Miracle-dz/UniFAR-FTUs huggingface dataset:
Neural Circuit and Clinical Insights from Intraoperative Recordings During Deep Brain Stimulation Surgery

Observations using invasive neural recordings from patient populations undergoing neurosurgical interventions have led to critical breakthroughs in our understanding of human neural circuit function and malfunction. The opportunity to interact with patients during neurophysiological mapping allowed for early insights in functional localization to improve surgical outcomes, but has since expanded into exploring fundamental aspects of human cognition including reward processing, language, the storage and retrieval of memory, decision-making, as well as sensory and motor processing. The increasing use of chronic neuromodulation, via deep brain stimulation, for a spectrum of neurological and psychiatric conditions has in tandem led to increased opportunity for linking theories of cognitive processing and neural circuit function. Our purpose here is to motivate the neuroscience and neurosurgical community to capitalize on the opportunities that this next decade will bring. To this end, we will highlight recent studies that have successfully leveraged invasive recordings during deep brain stimulation surgery to advance our understanding of human cognition with an emphasis on reward processing, improving clinical outcomes, and informing advances in neuromodulatory interventions.
Deep Learning Based on Event-Related EEG Differentiates Children with ADHD from Healthy Controls

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent neuropsychiatric disorders in childhood and adolescence and its diagnosis is based on clinical interviews, symptom questionnaires, and neuropsychological testing. Much research effort has been undertaken to evaluate the usefulness of neurophysiological (EEG) data to aid this diagnostic process. In the current study, we applied deep learning methods on event-related EEG data to examine whether it is possible to distinguish ADHD patients from healthy controls using purely neurophysiological measures. The same was done to distinguish between ADHD subtypes. The results show that the applied deep learning model (“EEGNet”) was able to distinguish between both ADHD subtypes and healthy controls with an accuracy of up to 83%. However, a significant fraction of individuals could not be classified correctly. It is shown that neurophysiological processes indicating attentional selection associated with superior parietal cortical areas were the most important for that. Using the applied deep learning method, it was not possible to distinguish ADHD subtypes from each other. This is the first study showing that deep learning methods applied to EEG data are able to dissociate between ADHD patients and healthy controls. The results show that the applied method reflects a promising means to support clinical diagnosis in ADHD. However, more work needs to be done to increase the reliability of the taken approach.
CD24 expression indicates healthier phenotype and less tendency of cellular senescence in human nucleus pulposus cells

Abstract Identification of specific cell markers is crucial for recognizing functionally healthy nucleus pulposus (NP) cells. The objective of this study was to investigate the role of CD24 expression in adult human NP cells. Cells were retrieved from NP tissues of 20 patients (aged 17–44) operated on for lumbar disc herniation. Based on CD24 expression, NP cells were separated by sorting and then used to examine phenotypic behavior, the effects of culture conditions and cellular senescence pathway related proteins. CD24 expression was positive in 35.5 ± 3.7% (range 9.1–65.2%) of NP cells. Consistently, normoxic expansion and serial passages in monolayers decreased percentage positivity for CD24 in NP cells. CD24– NP cells showed a markedly decreased GSK-3β activity and increased mitogen-activated protein kinase phosphorylation accompanying by an increased β-catenin expression. Higher levels of matrix metalloproteinases, as well as lower levels of ACAN and COL2 in CD24– cells, indicated the breakdown and reduced the formation of key extracellular matrix components. CD24+ NP cells presented a more favorable phenotype while CD24– cells showed a more prominent cellular senescence fate. CD24 in NP cells may be a surrogate marker of healthy cells, in the cell-based therapeutic treatment of degenerative disc disorders.
Multiscale Molecular Dynamics Simulation of Multiple Protein Adsorption on Gold Nanoparticles

A multiscale molecular dynamics simulation study has been carried out in order to provide in-depth information on the adsorption of hemoglobin, myoglobin, and trypsin over citrate-capped AuNPs of 15 nm diameter. In particular, determinants for single proteins adsorption and simultaneous adsorption of the three types of proteins considered have been studied by Coarse-Grained and Meso-Scale molecular simulations, respectively. The results, discussed in the light of the controversial experimental data reported in the current experimental literature, have provided a detailed description of the (i) recognition process, (ii) number of proteins involved in the early stages of corona formation, (iii) protein competition for AuNP adsorption, (iv) interaction modalities between AuNP and protein binding sites, and (v) protein structural preservation and alteration.
Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins

Abstract Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.
How to Diagnose and Treat Local Allergic Rhinitis: A Challenge for Clinicians

Chronic rhinitis is a very common disease that can be divided in various phenotypes. Historically, the condition has been classified into the allergic rhinitis (AR) and non-allergic non-infectious rhinitis (NAR) forms, based on the results of the classical biomarkers of atopy: skin prick test and serum allergen-specific IgE However, this classification does not reflect the complexity of the rhinitis syndrome, as illustrated by the existence of non-atopic rhinitis patients who display a nasal reactivity to environmental allergens. This new phenotype has been termed local allergic rhinitis (LAR) and can be only recognized if an additional test such as the nasal allergen challenge (NAC) is integrated in the diagnostic algorithm for chronic rhinitis. Recent data shows that the NAC is a very safe and reliable technique ready for the clinical practice. LAR is a differentiated rhinitis phenotype which often commences during childhood and quickly progresses towards a clinical worsening and the association of comorbidities in other mucosal organs. Recent evidence supports the existence of a bronchial counterpart of LAR (local allergic asthma), which highlights the pathophysiological links between the upper and lower airways and reinforces the united airways concept. Importantly, several controlled studies have demonstrated the ability of allergen immunotherapy to control LAR symptoms while the therapy is being administered. This review emphasizes the need to implement the NAC in the clinical practice in order to facilitate the recognition of LAR patients, allowing for an early prescription of specific therapies with disease-modifying potential.
Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis

Leishmaniasis is a neglected tropical disease affecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse effects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new effective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-effective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose <10°) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-effective and readily scalable repurposed medicine for VL.
Development of Human Emotion Circuits Investigated Using a Big-Data Analytic Approach: Stability, Reliability, and Robustness

Emotion perception is fundamental to affective and cognitive development and is thought to involve distributed brain circuits. Efforts to chart neurodevelopmental changes in emotion have been severely hampered by narrowly focused approaches centered on activation of individual brain regions and small sample sizes. Here we investigate the maturation of human functional brain circuits associated with identification of fearful, angry, sad, happy, and neutral faces using a large sample of 759 children, adolescents, and adults (ages 8–23; female/male = 419/340). Network analysis of emotion-related brain circuits revealed three functional modules, encompassing lateral frontoparietal, medial prefrontal-posterior cingulate, and subcortical-posterior insular cortices, with hubs in medial prefrontal, but not posterior cingulate, cortex. This overall network architecture was stable by age 8, and it anchored maturation of circuits important for salience detection and cognitive control, as well as dissociable circuit patterns across distinct emotion categories. Our findings point to similarities and differences in functional circuits associated with identification of fearful, angry, sad, happy, and neutral faces, and reveal aspects of brain circuit organization underlying emotion perception that are stable over development as well as features that change with age. Reliability analyses demonstrated the robustness of our findings and highlighted the importance of large samples for probing functional brain circuit development. Our study emphasizes a need to focus beyond amygdala circuits and provides a robust neurodevelopmental template for investigating emotion perception and identification in psychopathology. SIGNIFICANCE STATEMENT Emotion perception is fundamental to cognitive and affective development. However, efforts to chart neurodevelopmental changes in emotion perception have been hampered by narrowly focused approaches centered on the amygdala and prefrontal cortex and small sample sizes. Using a large sample of 759 children, adolescents, and adults and a multipronged analytical strategy, we investigated the development of brain network organization underlying identification and categorization of fearful, happy, angry, sad, and neutral facial expressions. Results revealed a developmentally stable modular architecture that anchored robust age-related and emotion category-related changes in brain connectivity across multiple brain systems that extend far beyond amygdala circuits and provide a new template for investigation of emotion processing in the developing brain.
Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD.

The investigation of extracorporeal photopheresis (ECP) plus standard of care (SoC) (SoC+ECP) in chronic graft-versus-host disease (cGVHD) within prospective, randomized clinical studies is limited, despite its frequent clinical use. This phase 1/pilot study was the first randomized, prospective study to investigate ECP use as first-line therapy in cGVHD, based on the 2015 National Institutes of Health (NIH) consensus criteria for diagnosis and response assessment. Adult patients with new-onset (≤3 years of hematopoietic stem cell transplantation) moderate or severe cGVHD were randomized 1:1 to 26 weeks of SoC+ECP vs SoC (corticosteroids and cyclosporine A/tacrolimus) between 2011 and 2015. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at week 28 in the intention-to-treat population (ITT). Other outcomes included quality of life (QoL) measures and safety. Sixty patients were randomized; ITT included 53 patients (SoC+ECP: 29; SoC: 24). Week 28 ORR was 74.1% (SoC+ECP) and 60.9% (SoC). Investigator-assessed ORR was 56.0% (SoC+ECP) and 66.7% (SoC). Patients treated with SoC experienced a decline in QoL over the 28-week study period; QoL remained unchanged in SoC+ECP patients. Most frequent treatment-emergent adverse events (TEAEs) in SoC+ECP patients were hypertension (31.0%), cough (20.7%), dyspnea (17.2%), and fatigue (17.2%). Seventeen patients (SoC+ECP: 8; SoC: 9) experienced 35 serious adverse events (SAEs). No TEAEs or SAEs were considered related to the ECP instrument or methoxsalen. The encouraging short-term results of this study could inform the design of subsequent studies. This trial was registered at www.clinicaltrials. gov as #NCT01380535.
Adult attachment: Investigating the factor structure of the Relationship Scales Questionnaire.

OBJECTIVE In this study, we aimed to conduct an in-depth psychometric investigation of the Relationships Scales Questionnaire (RSQ). METHOD About 717 UK-based participants responded to an online questionnaire (F = 540, M = 177; age range 18-66 years, M = 25, SD = 8.46). We conducted (a) a series of confirmatory factor analyses (CFA) to test previously published factor models of the RSQ, (b) traditional (exploratory factor analysis and confirmatory factor analysis) and contemporary (exploratory graph analysis) exploratory techniques, followed by (c) validity and reliability analyses. RESULTS Although the RSQ was developed to assess four categories of adult attachment (typological approach - i.e., secure, preoccupied, dismissing, and fearful), our findings do not support the hypothesis that the RSQ delivers a psychometrically consistent measure of adult attachment styles. CONCLUSION The results of the present study suggest that a two-dimensional approach (i.e., anxiety and avoidance) to assessing adult attachment is optimal.
Age‐Related Trends in Home Blood Pressure, Home Pulse Rate, and Day‐to‐Day Blood Pressure and Pulse Rate Variability Based on Longitudinal Cohort Data: The Ohasama Study

Background Home blood pressure is a more accurate prognosticator than office blood pressure and allows the observation of day‐to‐day blood pressure variability. Information on blood pressure change during the life course links the prediction of blood pressure elevation with age. We prospectively assessed age‐related trends in home blood pressure, home pulse rate, and their day‐to‐day variability evaluated as a coefficient of variation. Methods and Results We examined 1665 participants (men, 36.0%; mean age, 56.2 years) from the general population of Ohasama, Japan. A repeated‐measures mixed linear model was used to estimate the age‐related trends. In a mean of 15.9 years, we observed 5438 points of measurements including those at baseline. The home systolic blood pressure linearly increased with age and was higher in men than in women aged <70 years. There was an inverse‐U‐shaped age‐related trend in home diastolic blood pressure. The day‐to‐day home systolic blood pressure linearly increased with age in individuals aged >40 years. However, an U‐shaped age‐related trend in day‐to‐day diastolic blood pressure variability with the nadir point at 65 to 69 years of age was observed. No significant sex differences in the day‐to‐day blood pressure variability were observed (P≥0.22). The average and day‐to‐day variability of home pulse rate decreased with age but were lower and higher, respectively, in men than in women. Conclusions The current descriptive data are needed to predict future home blood pressure and pulse rate. The data also provide information on the mechanism of day‐to‐day blood pressure and pulse rate variability.
Cortical network dynamics are coupled with cognitive aging in rats

Changes in neuronal network activity and increased interindividual variability in memory are among the most consistent features of growing older. Here, we examined the relationship between these hallmarks of aging. Young and aged rats were trained on a water maze task where aged individuals reliably display an increased range of spatial memory capacities relative to young. Two weeks later, neuronal activity was induced pharmacologically with a low dose of pilocarpine and control animals received vehicle. Activity levels were proxied by quantifying the immediate early gene products Arc and c‐Fos. While no relationship was observed between basal, resting activity, and individual differences in spatial memory in any brain region, pilocarpine‐induced marker expression was tightly coupled with memory in all areas of the prefrontal cortex (PFC) and hippocampus examined. The nature of this association, however, differed across regions and in relation to age‐related cognitive outcome. Specifically, in the medial PFC, induced activity was greatest in aged rats with cognitive impairment and correlated with water maze performance across all subjects. In the hippocampus, the range of induced marker expression was comparable between groups and similarly coupled with memory in both impaired and unimpaired aged rats. Together the findings highlight that the dynamic range of neural network activity across multiple brain regions is a critical component of neurocognitive aging.
Treatment Outcomes and Adverse Events from a Standardized Multidrug-Resistant Tuberculosis Regimen in a Rural Setting in Angola.

Treatment for multidrug-resistant tuberculosis (MDR TB) is associated with adverse events (AE). Patients treated with an MDR TB regimen in Hospital Nossa Senhora da Paz, Cubal, Angola, were prospectively enrolled from May 2013 to July 2015. Baseline characteristics, AE, and clinical and microbiological outcomes were recorded. A total of 216 patients were treated with an MDR TB regimen and 179 (82.9%) patients developed at least one AE. The most common AE were elevation of liver enzymes (46.8% of patients), elevated creatinine (44.4% of patients), and ototoxicity (40.7% of patients). Previous TB treatment was associated with the occurrence of AE (OR 4.89, 95% CI: 2.09-11.46, P < 0.001) and months on treatment was associated to severe AE (OR 1.11 95% CI: 1.04-1.18, P = 0.001). Incidence of AE was associated with an unsuccessful outcome (OR 1.23, 95% CI: 1.09-1.40, P = 0.001). Patients treated with MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. The occurrence of AE was associated with an unsuccessful treatment outcome. Successful treatment was achieved in 117 (54.2%) patients. Given the high percentage of patients experiencing AE and the low treatment success rates, more effective and less toxic drugs to treat MDR TB are urgently needed.
Lessons Learned: Gastric Motility Assessment During Driving Simulation

In the era of technological advances and innovations in transportation technologies, application of driving simulators for the investigation and assessment of the driving process provides a safe and suitable testing environment. Although driving simulators are crucial for further improvements in transportation, it is important to resolve one of their main disadvantages–simulator sickness. Therefore, suitable methods for the assessment of simulator sickness are required. The main aim of this paper was to present a non-invasive method for assessing simulator sickness by recording gastric myoelectrical activity–electrogastrography. Open-source hardware for electrogastrography together with recordings obtained in 13 healthy volunteers is presented, and the main aspects of signal processing for artifact cancellation and feature extraction were discussed. Based on the obtained results, it was concluded that slow-wave electrical gastric activity can be recorded during driving simulation by following adequate recommendations and that proposed features could be beneficial in describing non-ordinary electrogastrography signals.
In Situ Temporospatial Characterization of the Glial Response to Prion Infection

Mammalian transmissible spongiform encephalopathies (TSEs) display marked activation of astrocytes and microglia that precedes neuronal loss. Investigation of clinical parallels between TSEs and other neurodegenerative protein misfolding diseases, such as Alzheimer’s disease, has revealed similar patterns of neuroinflammatory responses to the accumulation of self-propagating amyloids. The contribution of glial activation to the progression of protein misfolding diseases is incompletely understood, with evidence for mediation of both protective and deleterious effects. Glial populations are heterogeneously distributed throughout the brain and capable of dynamic transitions along a spectrum of functional activation states between pro- and antiinflammatory polarization extremes. Using a murine model of Rocky Mountain Laboratory scrapie, the neuroinflammatory response to prion infection was characterized by evaluating glial activation across 15 brain regions over time and correlating it to traditional markers of prion neuropathology, including vacuolation and PrPSc deposition. Quantitative immunohistochemistry was used to evaluate glial expression of iNOS and Arg1, markers of classical and alternative glial activation, respectively. The results indicate progressive upregulation of iNOS in microglia and a mixed astrocytic profile featuring iNOS expression in white matter tracts and detection of Arg1-positive populations throughout the brain. These data establish a temporospatial lesion profile for this prion infection model and demonstrate evidence of multiple glial activation states.