 displayed a more favorable overall microenvironment. This study provides a clinical classification of Chinese AM based on diverse clinical onset characteristics and highlights the important role of trauma in AM. These findings may help to guide the diagnosis, treatment, and prognosis of AM patients. Further investigations are imperative to elucidate the underlying mechanisms governing the association between trauma and AM.

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia.

The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

Alcohol drinking, DNA methylation and psychiatric disorders: A multi-omics Mendelian randomization study to investigate causal pathways.

Whether alcohol-related DNA methylation has a causal effect on psychiatric disorders has not been investigated. Furthermore, a comprehensive investigation into the causal relationship and underlying mechanisms linking alcohol consumption and psychiatric disorders has been lacking. This study aimed to evaluate the causal effect of general alcohol intake and pathological drinking behaviors on psychiatric disorders, alcohol-associated DNA methylation on gene expression and psychiatric disorders, and gene expression on psychiatric disorders. Two-sample design Mendelian randomization (MR) analysis. Various sensitivity and validation analyses, including colocalization analysis, were conducted to test the robustness of the results. Genome-wide association study (GWAS) data mainly from GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetics of DNA Methylation Consortium (GoDMC) and Psychiatric Genomics Consortium (PGC) with European ancestry. The GWAS summary data on general alcohol intake (drinks per week, n = 941 280), pathological drinking behaviors (including alcohol use disorder [AUD, n = 313 959] and problematic alcohol use [PAU, n = 435 563]) and psychiatric disorders (including schizophrenia, major depressive disorder and bipolar disorder, n = 51 710-500 199) were included. Alcohol-related DNA methylation CpG sites (n = 9643) and mQTL data from blood (n = 27 750) and brain (n = 1160), BrainMeta v2 and GTEx V8 eQTL summary data (n = 73-2865) were also included. Genetic variants were selected as instrumental variables for exposures, including drinks per week, AUD, PAU, alcohol-related DNA methylation CpG sites (mQTL) and genes selected (eQTL). Pathological drinking behaviors were associated with an increased risk of psychiatric disorders after removing outliers or controlling for alcohol consumption. MR analysis identified 10 alcohol-related CpG sites with colocalization evidence that were causally associated with psychiatric disorders (P = 1.65 × 10-4-7.52 × 10-22). Furthermore, the expression of genes (RERE, PTK6, GATAD2B, COG8, PDF and GAS5) mapped to these CpG sites in the brain, led by the cortex, were significantly associated with psychiatric disorders (P = 1.19 × 10-2-3.51 × 10-7). Pathological drinking behavior and alcohol-related DNA methylation appear to have a causal effect on psychiatric disorders. The expression of genes regulated by the alcohol-related DNA methylation sites may underpin this association.

Abstract 1057: A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies

Abstract Background: Recent studies have demonstrated that blood-based multi-cancer early detection (MCED) approaches may hold promise for identifying asymptomatic cancer patients from general population. However, most studies only exploit a single aspect of cancer hallmarks, which is challenging for the biological reasons as cancer is a heterogenous disease with a wide spectrum of pathological and clinical behaviors. Here we report a multi-omics MCED assay named SeekInCare, a CE-IVD Mark blood test, which incorporates genomic hallmarks: copy number aberrations, fragment size, end motifs and oncogenic viruses via shallow whole genome sequencing from cfDNA, and seven plasma protein tumor markers in 8 ml blood. Methods: SeekInCare was developed using several retrospective cohorts and the method has been described in a publication (DOI: 10.1016/j.jmoldx.2021.06.003) IF: 4.1 Q2. Results: We present the validation in a retrospective cohort consisting of 584 non-cancer individuals and 617 cancer patients covering 27 cancer types. SeekInCare achieved 65.5% sensitivity at 97.9% specificity, resulting in an AUC of 0.936. The sensitivities were 46.9%, 60.0%, 68.9%, 81.8% in stage I, II, III, IV patients. The sensitivities of 10 common cancer types are as the following: breast (46.2%), stomach (46.4%), colorectum (56.5%), gallbladder (60.0%), lung (62.8%), pancreas (64.7%), lymphoma (68.5%), esophagus (70.0%), liver (77.5%), and leukemia (86.7%). These cancer types account for 73.5% of cancer incidence and 81.8% of cancer-related mortality in China. We prospectively evaluated SeekInCare in a real-world cohort consisting of 1203 individuals who received the test as a laboratory developed test (median follow-up time: 753 days) in which it achieved 60.0% sensitivity, 96.1% specificity, 11.5% PPV and 99.7% NPV. Conclusion: The performances of SeekInCare in both retrospective and prospective studies demonstrate that SeekInCare is an effective blood-based MCED test with similar performance as Grail’s Galleri test, which paves the way for clinical utility as a cancer screening test in average-risk populations. Citation Format: Mao Mao, Shiyong Li, Qingqi Ren, Yi Luan, Weijie Liang, Shuaipeng Geng, Dao-Ling Huang, Dandan Zhu, Yinyin Chang, Wei Wu, Yingying Zhang, Linfeng Zhang, Yan Wang, Yumin Feng, Bing Wei, Jie Ma, Chaohui Duan, Guanghui Long. A blood-based multi-omics test for multicancer early detection: Combined retrospective and prospective studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1057.

Analyzing Robustness of Angluin's L$^*$ Algorithm in Presence of Noise

Angluin's L$^*$ algorithm learns the minimal deterministic finite automaton (DFA) of a regular language using membership and equivalence queries. Its probabilistic approximatively correct (PAC) version substitutes an equivalence query by numerous random membership queries to get a high level confidence to the answer. Thus it can be applied to any kind of device and may be viewed as an algorithm for synthesizing an automaton abstracting the behavior of the device based on observations. Here we are interested on how Angluin's PAC learning algorithm behaves for devices which are obtained from a DFA by introducing some noise. More precisely we study whether Angluin's algorithm reduces the noise and produces a DFA closer to the original one than the noisy device. We propose several ways to introduce the noise: (1) the noisy device inverts the classification of words w.r.t. the DFA with a small probability, (2) the noisy device modifies with a small probability the letters of the word before asking its classification w.r.t. the DFA, (3) the noisy device combines the classification of a word w.r.t. the DFA and its classification w.r.t. a counter automaton, and (4) the noisy DFA is obtained by a random process from two DFA such that the language of the first one is included in the second one. Then when a word is accepted (resp. rejected) by the first (resp. second) one, it is also accepted (resp. rejected) and in the remaining cases, it is accepted with probability 0.5. Our main experimental contributions consist in showing that: (1) Angluin's algorithm behaves well whenever the noisy device is produced by a random process, (2) but poorly with a structured noise, and, that (3) is able to eliminate pathological behaviours specified in a regular way. Theoretically, we show that randomness almost surely yields systems with non-recursively enumerable languages.

Psychometric properties of the exercise addiction inventory (EAI) questionnaire among physically active young adults

BackgroundExercise addiction (EA) is a pathological behavior pattern in which a person loses control over his exercise habits and exercises excessively and suffers negative consequences for his health and even his social life. One of the best tools to measure EA is EAI. The aim of this study was to examine the psychometric properties of the EAI among Iranian physically active young adults.MethodsParticipants were randomly selected from sports clubs in Tabriz, Iran. A total of 200 questionnaires were completed. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted along with tests of convergent validity. Reliability was assessed using Cronbach’s alpha and test-retest methods.ResultsEFA indicated a one-factor structure explaining 40.43% of variance. CFA confirmed the one-factor model with good fit (Root Mean Square Error of Approximation [RMSEA] = 0.076; Comparative Fit Index [CFI] = 0.968). Internal consistency was acceptable (Cronbach’s alpha = 0.71) and convergent validity was adequate. Test-retest reliability was also adequate (intraclass correlation coefficient [ICC] = 0.71).ConclusionThe results of our study show that the Persian EAI has satisfactory psychometric properties and can be used as a valid tool to assess EA.

The Risk of Eating Disorders in Adolescent Athletes: How We Might Address This Phenomenon?

Eating disorders are psychiatric and behavioral health pathologies of high complexity and different etiology, which can affect age groups, sexes, and ethnicities indistinctly. This study aimed to evaluate the risk of eating disorders and the possible relation with the sports profile of Colombian adolescent athletes. This was an exploratory cross-sectional quantitative study that used an online form designed with a sociodemographic questionnaire and the EAT-26 scale to determine the eating disorder risk of the object population. A total of 354 adolescent athletes participated. There were 182 men and 172 women and the mean age was 15.59 (range: 10-19 years, SD = 1.938). The participants presented a significantly low risk of eating disorders (21.2%) with no differences in prevalence between both sexes. The risk of eating disorder was related to the result of the last competition (p = 0.01), the type of sport (p = 0.032), the years of sports practice (p = 0.004), and the number of training hours a day (p = 0.011). It is relevant to recognize that adolescents and athletes are vulnerable populations regarding eating disorders. In conclusion, adolescent athletes should be the object of special attention to prevent eating disorders and their consequences on health and sports performance.

MSR405: Inhibiting Neuroinflammation after Spinal Cord Injury in Rats.

The treatment of spinal cord injury (SCI) is often ineffective. Additionally, SCI-induced inflammation leads to secondary injury. Current anti-inflammatory hydrophilic drugs fail to reach the nerve injury site due to the blood-brain barrier. Here, we synthesized MSR405, a new lipophilic unsaturated fatty acid derivative of Radix Isatidis and investigated its therapeutic effect in SCI model rats. Furthermore, we systematically investigated its structure, toxicity, anti-inflammatory effect, and the underlying mechanism. MSR405 was injected into the abdominal cavity of the Sprague Dawley SCI model rats, and the effect on their behavioral scores and pathology was estimated to assess the status of neurological inflammation. Our data show that MSR405 treatment significantly improved the motor function of SCI rats, and markedly suppressed the associated neuroinflammation. Moreover, MSR405 could attenuate LPS-induced inflammatory response in BV2 cells (Mouse microglia cells) in vitro. Mechanistically, MSR405 inhibits proinflammatory cytokines, supporting the anti-inflammatory response. Additionally, MSR405 can significantly block the TLR4/NF-κB signaling pathway and nitric oxide production. In summary, MSR405 reduces inflammation in SCI rats through the TLR4/NF-κB signal cascade and can inhibit neuroinflammation after spinal cord injury.

Digital twinning of the human ventricular activation sequence to Clinical 12-lead ECGs and magnetic resonance imaging using realistic Purkinje networks for in silico clinical trials

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions.

Measuring Pathological and Nonpathological Orthorexic Behavior: Validation of the Teruel Orthorexia Scale (TOS) among Polish Adults.

Measuring orthorexia nervosa is challenging due to the use of various existing tools and problems with sample representativeness. Another challenge for the Polish population is the adaptation of existing research tools and the evaluation of their relevance and research reliability. Our research aimed to adapt the TOS to the Polish language and measure pathological and nonpathological orthorexic behavior among the Polish population. The adaptation of the PL-TOS has high psychometric value and allows us to assess healthy and nervous orthorexia levels. This scale can be used not only for further research but also for diagnostic purposes in the daily work of clinicians and psychologists. Our results obtained in the present study indicate a correlation between TOS and both the use of supplements and diet. Higher TOS, ORTO_R and KZZJ_Diet Restrictions scores were obtained for individuals using dietary supplements than for those not using dietary supplements. In the future, it is worth conducting research aimed at various risk groups of individuals with orthorexia to confirm the psychometric properties of this adaptation of the TOS.

Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.

Ceftriaxone alters the gut microbiome composition and reduces alcohol intake in male and female Sprague–Dawley rats

Ceftriaxone is an antibiotic that increases central nervous system (CNS) protein expression of the glutamate transporters GLT-1 and xCT and ameliorates pathological behaviors in rodent models of neurological disease and substance use disorder. However, little ceftriaxone passes through the blood–brain barrier, the CNS binding partner of ceftriaxone is unknown, and ceftriaxone does not consistently upregulate GLT-1 and xCT in cell culture. Ceftriaxone alters the gut microbiome composition in rodents and humans, and the microbiome–gut–brain axis regulates drug-seeking. Thus, here we test the hypothesis that ceftriaxone reduces alcohol intake while ameliorating alcohol-induced disruption of the gut microbiome composition. Male and female Sprague–Dawley rats received intermittent access to alcohol (IAA) while controls received access to only water. Following 17 IAA sessions, ceftriaxone/vehicle treatment was given for 5 days. Analysis of the gut microbiome composition was assessed by 16S rRNA gene amplicon sequencing conducted on fecal pellets collected prior to and after alcohol consumption and following ceftriaxone treatment. Male rats displayed escalated alcohol intake and preference over the course of the 17 sessions; however, total alcohol intake did not differ between the sexes. Ceftriaxone reduced alcohol intake and preference in male and female rats. While alcohol affected a diverse set of amplicon sequencing variants (ASV), ceftriaxone markedly reduced the diversity of microbial communities reflected by a blooming of the Enterococcaceae family. The remaining effects of ceftriaxone, however, encompassed families both affected and unaffected by prior alcohol drinking and highlight the Ruminococcaceae and Muribaculaceae families as bidirectionally modulated by alcohol and ceftriaxone. Altogether, our study confirms that ceftriaxone reduces alcohol intake in rats and partially reverses alcohol-induced dysbiosis.