Miracle-dz/UniFAR-FTUs huggingface dataset:
On the Resistance to Relapse to Cocaine-Seeking Following Impairment of Instrumental Cocaine Memory Reconsolidation

Reconsolidation normally functions to update and maintain memories in the long-term. However, this process can be disrupted pharmacologically to weaken memories. Exploiting such experimental amnesia to disrupt the maladaptive reward memories underpinning addiction may provide a novel therapeutic avenue to prevent relapse. Here, we tested whether targeted disruption of the reconsolidation of instrumental (operant) lever pressing for cocaine resulted in protection against different forms of relapse in a rat self-administration model. We first confirmed that systemic injection of the non-competitive N-methyl–D-aspartate receptor (NMDAR) antagonist MK-801 did impair reconsolidation to reduce spontaneous instrumental drug-seeking memory at test. This deficit was not rescued by pharmacological induction of stress with the anxiogenic α2-noradrenergic receptor antagonist yohimbine. In contrast, cocaine-seeking was restored to control levels following priming with cocaine itself, or presentation of a cocaine-associated cue. These results suggest that while stress-induced relapse can be reduced by disruption of instrumental memory reconsolidation, the apparent sparing of the pavlovian cue-drug memory permitted other routes to relapse. Therefore, future reconsolidation-based therapeutic strategies for addictive drug-seeking may need to target both instrumental and pavlovian memories.
Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.
Genetics and Omics Analysis of Autoimmune Skin Blistering Diseases

Autoimmune blistering diseases (AIBDs) of the skin are characterized by autoantibodies against different intra-/extracellular structures within the epidermis and at the basement membrane zone (BMZ). Binding of the antibodies to their target antigen leads to inflammation at the respective binding site and degradation of these structures, resulting in the separation of the affected skin layers. Clinically, blistering, erythema and lesions of the skin and/or mucous membranes can be observed. Based on the localization of the autoantigen, AIBDs can be divided into pemphigus (intra-epidermal blistering diseases) and pemphigoid diseases (sub-epidermal blistering diseases), respectively. Although autoantigens have been extensively characterized, the underlying causes that trigger the diseases are still poorly understood. Besides the environment, genetic factors seem to play an important role in a predisposition to AIBDs. Here, we review currently known genetic and immunological mechanisms that contribute to the pathogenesis of AIBDs. Among the most commonly encountered genetic predispositions for AIBDs are the HLA gene region, and deleterious mutations of key genes for the immune system. Particularly, HLA class II genes such as the HLA-DR and HLA-DQ alleles have been shown to be prevalent in patients. This has prompted further epidemiological studies as well as unbiased Omics approaches on the transcriptome, microbiome, and proteome level to elucidate common and individual genetic risk factors as well as the molecular pathways that lead to the pathogenesis of AIBDs.
Acute MR-Guided High-Intensity Focused Ultrasound Lesion Assessment Using Diffusion-Weighted Imaging and Histological Analysis

Objectives: The application of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of neurological conditions has been of increasing interest. Conventional MR imaging can provide structural information about the effect of MRgFUS, where differences in ablated tissue can be seen, but it lacks information about the status of the cellular environment or neural microstructure. We investigate in vivo acute changes in water diffusion and white matter tracts in the brain of a piglet model after MRgFUS treatment using diffusion-weighted imaging (DWI) with histological verification of treatment-related changes. Methods: MRgFUS was used to treat the anterior body of the fornix in four piglets. T1 and diffusion-weighted images were collected before and after treatment. Mean diffusion-weighted imaging (MDWI) images were generated to measure lesion volumes via signal intensity thresholds. Histological data were collected for volume comparison and assessment of treatment effect. DWI metric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were generated for quantitative assessment. Fornix-related fiber tracts were generated before and after treatment for qualitative assessment. Results: The volume of treated tissue measured via MDWI did not differ significantly from histological measurements, and both were significantly larger than the treatment cell volume. Diffusion metrics in the treatment region were significantly decreased following MRgFUS treatment, with the peak change seen at the lesion core and decreasing radially. Histological analysis confirmed an area of coagulative necrosis in the targeted region with sharp demarcation zone with surrounding brain. Tractography from the lesion core and the fornix revealed fiber disruptions following treatment. Conclusions: Diffusion maps and fiber tractography are an effective method for assessing lesion volumes and microstructural changes in vivo following MRgFUS treatment. This study demonstrates that DWI has the potential to advance MRgFUS by providing convenient in vivo microstructural lesion and fiber tractography assessment after treatment.
Adaptive Features of Natural Killer Cells in Multiple Sclerosis

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(–), and PLZF(–) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(–) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(–) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(–) CD56dim NK cells in HCMV(+) and increased PLZF(–) CD56bright NK cells in HCMV(–) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(–) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.
Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors

Objectives: Thymic epithelial tumors (TETs) are rare malignant tumors that exhibit heterogeneous histology and clinical behavior. As immune check point inhibitors, drugs targeting anti-programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown remarkable results against many cancers; thus, the importance of PD-1/PD-L1 immunohistochemistry as a predictive or prognostic biomarker has grown. However, limited data on PD-L1 and PD-1 expression in TETs have been reported; moreover, these results have been variable. Here, we examined the expression of PD-1/PD-L1 proteins in TETs and analyzed the clinicopathologic significance of this expression. Patients and Methods: A tissue microarray was constructed using 368 samples of TETs, each in triplicate. Immunohistochemistry for PD-L1 (SP263 assay) and PD-1 in TETs and CD8 in thymic carcinoma (TC) was performed; next, correlations with clinicopathologic characteristics were analyzed. PD-L1high was designated as ≥50% of tumor proportion score; PD-1high and CD8high were defined as ≥5% and 1% of tumoral immune cells, respectively. Results: The cohort consisted of 308 patients with thymomas and 60 patients with TC. PD-L1 positivity was identified in 90.6% (328/362, ≥1%) of TETs, PD-1 expression of intra-/peritumoral T cells was identified in 53.6% (194/362) of TETs and CD8 positivity was identified in 11% (7/60, ≥1%) of TC. Of the 362 patients, 141 (39.0%) exhibited high PD-L1 expression (PD-L1high). The PD-L1high thymoma group was correlated with high Masaoka-Koga stage (p < 0.001), type B3 histology (p < 0.001), and myasthenia gravis (p < 0.001). This group exhibited poor overall survival (OS, p = 0.003, log-rank) and worse disease-free survival (DFS, p = 0.042, log-rank). No survival differences were detected between PD-L1high and PD-L1low groups in TC. Additionally, there was no correlation between PD-1 expression and survival in patients with TETs. Multivariate analysis revealed that PD-L1high expression was an independent poor prognostic factor (p = 0.047, HR 2.087, 95% CI, 1.009–4.318) in thymomas. Conclusions: To our knowledge, this is the largest study on TETs published in English literature. This study provides useful information regarding the prognosis of and potential therapeutic options for patients with TETs.
Effects of a Brief Stair-Climbing Intervention on Cognitive Performance and Mood States in Healthy Young Adults

Objective Previous studies focused on the benefits of acute exercise on cognition and mood have mostly used specialized laboratory-based equipment, thus little is known about how such protocols generalize to naturalistic settings. Stair climbing is a simple and readily accessible means of exercise that can be performed in naturalistic settings (e.g., at home or at the workplace). In the present study we examined the effects of stair-climbing intervals on subsequent cognitive performance and mood in healthy young adults. Method Thirty-two undergraduate students (Mage = 19.4 years, SD = 1.3; 21 females) completed a controlled randomized crossover trial with session order counterbalanced across participants. Participants visited the lab on two occasions, one week apart, and completed one control session (no exercise) and one stair-climbing session (3 × 1 min stair-climbing intervals) with cognitive performance and mood assessed at the end of each session. Results Repeated measures ANCOVA revealed that males (Hedges’ gav = 0.45) showed better switching performance following the stair climbing but females (Hedges’ gav < 0.03) did not. Participants felt more energetic (Hedges’ gav = 1.05), less tense (Hedges’ gav = 0.61), and less tired (Hedges’ gav = 0.43) following the stair climbing. In addition, higher exercise intensity during the stair climbing predicted better subsequent switching performance and higher energetic ratings. Conclusion These findings indicate that short bouts of stair climbing in a naturalistic setting can induce cognitive benefits for more challenging tasks, albeit only in males, indicating a sex-specific effect. Short bouts of stair climbing can be a practical approach to increase feelings of energy in daily life.
Conserving the Last Great Forests: A Meta-Analysis Review of the Drivers of Intact Forest Loss and the Strategies and Policies to Save Them

The conservation of Earth’s remaining intact forests (IFs) is a global priority, but improved understanding of the causes and solutions to IF loss is urgently needed to improve conservation efforts. This meta-analysis examines 207 case studies of IF loss occurring since 1970 to identify the multi-scale drivers of forest change and proposed case-specific solutions to IF loss. The goal of this study is to build a portfolio of conservation best practices for retaining IFs. The most frequently reported direct drivers of IF loss were logging, agriculture, ranching, and infrastructure expansion. Mining and fire were also prominent threats to IFs in selected areas. Indirect drivers of IF loss varied between continents, with high demographic pressures driving forest loss in Latin America, Asia, and Africa, contrasting with North America and Europe-Russia. Indirect economic and socio-political drivers were most frequently reported at the national scale for all continents studied, indicating a central role for national institutions in IF loss and conservation. Decisive socio-political factors underlying IF loss worldwide include political failures, institutional failures, and pro-development policies. A wide range of conservation interventions were recommended in the case studies. The proposed actions were most frequently within the forest, finance, and education and science sectors, and also emphasized inter-sectoral activities. Based on the results of this study, three core approaches to IF conservation that can be combined at the landscape scale are identified: protected areas, payments for ecosystem services, and agricultural reforms. Related enabling conditions include cooperative landscape management, effective enforcement, and political advocacy. The success of IF conservation efforts ultimately depends on sustained political support and the prioritization of high-value forest landscapes. Such efforts should mitigate socio-economic pressures through policy mixes that are cross-sectoral and place-based. Key policy priorities for IF conservation include addressing the systemic failures of public institutions, increasing political support for IF conservation, and countering harmful development activities.
Nanodomain Clustering of the Plant Protein Remorin by Solid-State NMR

Nanodomains are dynamic membrane subcompartments, enriched in specific lipid, and protein components that act as functional platforms to manage an abundance of cellular processes. The remorin protein of plants is a well-established nanodomain marker and widely serves as a paradigm to study nanodomain clustering. Located at the inner leaflet of the plasma membrane, remorins perform essential functions during signaling. Using deuterium and phosphorus solid-state NMR, we inquire on the molecular determinants of the lipid-protein and protein-protein interactions driving nanodomain clustering. By monitoring thermotropism properties, lipid acyl chain order and membrane thickness, we report the effects of phosphoinositides and sterols on the interaction of various remorin peptides and protein constructs with the membrane. We probed several critical residues involved in this interaction and the involvement of the coiled-coil homo-oligomerisation domain into the formation of remorin nanodomains. We trace the essential role of the pH in nanodomain clustering based on anionic lipids such as phosphoinositides. Our results reveal a complex interplay between specific remorin residues and domains, the environmental pH and their resulting effects on the lipid dynamics for phosphoinositide-enriched membranes.
Sensorimotor and Posterior Brain Activations During the Observation of Illusory Embodied Fake Hand Movement

In the rubber hand illusion (RHI), the subject recognizes a fake hand as his or her own. We recently found that the observation of embodied fake hand movement elicited mu-rhythm (8–13 Hz) desynchronization on electroencephalography (EEG), suggesting brain activation in the sensorimotor regions. However, it is known that mu-rhythm desynchronization during action observation is confounded with occipital alpha-rhythm desynchronization, which is modulated by attention. This study examined the independence of brain activities in the sensorimotor and occipital regions relating to the movement observation under the RHI. The invisible participant’s left and fake right hands were stroked simultaneously, which was interrupted by unexpected fake hand movements. A mirror-reversed image of the fake hand was shown on a monitor in front of the participant with a delay of 80, 280, or 480 ms. Illusion strength decreased as a function of the delay. EEG independent component analysis (ICA) and ICA clustering revealed six clusters with observation-induced desynchronization of 8–13 Hz frequency band. In the right sensorimotor cluster, mu-rhythm desynchronization was the greatest under the 80-ms delay, while alpha-rhythm desynchronization of the occipital clusters did not show delay-dependence. These results suggest that brain activation in the sensorimotor areas (i.e., mu-rhythm desynchronization) induced by embodied fake hand movement is independent of that in the occipital areas (alpha-rhythm desynchronization).
Change-Related Acceleration Effects on Auditory Steady State Response

Rapid detection of sensory changes is important for survival. We have previously used change-related cortical responses to study the change detection system and found that the generation of a change-related response was based on sensory memory and comparison processes. However, it remains unclear whether change-related cortical responses reflect processing speed. In the present study, we simultaneously recorded the auditory steady-state response (ASSR) and change-related response using magnetoencephalography to investigate the acceleration effects of sensory change events. Overall, 13 healthy human subjects (four females and nine males) completed an oddball paradigm with a sudden change in sound pressure used as the test stimulus, i.e., the control stimulus was a train of 25-ms pure tones at 75 dB for 1,200 ms, whereas the 29th sound at 700 ms of the test stimulus was replaced with a 90-dB tone. Thereafter, we compared the latency of ASSR among four probabilities of test stimulus (0, 25, 75, and 100%). For both the control and test stimulus, stronger effects of acceleration on ASSR were observed when the stimulus was rarer. This finding indicates that ASSR and change-related cortical response depend on physical changes as well as sensory memory and comparison processes. ASSR was modulated without changes in peripheral inputs, and brain areas higher than the primary cortex could be involved in exerting acceleration effects. Furthermore, the reduced latency of ASSR clearly indicated that a new sensory event increased the speed of ongoing sensory processing. Therefore, changes in the latency of ASSR are a sensitive index of accelerated processing.
Trans-Cultural Validation of the “Academic Flow Scale” (Flow 4D 16) in Arabic Language: Insights for Occupational and Educational Psychology From an Exploratory Study

Background: As an optimal psychological state, flow represents those moments when everything comes together for the performer. Flow is often associated with high levels of performance and is a positive psychological experience. Aim: Our study aimed to validate the “Academic Flow Scale” (Flow 4D 16) in Arabic language across Tunisian population, and to test its factor structure, in terms of internal consistency/reliability, predictive validity, and sensitivity. Methods: The population is composed of 320 students (139 men and 181 women) belonging to the University of Sfax, with a mean age of 22.26 years. The students voluntarily responded to the scale of academic flow (Flow 4D 16). Both exploratory (EFA) and confirmatory (CFA) factor analyses were performed. Results: The four-dimensional alpha coefficients of the Flow 4D 16 indicate an excellent internal consistency, respectively, of 0.902 (Cognitive), 0.959 (Time), 0.974 (Ego) and 0.960 (Well-being). The CFA fit indices were satisfactory. Conclusion: In summary, the 16-items model (original version) showed for all the indices an excellent fit to the theoretical model, confirming the four-dimensional factor structure among Tunisian student population.