Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

There has been significant increase of studies investigating plasma biomarkers of Alzheimer’s and their relationship to cognitive functioning. The impact of ethnicity on this relationship has not been extensively studied. The current research investigated the relationship between the plasma biomarkers of total tau, Aβ40, Aβ42 and NfL and neuropsychological test performance in a bi-ethnic sample of cognitively unimpaired, older community dwelling adults. The 1326 cognitively unimpaired participants drawn from The Health & Aging Brain Study – Health Disparities (HABS-HD) study included 765 Mexican American participants and 860 non-Hispanic White participants with complete plasma biomarkers and neuropsychological testing. Plasma samples were assayed using Simoa technology. Significant differences in concentrations were found for all of the plasma biomarkers. NHWs had significantly higher levels of each of the biomarkers with a lower Aβ42/ Aβ40. With none of the biomarkers related to performance on any of the neuropsychological tests. For MAs, Aβ40 was the only biomarker that was significantly related to neuropsychological test performance. Aβ40 levels were negatively related to performance on Trails A, Trails B and Digit Symbol Substitution. Results suggest that the relationship of these biomarkers to cognitive functioning is impacted by ethnicity and may be domain specific.

Ecuador is an important center of biodiversity of the plant family Amaryllidaceae, specially the subfamily Amaryllidoideae, known as a source of important bioactive molecules. The aim of this study was to assess the chemical and biological potential of four different species of Amaryllidoideae collected in Ecuador: Urceolina formosa, Urceolina ruthiana, Clinanthus incarnatus, and Stenomesson aurantiacum. Sixteen alkaloids were identified in the bulb extract of these species by GC-MS, which the extract of S. aurantiacum exhibiting the greatest structural diversity. The potential of these three genera against Alzheimer’s disease was evaluated by measuring their AChE and BuChE inhibitory activity, revealing that C. incarnatus and U. formosa (from Sucumbíos province) showed the best results with IC50 values of 1.73 ± 0.25 and 30.56 ± 1.56 g·ml-1, respectively. Molecular dynamic assays were conducted to elucidate the possible interactions that occurs among 2-hydroxyanhydrolycorine and AChE enzyme, suggesting some similarity with those observed for galanthamine. This study enhances our understanding of the biodiversity of Amaryllidoideae species from Ecuador, highlighting their potential as a source of chemical compounds with pharmaceutical potential.

Alzheimer's Disease (AD) presents a significant challenge in the wake of its multifaceted nature, characterized by cognitive decline, memory impairment, and neuroinflammation. Despite extensive research, effective pharmacological interventions remain elusive, prompting exploration into non-pharmacological approaches. Microcurrent therapy (MC), utilizing imperceptible currents, has emerged as a potent clinical protocol. While previous studies have focused on its therapeutic effects, this study investigates its impact on neuronal damage and neuroinflammation in an AD mouse model, specifically addressing potential side effects. Utilizing 5xFAD transgenic mice, we examined the effects of MC therapy on neuronal integrity and inflammation. Our findings suggest that MC therapy attenuates memory impairment and reduces neurodegeneration, as evidenced by improved performance in memory tests and preservation of neuronal structure. Additionally, MC therapy significantly decreases amyloid-beta (Aβ) plaque deposition and inhibits apoptosis, indicating its potential to mitigate AD pathology. Our study discovered that MC therapy effectively reduces glial activation by inhibiting the TLR4-MyD88-NFκB pathway, consequently leading to decreased levels of inflammatory factors TNF-α, IL-1β, and IL-6, thus implicating TLR4 in neurodegenerative disease-related neuroinflammation. Furthermore, while our study did not observe significant adverse effects, further clinical trial into potential side effects and neuroinflammatory responses associated with MC therapy is warranted.

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop of new, disease-modifying drugs to treat AD and PD, thereby decreasing the social and economic burdens linked to these NDs.

Late-onset Alzheimer’s disease (LOAD) is a dementia category disease that starts after the age of 65. Progressive problems in thinking, behaviour, learning etc. are its characteristics. Due to its progressive nature, early diagnosis is crucial. A complex pathway mechanism with different risk factors is involved in LOAD progression. A comprehensive study is done on factors causing LOAD, biomarkers used for diagnosis in clinical and preclinical stage of the disease, ML (Machine Learning) techniques to identify disease stage. We reviewed research papers on clinical and preclinical diagnosis of LOAD using ML techniques from biomarker data: MRI, PET image, MMSE, Genome / Gene expression, DNA / RNA binding sites with protein, Epigenetic expression /DNA, methylation, Speech and text. We have listed improvement scope after finding the gaps and scope of using Generative AI and SMOTE (Synthetic Minority Oversampling Technique) for data augmentation. At the end, we have elaborated current use of DL (Deep Learning) and CNN (‘Convolution Neural Network’) in Alzheimer’s disease (AD) diagnosis.

Blood biomarkers represent a promising future for studying cognitive impairment, particularly in Alzheimer's Disease (AD), as they offer a non-invasive alternative to cerebrospinal fluid tests and have potential as population screening tools. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations between Amyloid-β, Total Tau, Phosphorylated Tau (p-tau), Neurofilament Light (Nfl), and Glial Fibrillary Acidic Protein (GFAP) with cognition. The reviewed studies are heterogeneous, varying in design and population (mixed, cognitively impaired, or unimpaired), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ42/Aβ40 ratio. In contrast, Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-tau measures tend to show stronger associations with cognitive functions than other biomarkers, no single blood marker has emerged as predominantly associated with a specific cognitive domain. These findings add to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical evaluations of cognition.

Background: Monogenic Alzheimer's disease (AD) has severe health and socioeconomic repercussions. Its rarest cause are presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD, with unusual clinical and neuroimaging findings in order to provide more information on the pathophysiology and semiology of these patients. Methods: Women aged 69 and 62 years at clinical onset, marked by prominent behavioral and language dysfunction, progressing to severe dementia within three years. Neuroimaging, laboratory study, genetic testing. In addition, a systematic review of the PSEN2-AD were performed. Results: Neuroimaging revealed pronounced frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism. The genetic study unveiled PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del. Both cerebrospinal fluid (CSF) and experimental blood biomarkers shouldered AD etiology. Conclusions: Prominent behavioral and language dysfunction suggesting frontotemporal dementia (FTD) may be underestimated in the literature as a clinical picture in PSEN2 mutations. Thus, it may be reasonable to include PSEN2 in genetic panels when suspecting FTDL. PSEN2 mutations may cause striking WMH, arguably related with myelin disruption induced by amyloid accumulation.

(1) Background: Alzheimer’s Disease (AD) accounts for 70% of dementia cases and with no effective pharmacological treatments, new rehabilitation methods are needed. Motor activities and transcranial direct current stimulation (tDCS) have shown promise in stabilizing and enhancing cognitive functions. Objective: We want to investigate the effects of combined motor or cognitive activity with tDCS on cognitive functions in AD patients. (2) Methods: Patients with mild or moderate AD were randomized into four groups: motor activity or cognitive activity associated with anodic or sham tDCS (MotA, MotS, CogA, CogS). They received two weeks of treatment (45 minutes, 5 days/week), with the first 15 minutes using 2mA tDCS on the dorsolateral prefrontal cortex. Cognitive assessments were conducted pre-treatment (T0), post-treatment (T1), and one week after (T2). (3) Results: Twenty patients were included. Mann-Whitney test showed significant improvements in anodic groups (MotA+CogA) in the global cognitive status (p=.042), in selective attention (p=.012), and sustained attention (p=.012) at T1, but not at T2. In addition, MotA improved in the Picture Recognition Test (p=.027) and in sustained attention (p=.047) at T2. (4) Conclusion: Combined motor or cognitive activity with anodic tDCS could slow cognitive decline in AD patients, with notable improvements in global cognitive state and attention at T1.

Many neurodegenerative diseases are directly related to the formation of toxic protein aggregates, such as Parkinson’s and Alzheimer’s diseases, which are associated with the aggregation of alpha-synuclein (α-syn) and beta-amyloid (Aβ ), respectively. In this context, protein fibrils are the hallmark of these neurodegenerative diseases. In this sense, planning or designing compounds that are capable of preventing or reducing the formation of protein aggregation in the brain can be of fundamental importance for the curative treatment of these diseases. This work presents an in silico and experimental study to investigate the inhibitory potential of the ligands Octovespin (bioinspired by the wasp venom Polybia Occidentalis) and Fraternine-10 (bioinspired by the wasp venom Parachartergus fraternus wasp) against the aggregation of fibrils of the peptides Aβ(17-42) and α-syn, respectively. Using molecular docking and molecular dynamics simulations with 100 ns, the disaggregation capacity of these ligands was studied. The results obtained indicate that Octovespin and Fraternine-10 interact with the Aβ and α-syn protein fibrils throughout the simulation time. The RMSD values and the interactions with amino acids responsible for fibril aggregation demonstrate that both Octovespin and Fraternine-10 have a significant disaggregation potential, which corroborates the observations in vitro and in vivo. Furthermore, experimental results of Fraternine-10 demonstrate an anti-aggregation effect, indicating that it can promote the disaggregation of fibrils and prevent them from aggregating again to form oligomers. These discoveries qualify these molecules as potential candidates to become medicines against Parkinson’s and Alzheimer’s diseases.

Alzheimer's Disease (AD) and Parkinson's Disease (PD) are two neurodegenerative diseases posing a significant disease burden due to their increasing prevalence and socio-economic cost. Traditional therapeutic approaches for these diseases exist but provide limited symptomatic relief without addressing the underlying pathologies. This review examines the potential of immunotherapy, specifically monoclonal antibodies (mAbs), as disease-modifying treatments for AD and PD. We analyze the pathological mechanisms of AD and PD, focusing on the roles of amyloid-beta (Aβ), tau (τ), and alpha-synuclein (α-syn) proteins. We discuss the latest advancements in mAbs therapies targeting these proteins, evaluating their efficacy in clinical trials and preclinical studies. We also explore the challenges faced in translating these therapies from bench to bedside, including issues related to safety, specificity, and clinical trial design. Additionally, we highlight future directions for research, emphasizing the need for combination therapies, improved biomarkers, and personalized treatment strategies. This review aims to provide insights into the current state and future potential of antibody-based immunotherapy in modifying the course of AD and PD, ultimately improving patient outcomes and quality of life.

In this work we looked for a stable and accurate procedure to perform feature selection in datasets with a much higher number of predictors than individuals, as in Genome-Wide Association Studies. Due to the instability in feature selection when many potential predictors are measured, a variable selection procedure is proposed that combines several replications of shrinkage regression models. A weighted formulation is used to define the final predictors. The procedure is applied to investigate Single Nucleotide Polymorphisms (SNPs) predictors associated to Alzheimer’s disease in the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset. Two data scenarios are investigated: one considering only the set of SNPs and another with the covariates age, sex, educational level and APOE4 genotype. The SNP rs2075650 and the APOE4 genotype are given as risk factors for AD, which is in line with the literature, and other four new SNPs are pointed, opening new hypotheses for in vivo analyses. These experiments demonstrate the potential of the new method for stable feature selection.

The following systematic and bibliographic review investigates the intersection between the treatment of cognitive impairments and virtual and augmented reality-based game-oriented applications. The review provides a view into the last 12 years of research. The PubMed Database served as the main source for the review. We defined a comprehensive set of investigation variables and classified three main topics: bibliography, medical, and technical. Of a total of 61 identified articles, 19 were included. The findings from these studies indicate the positive effects of using virtual and augmented reality applications to improve cognitive function and depression. There is also a gap in high-quality evidence since clinical trials have been conducted only with a few patients. Preliminary results indicate positive cognitive and physical well-being effects, but the field demands further investigation to determine the effectiveness. Future research needs to focus on larger studies and the quality of the developed applications. Further, it is important to look at scores like Quality of Living and Satisfaction in Daily Activities to create a functioning environment for the patient.

Objective: Fludeoxyglucose F18 positron emission tomography (FDG PET) can give early clues for diagnosing Alzheimer’s disease (AD). Our objective was to use the same scan to predict Apolipoprotein E4 (ApoE4), known to be a risk factor. A second objective was to determine the brain regions and imaging features associated with this gene allele that can potentially help elucidate the mechanisms of the disease and better comprehend the images. Method: We employed data from 112 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). PET and structural MRI data were co-registered with ANTx, and the Freesurfer tool delineated 95 whole brain, 19 hippocampal, and 9 amygdala regions. Using PyRadiomics we extracted 120 radiomic features from these segments. We employed a hybrid feature selection strategy. The HistGradientBoosting (HGB) classifier was evaluated using stratified five-fold cross-validation. Results: The proposed radiomics model predicted the homozygous ApoE4 genotype, with an AUC of 0.945 an accuracy of 0.875, a sensitivity of 0.914, and a specificity of 0.838. Reducing the feature set to seven key features resulted in a slightly decreased performance (AUC: 0.889). The mean values of the features showed statistically significant (p<0.05) incremental deterioration between different groups of homozygous ApoE4 carriers. Conclusion: Our findings underscore the critical role of specific brain regions and associated features in differentiating ApoE4 carriers. The hippocampus, entorhinal cortex, amygdala, thalamus, and pars orbitalis exhibited significant associations with the ApoE4 genotype. By employing SHAP analysis, we identified key features driving model predictions, enhancing interpretability, and providing insights into the underlying pathophysiology.

Elevated levels of homocysteine (Hcy) and related metabolites are associated with Alzheimer’s disease (AD). Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, and thus is a non-protein amino acid, it can be attached to proteins via an N-homocysteinylation reaction mediated by Hcy-thiolactone. Because N-homocysteinylation is detrimental to protein’s function and biological integrity, Hcy-thiolactone detoxifying enzymes – PON1, BLMH, BPHL – have evolved. This review provides an account of the biological function of these enzymes and of consequences of their impairments leading to phenotypes characteristic of AD.

Cholinesterase (ChE) and secretase (BACE) inhibitors, and fibril- and β-amyloid-suppressing medicines are used to treat Alzheimer's disease (AD) symptomatically. The prevalence and complex nature of AD have increased the urgent need for multi-targeted directed ligands (MTDLs). This is because MTDLs can prevent potential drug-drug interactions during poly-therapy and have a better therapeutic profile than single targeted agents. Using piperazine linker or spacer and two primary scaffolds, benzofuran and 8-hydroxyquinoline, a unique class of multi-targeted medicines was recently reported by our group. These compounds showed re-markable effectiveness in inhibiting Aβ1-42 aggregation and acting as iron chelators.The results prompted us to synthesize an additional series of compounds as multimodal anti-AD agents and investigate its inhibitor activities to ChE (AChE/BChE) and BACE1 enzymes. The resulting in-hibitory effects suggested that the compounds under study might be used to improve cognitive function. The docking analysis' findings revealed that the compounds bind to AChE and BChE by forming H-bond interactions with amino acid residues at binding sites and µ-stacking inter-actions with aromatic residues, whereas the binding to BACE1 only revealed H-bond interac-tions with amino acid residues at binding sites.

Background: Neurocognitive disorders (NCDs) have a variable decline in cognitive function, while loneliness was associated with cognitive impairment and increased dementia risk. In the present study, we examined the associations of loneliness with functional and cognitive status in patients with minor (mild cognitive impairment) and major NCDs (dementia). Methods: We diagnosed mild NCD (n=42) and major NCD (n=164) through DSM-5 criteria on 206 participants aged>65 years using the UCLA 3-Item Loneliness Scale (UCLA-3) to evaluate loneliness, the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales to measure functional status, and Mini-Mental State Examination (MMSE) to assess cognitive functions. Results: In a multivariate regression model, the effect of loneliness on cognitive functions was negative in major (=-1.05-p<.0001) and minor NCD (=-0.06-p<.01). In the fully-adjusted multivariate regression model (sex-age-education-multimorbidity-depressive symptoms-antidementia drug treatment), the effect of loneliness remained negative for major NCD and became positive for minor NCD (=0.09-p<.001). The effect of loneliness on IADL (=-0.26-p<.0001) and ADL (=-0.24-p<.001) showed a negative effect for major NCD across the different models, while for minor NCD, the effect was positive (IADL:=0.26-p<.0001-ADL:=0.05-p=0.01). Minor NCD displayed different levels of MMSE (=6.68-p<.001), but not ADL or IADL, compared to major NCD for the same levels of loneliness. MANOVA pill’s test suggested a statistically significant and different interactive effect of loneliness on functional and cognitive variables between minor and major NCDs. Conclusions: We confirmed the relationships between loneliness and cognitive and functional status in major NCD, observing a novel trend in minor NCD.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

The editorial explores the realm of emerging translational research in neurology and psychiatry, providing insights into various subjects, including neurodegenerative disorders and innovative therapeutic methods. The main objective is to study neurological and psychiatric disorders, such as Alzheimer's disease, with a particular emphasis on techniques for neural regeneration and repair. The editorial highlights the importance of taking a comprehensive approach to studying and treating complex neurological and psychiatric conditions. This involves thoroughly reviewing research papers on the causes, development, biomarkers, and treatment options for these conditions. The editorial emphasizes the necessity of using multidisciplinary and integrative methods to gain a deeper understanding and improve the treatment of these conditions. The development of an animal model for recurrent primary dysmenorrhea showcases the innovative techniques employed in the investigation of gynecological disorders, illustrating the capacity of translational research to connect fundamental scientific knowledge with practical medical applications. The cooperative endeavors of researchers and clinicians emphasized in this editorial lay the foundation for revolutionary advancements that hold the potential to enhance outcomes for individuals afflicted with neurological and psychiatric disorders globally.

(1) Background: Alzheimer’s disease (AD) presents a significant challenge in terms of discovering novel diagnostic methods and therapies. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate the mechanism of action of Apelin-13 in an in vivo model of AD induced by streptozocin (STZ); (2) Methods: We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. The Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests. The main methods included behavioral assessment, histological analysis, and biochemical assays to evaluate synaptic plasticity and oxidative stress signaling pathways; (3) Results: Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated through the enhancement of synaptic plasticity and attenuation of oxidative stress signaling pathways; (4) Conclusions: The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions.

This study aimed to investigate the relationship between sleep duration, dementia severity, age, and ANS regulation. This cross-sectional pilot study included 27 older patients with probable Alzheimer’s disease, hospitalized at a psychiatric center. We measured heart rate variability to assess ANS regulation at night, evaluated dementia severity using the Clinical Dementia Rating scale, and obtained sleep duration data from sleep diaries maintained by psychiatric nurses. The data were analyzed using repeated-measures generalized linear models with age, sex, dementia severity, and medication (antipsychotics) as covariates. A sleep duration of 7–8 h per night was associated with better ANS regulation than other sleep durations, as indicated by sympathovagal balance (p = 0.005). ANS dysregulation was characterized by a 20.7% increase in sympathetic nervous system activity and a 14.8% decrease in parasympathetic nervous system (PSNS) activity. We found a significant correlation between dementia severity and PSNS activity (p = 0.04) and observed an inverted U-shaped association between sleep duration and ANS regulation. This pilot study demonstrated that a sleep duration of 7–8 h per night may be critical in maintaining optimal ANS regulation. Bidirectional associations between sleep duration, inadequate sleep duration, aging, and ANS regulation warrant further investigation.

Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD. We will also extend beyond these mere associations by carefully analyzing the potential mechanisms by which viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, dysregulation of immune responses, and the impact on protein processing. Controversies and challenges of the viral-AD relationship emerge as we tease out these potential mechanisms considered. Looking forward, we emphasize the future directions the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development.

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful noninvasive method which can measure Alzheimer’s disease (AD) related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis, but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers, and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate to develop potential novel therapeutic approaches.

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aβ42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS assay for plasma Ab42/40 into a new multiple analyte blood test and algorithm (PrecivityAD2™) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found: (a) the %p-tau217 assay is precise, accurate, sensitive, linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aβ42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test’s intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

Background: Critical states present scale-free dynamics, optimizing neuronal complexity. We explored electroencephalogram (EEG) criticality in amnesic Mild Cognitive Impairment (aMCI) patients with clinical improvement in working memory, verbal memory, verbal fluency and overall executive functions after the completion of a 6-month prospective memory training. (2) Methods: We compared “before” and “after” stationary resting-state EEG records of right-handed MCI patients (n = 17; 11 females), using the method of critical fluctuations and Haar wavelet analysis. (3) Results: Significant criticality enhancement was present in frontotemporal electrodes [mean dif: 0.10; Z = 7, p = .019] and isolated electrodes T6 [mean dif: 0.204; t (10) = - 2.3, p = .044] and F4 [mean dif: 0.0194; t (10) = - 2.82; p = .018]. (4) Conclusions: EEG criticality agreed with clinical improvement, consisting a possible monitoring biomarker in MCI and Alzheimer’s disease. Further evaluation is needed in patients under cognitive training or even drug-modifying therapies.

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect possibly can increase over time, there is still a need for alternative treatments that will improve the cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed neuroprotective effect against amyloid-beta or energy-deprivation induced neurotoxicity, and increased the levels of brain derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase of BDNF in the brains of 21-months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and progressive deterioration of cognitive functions. Being able to identify reliable biomarkers in easily available body fluids such as blood plasma is vital for the disease. To achieve this, we used a technique that applied human plasma to organotypic brain slice culture via microcontact print-ing. After a 2-week culture period, we performed immunolabeling for neurofilament and myelin oligodendrocyte glycoprotein (MOG) to visualize newly formed nerve fibers and oligodendro-cytes. There was no significant change in the number of new nerve fibers in the AD plasma group compared to the healthy control group, while the length of the produced fibers significantly de-creased. A significant increase in the number of MOG+ dots around these new fibers was detected in the patient group. According to our hypothesis, there are factors in the plasma of AD patients that affect the growth of new nerve fibers, which also affect the oligodendrocytes. Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry us-ing a differential approach and we identified 3 putative biomarkers: aldehyde-dehydrogenase 1A1, alpha-synuclein and protein S100-A4. Our method represents a novel and innovative ap-proach to translate research findings from mouse models to human applications.

Neurodegeneration is becoming one of the leading causes of death worldwide as the population expands and grows older. There is a growing desire to understand the mechanisms behind prion proteins as well as the prion-like proteins that make up neurodegenerative diseases (NDs) including Alzheimer’s Disease (AD). Both amyloid β (Aβ) and hyperphosphorylated tau (p-tau) proteins behave in ways similar to that of the infectious form of the prion protein, PrPSc, such as aggregating, seeding, and replicating under not yet fully understood mechanisms, thus the designation of prion-like. This review aims to highlight the shared mechanisms between prion-like proteins and prion proteins in the structural variations associated with aggregation and disease development. These mechanisms are largely focusing on the dysregulation of protein homeostasis, self-replication, and protein aggregation, and how this knowledge could contribute to diagnoses and treatments for the given NDs.

Oxidative stress and chronic inflammation, both at the systemic and central level, are critical early events in atherosclerosis and Alzheimer’s disease (AD). Purpose. To investigate the oxidative stress, inflammatory, and Tau-phosphorylation lowering effects of pomegranate polyphenols (PP) (punicalagin, ellagic acid, peels, and arils extracts). Methods. We used flow cytometry to quantify protein expression of proinflammatory cytokines (IL-1β) and anti-inflammatory mediators (IL-10) in THP-1 macrophages, as well as M1/M2 cell-specific markers (CD86 and CD163) expression in human microglia HMC3 cells. IL-10 protein expression was also quantified in U373-MG human astrocytes. The effect of PP on human amyloid beta 1-42 (Aβ1-42)-induced oxidative stress was assessed in microglia by measuring ROS generation and lipid peroxidation, using respectively two ′,7′-dichlorofluorescein diacetate (DCFH-DA) and thiobarbituric acid reactive substances (TBARS) tests. Neuronal viability and cell apoptotic response to Aβ1-42 toxicity were assayed using the MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay and the annexinV-FITC apoptosis detection kit; respectively. Finally, flow cytometry analysis was also performed to evaluate the ability of PP to modulate Aβ1-42-induced Tau-181 phosphorylation (pTau-181). Results. Our data indicate that PP was significantly (p<0.05) effective in countering Aβ1-42-induced inflammation through increasing the anti-inflammatory cytokines (IL-10) (in U373-MG astrocytes and THP1 macrophages) and decreasing proinflammatory markers (IL-1β) expression in THP1 macrophages. PP was also significantly (p<0.05) effective in inducing the phenotypic transition of THP-1 macrophages and microglial cells from M1 to M2 by decreasing CD86 and increasing CD163 surface receptor expression. Moreover, our treatments have a significant (p<0.05) beneficial impact on oxidative stress, illustrated in the reduction of TBARS and ROS generation. Our treatments have significant (p<0.05) cell viability improvement capacities and anti-apoptotic effects on human H4 neurons. Furthermore, our results suggest that Aβ1-42 significantly (p<0.05) increases pTau-181. This effect was significantly (p<0.05) attenuated by arils, peels, and punicalagin and drastically reduced by ellagic acid treatments. Conclusion. Our results are attributed to PP's anti-inflammatory, antioxidant, anti-apoptotic, and anti-Tau pathology potential. Future studies should aim to extend our knowledge of the potential role of PP on A1-42-induced neurodegeneration, mainly its association with the tauopathy involved in AD.

The multifactorial nature of some diseases, and in particular neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug-drug interactions or adherence to treatment. The concept of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs, generally, lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines.

An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is reduction of free Aβ level by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) of HSA to improve its affinity for Aβ. Here we develop this approach by bioinformatic search for the clinically approved AD-related LMWLs of HSA, followed by classification of the candidates according to the predicted location of their binding sites on HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into the five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA-Aβ40 interaction: prednisone favors HSA-Aβ interaction, mefenamic acid shows the opposite effect, while levothyroxine exhibits the bidirectional effects. Overall, the LMWLs of HSA chosen here provide a basis for drug repurposing for AD prevention, and for search for the medications promoting AD progression.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from the infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules each of which can downregulate ACE2, while the infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19 associated neurological disorders.

Inhibition of acetylcholinesterase (AChE) enzyme is a known procedure to treat severe Alzheimer's disease through increasing the acetylcholine level in the brain and thus slowing down the progression of Alzheimer's symptoms. The approved medications are only considered as palliative and addressed some reported deficiencies. Therefore, the demand for safe and effective compounds is substantially increasing. A newly series of coumaryl 1,3-selenazoles derivatives was synthesized in four steps. Then, their antioxidant activities were evaluated using DPPH, ABTS cation radical scavenging assay and cupric reducing antioxidant capacities (CUPRAC). The anticholinesterase activities were evaluated using the Ellman method. Then, the docking studies were carried out to explain the possible correlation between in vitro anticholinesterase activity results and the ligand-receptor interactions. Ten new coumaryl 1,3-selenazoles (5a-5d series and 6a-6f series) derivatives were successfully synthesized. The DPPH radical scavenging assay showed that all tested compounds have IC50 value &gt; 200 μM, for ABTS cation radical scavenging assay the IC50 value &gt; 1000 μM and for CUPRAC assay the IC50 value &gt; 200 μM. Compound 5c was found to be the most active compound against AChE and BChE in its series with IC50 value for AChE is 99.76 μM and IC50 for BChE is 140.28 μM while 6b exhibited the most potent inhibition in its series with IC50 value for AChE is 56.01 μM and IC50 for BChE is 121.34 μM. Besides, the docking studies showed that compound 5c and 6b formed π-π stacking interaction with aromatic residues at the active site of AChE and BChE, which is responsible for inhibiting the enzymes. This shows that the synthesized compounds contain skeletal structures that can interact and inhibit within the enzymes active site.

Viral infections leading to inflammation have been implicated in several common diseases such as Alzheimer’s disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus 1 (HSV-1) has been reported to be associated with AD. We sought to identify the transcriptomic changes due to HSV-1 infection and anti-viral drug (acyclovir, ACV) treatment of HSV-1 infection in dissoci-ated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) to gain potential biological insights into the relevance of HSV-1-induced inflammation in AD and T1D. We observed that differentially expressed genes (DEGs) in HSV-1-infected sc-islets were enriched for genes associated with several autoimmune diseases, most significantly T1D but also rheumatoid arthritis, psoriasis, Crohn’s disease, and multiple sclerosis, whereas DEGs in HSV-1-infected dcOrgs were exclusively enriched for genes associated with AD. ACV treatment of sc-islets did not rescue transcript expression of autoimmune disease-associated genes. Finally, we identified gene ontology categories that were enriched for DEGs that were in common across, or unique to, viral treatment of dcOrgs and sc-islets, such as categories involved in the transferase complex, mitochondrial and autophagy function. Collectively, this studies pro-vide insight to the molecular effects of inflammation in AD and T1D.

Our previous research provides evidence that vergence eye movements may significantly influence cognitive processing and could serve as a reliable measure of cognitive issues. The rise of consumer-grade eye tracking technology, which uses sophisticated imaging techniques in the visible light spectrum to determine gaze position, is noteworthy. In our study, we explored the feasibility of using webcam-based eye tracking to monitor the vergence eye movements of patients with Mild Cognitive Impairment (MCI) during a visual oddball paradigm. We simultaneously recorded eye positions using a remote infrared-based pupil eye tracker. Both tracking methods demonstrated more pronounced cognitive vergence responses for targets as opposed to distractors. In summary, the use of a consumer-grade webcam to record cognitive vergence shows potential. This method could potentially lay the groundwork for future research aimed at creating an affordable screening tool for mental health care.

Human endogenous retroviruses (HERV) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV promoting pathological conditions including the development of autoimmunity, neurodegenerative disease and cancer. What infections then trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases Crohn’s, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis and autoimmune thyroiditis. MAP is also associated with Parkinson’s disease. Autoimmune diabetes, multiple sclerosis and rheumatoid arthritis are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via unsilencing of HERV. We examine the link between the ever-increasing number of MAP- associated diseases, the MAP/HERV intersection with these diverse medical conditions and propose treatment opportunities based upon this association.

Alzheimer’s disease (AD), the leading cause of dementia (50-70%), is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and significant neuropathological changes, including β-amyloid plaques and neurofibrillary tangles. This review synthesizes current understanding of the complex interplays that contribute to the pathogenesis of AD, while exploring the mechanisms underlying the formation of β-amyloid plaques and neurofibrillary tangles, with a focus on the amyloidogenic and non-amyloidogenic pathways, Tau protein hyperphosphorylation, and the resultant neurotoxicity. Furthermore, the study delves into mitochondrial dysfunction and oxidative stress as critical contributors to neuronal degeneration, highlighting the mitochondrial cascade hypothesis and its implications in both early (EOAD) and late-onset AD (LOAD). The study emphasizes the irreversible nature of the disease’s progression, detailing the pathological transformations from the preclinical to the severe stage, where lesions disseminate throughout the entire cortex.

One of the most common forms of dementia is Alzheimer’s disease (AD), which leads to progressive mental deterioration. Unfortunately, there is no definitive diagnosis and cure that can stop the condition progressing. The diagnosis is often performed based on the clinical history and neuropsychological data, including magnetic resonance imaging (MRI). Deep neural networks (DNN) algorithms are gaining popularity for medical diagnosis, and have been used widely for the analysis of MRI data. DNNs can extract hidden features from thousands of training images automatically. However, they cannot judge how confident they are about their predictions. To use DNNs in safety-critical applications such as medical diagnosis, uncertainty quantification of DNNs predictions is crucial. For this purpose, Monte Carlo dropout (MCD) has been widely used, however, it may lead to overconfident and miss calibrated results. This paper proposes a framework in which the MCD algorithm’s hyper-parameters are optimized during training using Bayesian optimization for the first time. The conducted optimization leads to assigning high predictive entropy to erroneous predictions and making it possible to recognize risky predictions. The proposed framework is used for AD diagnosis, which has not been done before. We compare our method with some existing methods in the literature based on different uncertainty quantification criteria. The results of comprehensive experiments on the Kaggle dataset using a deep model pre-trained on the ImageNet dataset show that the proposed algorithm can quantify uncertainty much better than the existing methods.

In this work the seismic resilience of the Emergency Department of a real Hospital complex, located in Tuscany (Italy), has been quantified, with special reference to its nonstructural components and organizational features. Special attention has been paid to the ceilings, whose importance stood out in past earthquakes. A comprehensive meta-model has been set, able to relate all the considered parameters to the assumed response quantity, i.e. the waiting time of the red-code patients arriving to the Emergency Department in the hours immediately after the seismic event. The seismic resilience of the Emergency Department has been measured with reference to earthquakes compatible to the seismic hazard of the area.

In this paper, we focus on the influence of Riemann space-time curvature on the laws of electromagnetism, such as Gauss’s law, Maxwell-Amp´ere’s law, and Faraday’s law. Furthermore, we also introduce the work done on the unification of the gravitation and electromagnetic fields.

We present a modified version of the Szilard Engine, demonstrating that an explicit measurement procedure is entirely unnecessary for its operation. By considering our modified engine, we are able to provide a new interpretation of Landauer’s original argument for the cost of erasure. From this view, we demonstrate that a reset operation is strictly impossible in a dynamical system with only conservative forces. Then, we prove that to approach a reset yields an unavoidable instability at the reset point. Finally, we present an original proof of Landauer’s principle that is completely independent from the Second Law of Thermodynamics.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

The WFS1 gene was first identified in Wolfram Syndrome 1 (WS1), a rare autosomal recessive genetic disorder characterized by severe and progressive neurodegenerative changes. WFS1's role in various cellular mechanisms, particularly in calcium homeostasis and the modulation of endoplasmic reticulum (ER) stress, suggests its potential involvement in the pathogenesis of Alzheimer's disease (AD) and psychiatric sleep disorders. Because it is involved in maintaining ER balance, calcium signaling, and stress responses, WFS1 plays a multifaceted role in neuronal health. Numerous studies have shown that the absence or improper expression of WFS1 disrupts these cellular processes, leading to neurodegeneration and making neurons more vulnerable. In AD, WFS1 dysfunction is thought to contribute to the accumulation of amyloid-β (Aβ) plaques and tau tangles, thereby accelerating disease progression. Additionally, WFS1 plays an essential role in sleep regulation by influencing neuronal excitability and neurotransmitter release, which may explain the sleep disturbances frequently observed in neurodegenerative diseases. Due to its involvement in the pathological mechanisms of AD and sleep disorders, WFS1 is regarded as a potential early diagnostic marker for these diseases. Further research is required to fully elucidate WFS1’s role in the cellular pathway, perhaps facilitating the development of new therapeutic strategies for Alzheimer's disease and psychiatric sleep disorders.

Escalation of commitment explains the choice for investing in an option for which great investments have previously been made even though better choices became available. The last 25 years of producing innumerous versions of Alzheimer Disease animal models with virtually no predictive validity should have exposed the fact that using animals for studying AD is clearly a failing course of action and as such should have been abandoned long ago, giving room to other alternatives to flourish. In this assay, I explore the idea that the investment in new animal models for studying Alzheimer (AD) represents a classic case of escalation of commitment, and sunk cost dilemma, in the biomedical research.

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer’s Disease, are a scourge of the aging society, and in case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/ or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here we review current knowledge of tauopathies listing known genetic and important sporadic forms of this disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer’s, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tool and usage of epigenetic therapy strategies for these diseases.

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.

Background/Objectives: This study aimed to evaluate compliance and accuracy in comparison with traditional PD diaries for tracking motor symptoms using a new smartphone application (My Parkinson’s) and paper diary strategies. Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor symptoms. Treatment becomes more challenging as PD progresses, motor complications in the form of wearing-off phenomenon and levodopa-induced dyskinesia develop. Traditional paper diaries and clinical scales used to evaluate patients may be inadequate in assessing whether the patient is “on” or “off,” resulting in less-than-ideal treatment changes. Methods: A randomized crossover design was utilized to examine 22 advanced PD patients who underwent symptomatic assessment with both diaries during two separate 24-hour periods seven days apart. The compliance and accuracy of data were assessed by comparing diary entries with the clinical examination notes and WhatsApp queries. Latterly, patients' diary preferences were also evaluated.; Results: The digital diary had significantly better compliance and accuracy than the paper diaries, with substantial/almost perfect levels of agreement (κ = 0·615 to 0·818) between logged symptoms and clinical examination notes. 65% of patients preferred the digital diary for follow-ups, and there was no significant difference in ease of use compared to paper diaries. Conclusions: Digital diaries are helpful in the clinical management of PD patients as they minimize recall bias and reduce data errors in appropriately selected patients. Our study suggests a broader adoption of digital health technologies in PD management. Still, additional research is necessary to improve the tools and assess long-term patient outcomes.

This study aimed at investigating the quality statuses of graduates’ sustainable core competences development and the causes behind the identified competence statuses by applying the core competencies’ model. The study employed case study design with thematic analysis involving seven interviewees. This study used tracer study findings and national exit exam results as exhibits. The study revealed “very good” and “excellent” quality statuses for the graduates’ core competence development of College of medicine and Health Sciences (CMHS). Similarly, this study identified “Good +” statuses for the quality of graduates’ core competence development in College of Agriculture and Environmental Sciences ( CAES) and College of Science (CS). Furthermore, the study identified "good" - and +” statuses for the quality of graduates’ competence development at the Faculty of Social Sciences (FSS) and Faculty of Humanities (FH). Improved instruction with a balance of theory and practice, task-oriented deans’ leadership behavior with fairness and shared vision- mission identity, handling internal conflicts, and external ethnic-based war influences were the major reasons for the identified higher competence quality statuses in CMHS, CAES, and CS, whereas the opposite direction decline of these factors were the causes for the low statuses of FSS and FH. Sustainable graduates’ core competence development leads to sustainable employability, labor force, and individual to nation-wide holistic sustainable development

These counterexamples have shown the relationships between the power of a Pythagorean equation and Pythagorean’s triples. There are three positive integers that satisfy Fermat’s equation when the power n is equal to 2 in the case of the Pythagorean theorem and it’s applicable relationships in right triangles. On the other hand, as the power varies from positive to negative integers or any integers other than 2, such as in the case of Fermat’s last theorem, the hypotenuse z of a right triangle tends to be equal to one of the sides x or y of the triangle and the other side tends to be equal to zero. And the application of this idea describes the behavior of a mass object in motion. Since the total energy of the object is the sum of its energy in motion and its rest energy, at a particular power n, the total energy of the object tends to be equal to either the rest energy or the photon energy.

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form, and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation, and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB, and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. Inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation, and potential applications.

Alzheimer's disease (AD) is a stealthy and progressive neurological disorder that is a leading cause of dementia in the global elderly population, imposing a significant burden on both the elderly and society. Currently, the condition is treated with medications that alleviate symptoms. Nonetheless, these drugs may not consistently produce the desired results and can cause serious side effects. Hence, there is a vigorous pursuit of alternative options to enhance the quality of life for patients. Ginkgo biloba (GB), an herb with historical use in traditional medicine, contains bioactive compounds such as terpenoids (Ginkgolides A, B, and C), polyphenols, organic acids, and flavonoids (quercetin, kaempferol, and isorhamnetin). These compounds are associated with anti-inflammatory, antioxidant, and neuroprotective properties, making them valuable for cognitive health. A systematic search across three databases using specific keywords GB in AD and dementia yielded 1702 documents, leading to the selection of 15 clinical trials for synthesis. In eleven studies, GB extract/EGb 761® was shown to improve cognitive function, neuropsychiatric symptoms, and functional abilities in both dementia types. In four studies, however, there were no significant differences between the GB-treated and placebo groups. Significant improvements were observed in scores obtained from the Mini-Mental State Examination (MMSE), Short Cognitive Performance Test (SKT), and Neuropsychiatric Inventory (NPI). While the majority of synthesized clinical trials show Ginkgo biloba has promising potential in these conditions, more research is needed to determine optimal dosages, effective delivery methods, and appropriate pharmaceutical formulations. Furthermore, a thorough assessment of adverse effects, exploration of long-term use implications, and investigation into potential drug interactions are critical aspects that must be carefully evaluated in future studies.

Neurodegenerative diseases (NDs) affect millions of people worldwide, and to date Alzheimer's and Parkinson's disease are the most common NDs. The risk of developing NDs increases dra-matically with age, and genetic and environmental factors can be crucial in their progression. The main feature of NDs is the abnormal presence of specific proteins that can lead to neuronal death, proteotoxic stress, and alteration of catabolic systems, which are major players in the processes of neurodegeneration and neuroinflammation. Despite research efforts to date, the therapies cur-rently in use for the treatment of NDs provide marginal therapeutic benefit, so the focus is now being direct toward the search of natural products that could be a valuable aid in combating these diseases, including the natural compound Andrographis paniculata (Ap) and especially its main constituent Andrographolide (Andro). Preclinical studies have shown that the aqueous extract of Ap is capable to modulate neuroinflammatory and neurodegenerative responses, determining a reduction in inflammatory markers and oxidative stress in various NDs. Therefore, in this review we will focus on the molecular mechanisms through which Ap and Andro are able to modulate the processes of neurodegeneration and neuroinflammation that are major causes of neuronal death and cognitive decline.

The most common form of mixed dementia (MixD) is constituted by abnormal protein deposits associated with Alzheimer´s disease (AD) that coexist with vascular disease. Although olfactory dysfunction is considered a clinical sign of AD-related de-mentias, little is known about the impact of this sensorial impairment in MixD at molecular level. To address this gap in knowledge, we have assessed olfactory bulb (OB) proteome-wide expression in MixD subjects (n=6) respect to neurologically intact controls (n=7). Around 9% of the quantified proteins were differentially expressed, pinpointing aberrant proteostasis involved in synaptic transmission, nucleoside monophosphate and carbohydrate metabolisms and neuron projection regeneration. In addition, net-work-driven proteomics revealed a modulation in cell-survival related pathways such as ERK, AKT and PDK1-PKC axis. Part of the differential OB protein set was not specific of MixD, being also deregulated across different tauopathies, synucleinopathies and tardopathies. However, the comparative functional analysis of OB proteome data between MixD and pure AD pathologies deciphered commonalities and differences between both related phenotypes. Finally, olfactory proteomics allowed to propose serum Prolow-density lipoprotein receptor-related protein 1 (LRP1) as a candidate marker to differentiate AD from MixD phe-notypes.

Around 1637, Pierre de Fermat famously wrote in the margin of a book that he had a proof for the equation $a^n + b^n = c^n$ having no positive integer solutions for exponents $n$ greater than 2. This statement, now known as Fermat's Last Theorem, remained unproven for centuries, despite the efforts of countless mathematicians. Andrew Wiles' work in 1994 finally provided a rigorous proof of Fermat's Last Theorem. However, Wiles' proof relied on advanced mathematical techniques that were far beyond the scope of Fermat's time, raising questions about whether Fermat could have truly possessed a proof using the methods available to him. Wiles's achievement was widely celebrated, and he was awarded the Abel Prize in 2016 in recognition of his groundbreaking work. The citation for the award described his proof as a "stunning advance" in mathematics. The present work offers a potential solution to Fermat's Last Theorem that may be more aligned with the original approach that Fermat claimed to have used.

HIGHLIGHTS Mach's principle is linked with inertia and the mass around. Nowadays, physicists believe its effect is infinitesimal, so Mach's principle is simply ignored. This paper looks at the consequence of applying Mach's principle. It could replace dark matter. ABSTRACT After seeing the history of Mach's principle, we will work out a new model of galaxies inspired by Mach’s principle, which is more satisfactory than current dark matter models. This new model is just maths and needs an explanation. One possible explanation is obviously that Mach's principle is at work in a galaxy.

Urban tourism has witnessed significant growth in recent years, driven by various factors that foster the transformation of urban areas into tourist hotspots. These factors include a rising interest in culture and heritage, ongoing urban redevelopment and conversion processes, and the introduction of new experiences and activities. Two particularly influential factors contributing to this growth are low-cost travel, which facilitates more accessible access to urban destinations, and the emergence of new types of accommodation, such as short-term rental (also known as local accommodation or Airbnb-type accommodation). This sudden and continuous growth of this type of tourist accommodation brings new challenges to cities and local communities. On the positive side, it contributes to job opportunities, the dynamism of the local economy, and urban revitalization. On the other hand, it also represents more difficulty in retaining the local population in city centers, as more and more buildings are converted into hostels and tourist apartments. In this context, it becomes essential to conduct studies evaluating the impacts of these dynamics in urban areas and how they influence residents' and visitors' perspectives. Therefore, this study aims to identify the main transformations resulting from short-term rental (STR) development, focusing on the impacts felt by tourists and residents in Porto. A questionnaire was distributed to tourists and residents in Porto's city center in June 2023. The results reveal differences in opinions between tourists and residents, particularly concerning historical heritage preservation, local population relocation, and reduced housing availability for residents. Nevertheless, there is a similarity in their opinions regarding the stimulus that local accommodation brings to the economy and the rehabilitation of buildings and urban areas. This study reinforces the need to pay more attention to the future development of tourist accommodation in city centers, especially regarding local policies and territorial planning, to balance better tourism development and local communities' quality of life.

Although the empirical Kepler’s laws can be proven by applying Newton’s laws to the dynamics of two particles attracted due to the gravitational interaction, there is no explicit formula for the motion as a function of time. In this paper, a quasi-analytical solution for this problem is proposed. It approximates the real behavior of celestial bodies with an acceptable degree of accuracy. All calculations involved require a low computational cost. This problem is closely related to Kepler’s equation, since, the solution for the equations of motion as a function of time gives us the solution to Kepler’s equation as well. The results are presented for each planet of the solar system (including Pluto), and the solution is compared against the real orbits.

The conformity assessment of products or a measured value with the given standards is carried out based on the global risk of producers and consumers calculation. A product may conform to specifications but be falsely rejected as non-conforming. This is about the producer's risk. If a product doesn't meet the requirements but is falsely accepted as conforming, that poses a risk to the consumer. The conventional approach to risk assessment, which yields only a single numerical value for the global risk of producers and consumers, is naturally extended, and utilized for assessing risk in measurement models with linear regression. The outcomes of the two-dimensional extension, along a moderate scale, are the parabolas with an opening upwards. Risk surfaces were obtained through three-dimensional extension over the area limited by the moderate scale and guard band axes. Four models with different ranges of tolerance intervals were used to test this innovative method of risk assessment in linear regression. The corresponding standard measurement uncertainties are determined by applying a simplified measurement model with the use of comprehensive data on the measurement performance and by determining measurement uncertainty derived from consideration of the functional relationship obtained by linear regression analysis. Models that utilize information from linear regression analysis to determine measurement uncertainty are biased towards risks at the edges of the moderate scale. Testing the model's performances with metrics related to the confusion matrix, such as the F1 score, further substantiated this assertion. The diagnostic odds ratio has been proven to be extremely effective in identifying the curve along the guard band axis, along which the global risks of producers and consumers are at their lowest.

The geometry of structural members can influence the fatigue crack growth rate. In the paper, the T-stress depending on the element's geometry is used to quantify the effect of geometry on the fatigue crack growth rate. A series of fatigue tests on three-point bending specimens with different initial crack lengths were conducted. As a result, the dependence of the crack growth rate on the T-stress value was obtained.

Alzheimer´s disease (AD) is characterized by the brain deposition of senile plaques composed by amyloid-β peptides (Aβ) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE) has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 during 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1 and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme were also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

The blood–brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility by using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5—but not pTau181—decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of MCI and AD.

We report an unusual case of Terson's syndrome that resulted in the di-agnosis of a right posterior communicating artery aneurysm. Interest-ingly Terson's syndrome presented with Roth spot resembling features accompanied by third nerve palsy in a patient without any disturbance of consciousness. To our knowledge, the association of Terson's syndrome with third nerve palsy has not been described before in the absence of radiologically diagnosed subarachnoid haemorrhage. We present the case of a 48-year old woman who presented in the De-partment of Emergencies of the University Hospital of Patras with right-sided complete pupil-involving third nerve palsy combined with bilateral Terson's syndrome. More precisely, fundoscopy revealed multi-ple scattered intra- and pre-retinal haemorrhages in both eyes while some retinal haemorrhages had a white-centered pattern resembling Roth spots. Neurological examination revealed no nuchal rigidity or any other neurological signs. The Glasgow coma scale was 15/15. A cerebral computed tomography angiography revealed a 5mm aneurysm of the right posterior communicating artery and the patient underwent a mi-crovascular clipping operation after craniotomy. The significant contribution of the ophthalmological consultation to the appropriate and timely diagnosis and management of a life-threatening condition is highlighted.

Background and objective: Symptoms of most neurodegenerative diseases, including Parkinson’s disease (PD), usually do not occur until substantial neuronal loss occurs. This makes the process of early diagnosis very challenging. Hence, this research used variant call format (VCF) analysis to detect variants and novel genes that could be used as prognostic indicators in the early diagnosis of prodromal PD. Materials and Methods: Data were obtained from the Parkinson’s Progression Markers Initiative (PPMI), and we analyzed prodromal patients with gVCF data collected in the 2021 cohort. A total of 304 participants were included, including 100 healthy controls, 146 prodromal genetic individuals, 21 prodromal hyposmia individuals, and 37 prodromal RBDs. A pipeline was developed to process the samples from gVCF to reach variant annotation and pathway and disease association analysis. Results: Novel variant percentages were detected in the analyzed prodromal subgroups. The prodromal subgroup analysis revealed novel variations of 1.0%, 1.2%, 0.6%, 0.3%, 0.5%, and 0.4% for the genetic male, genetic female, hyposmia male, hyposmia female, RBD male, and RBD female, respectively. Interestingly, 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) that were recently detected in PD patients were detected in the prodromal stage of PD. Conclusion: Genetic biomarkers are crucial for the early detection of Parkinson’s disease and its prodromal stage. The novel PD genes detected in prodromal patients could aid in the use of gene biomarkers for early diagnosis of the prodromal stage without relying only on phenotypic traits.

The article proposes asymptotic methods for calculating Sommerfeld integrals, which enable us to calculate the integral using the expansion of a function into an infinite power series at the saddle point, where the role of a rapidly oscillating function under the integral can be fulfilled either by an exponential or by its product by the Hankel function. The proposed types of Sommerfeld integrals are generalized on the basis of integral representations of the Hertz radiator fields in the form of the inverse Hankel transform with the subsequent replacement of the Bessel function by the Hankel function. It is shown that the numerical values of the saddle point are complex. During integration, auxiliary or so-called standard integrals, which contain the main features of the integrand function, were used. As a demonstration of the accuracy of the technique, a previously known asymptotic formula for the Hankel functions was obtained in the form of an infinite series. The proposed method for calculating Sommerfeld integrals can be useful in solving the half-space Sommerfeld problem. An example is the expression in the form of an infinite series for the magnetic field of reflected waves, obtained directly through the Sommerfeld integral (SI).

Background: Alzheimer's disease causes great changes, with the prefrontal cortex be-ing frequently damaged zones, affecting physical and cognitive behavioural and compromising autonomy and quality of life. Objective: To evaluate the effectiveness of feedback-based tech-nology on the improvement of physical-cognitive capacities in Alzheimer. Methods: Forty pa-tients with Alzheimer were recruited from the Santa Elena Alzheimer's Association, Seville, of which 15 ended up being pilot participants, divided randomly into controls (8) and experi-mental (7). They were evaluated with: Cognitive Mini-Examination Scale, Oddball Test and At-tention Network, Berg Scale, Tinetti, Timed up and Go and Geriatric Deterioration Scale. The experimental group was treated with feedback-based technology under the supervision of physiotherapists, during 16 thirty-minute sessions, twice a week. The control group performed their usual care. Result: A significant improvement was observed in the experimental group (Cognitive Mini-Examination and Tinetti). In the group of control, a worsening of physical and motor skills was evidenced because of the degenerative disease. Discussion/Conclusion: This treatment could be a strategy to keep the patient in early stages for longer, and improve quali-ty of life delaying dependency. It creates intergenerational bonds and use at home to promote treatment adherence.

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of APP is likely the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element (IRE). Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Rather, these mutations likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.

Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system, and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer among others. Recent data provide compelling evidence that distinct reactive astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.

Additive manufacturing (AM) techniques are widely investigated for the cost-effective use of titanium (Ti) alloys in various aerospace applications. One of the AM techniques developed for such applications is plasma transferred arc solid free-form fabrication (PTA-SFFF). Materials manufactured through AM techniques often exhibit anisotropies in mechanical properties due to the layer-by-layer material build. In this regard, the present study investigates the isothermal directional fatigue of Ti-TiB metal matrix composite (MMC) manufactured by PTA-SFFF. This investigation includes rotating beam fatigue test, electron microscopy, and fatigue calculations. The fatigue experiments were performed at 350 ºC using specimen with the test axis oriented diagonally (45º) and parallel (90º) to the AM builds directions. The fatigue values from the current experiments along with literature data find that Ti MMC manufactured via PTA-SFFF exhibit fatigue anisotropy reporting highest strength in 90º and lowest in perpendicular (0º) AM build directions. Further, the electron microscopy investigations on 0º, 45º, and 90º AM build specimens reveal frequent TiB clusters in all three AM build directions and suggest that the spread of these TiB clusters play a role in fatigue anisotropy. Moreover, the fatigue calculations were performed using both the Paris’ and recently reported modified Paris’ equations. Comparison of R^2 values for these calculations show that modified Paris’ equation predicts the fatigue life of AM Ti-TiB MMC more accurately than the Paris’ equation.

In this paper, I introduce a new concept of representing numbers in base ; in other words, I have found new series for any number similar to series that could be written according to the collatz sequence which is called zi(n) in this article. These series need to end with 1. Then, we use two sets of rules to make a diagram which then proves the existence of such series for any number.In this diagram, by branching numbers into different branches in accordance to the modularity of 4 and continuing branching to the point that their numbers have enough common terms in their collatz series, we could reduce zi(n) to zi(k) so that k<n in any branch by Rule Number One. This diagram shows that zi(n) exists for every number, in other words, this proves the theorem (A) or zi-existence theorem. The proof of zi-existence theorem leads to a proof of the collatz conjecture because the collatz series could be written as a linear combination of such series that all of them end with 1, so the collatz series for any number ends with 1.

Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80-90% downregulation, making them unsuitable for targeting genes that require more complete disruption to elicit a phenotype. Genetic deletion, on the other hand, while enabling complete disruption of target genes, often produces undesirable irreversible consequences such as cytotoxicity or cell death. Here we describe the design, development and detailed characterization of a dual-function "TRE-Lox" system for effecting either (a) doxycycline (Dox)-mediated downregulation or (b) genetic deletion of cathepsin D (CatD), based on targeted insertion of a tetracycline-response element (TRE) and two LoxP sites into the 5' end of the endogenous gene (CTSD). Using an optimized reverse-tetracycline transrepressor (rtTR) variant fused with the Krüppel-associated box (KRAB) domain, we show that CatD expression can be disrupted by as much as 98% in mouse embryonic fibroblasts (MEFs). This system is highly sensitive to Dox (IC50 = 1.46 ng/mL) and results in rapid (t1/2 = 0.57 d) and titratable downregulation of CatD. Notably, even near-total disruption of CatD expression was completely reversed by withdrawal of Dox. As expected, transient expression of Cre recombinase results in complete deletion of the CTSD gene. The dual functionality of this novel system will facilitate future studies of the involvement of CatD in various diseases, particularly those attributable to partial loss of CatD function. In addition, the TRE-Lox approach should be applicable to the regulation of other target genes requiring more complete disruption than can be achieved by traditional methods.

Background and objectives: Alzheimer's disease (AD) is a progressive neurodegenerative illness, responsible for 60-70% of all dementias, affecting over 50 million people worldwide, and nearly 11 million in European countries. Several putative factors are identified in the literature as causative agents or risk factors for the development of AD. The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades. Recent studies raised the possible role of dysbiosis in the development of AD which prevents memory loss. The amyloid-β (Aβ) deposition might be considered as an inflammatory reaction to certain molecular products arising from the altered microbiome. Based on the above observations, it has been suspected, that antibiotic consumption patterns of different antibiotic classes might be associated with the prevalence of AD in European countries. Methods: Antibiotic consumption (ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, have been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the year 1997-2007 (p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-18, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (p: 0.063), but none for the years 1997-2007 (p: 0.241). Broad-spectrum, beta-lactamase sensitive penicillin (J01CA) consumption showed a positive (non-significant) correlation with the prevalence of AD for the years 2008-2018 (p:0.080).Discussion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.

Liquorpheresis (CSF filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. CSF replacement may be an alternative approach not explored so far. Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe previous developments and provide some new technical innovations in order to design bidirectional CSF shunting systems. These systems can be complemented either with a deposit of artificial CSF or with a CSF filter, allowing CSF replacement or liquorpheresis respectively. Both options would lead to mechanical dilution of the patient’s CSF.

Background/Objectives: The primary life-threatening complication in Spinal-bulbar muscular atrophy (SBMA) is ventilatory failure, which results from the weakening of the bulbar and respiratory muscles. However, systematic studies assessing respiratory function over the long-term have not been performed. The present study analyzes the longitudinal patterns of respiratory function tests over a follow-up of 11 years, aiming to identify any potential, sustained decline during this time. Furthermore, we explored possible correlations between respiratory function tests and clinical and biochemical serum indices. Methods: We collected data from 9 genetically confirmed SBMA patients and conducted spirometric measurements twice a year for eleven years. The spirometric data included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and forced vital capacity (FVC)]. Additionally, we measured serum biochemical indices and SBMA functional rating scale (SBMAFRS) for clinical analysis. Results: All three respiratory function tests showed a descending trend. A major decrease was observed for MEP (52%) and MIP (42%), while this was minor for FVC (25%). SBMAFRS score correlated with the three pulmonary function tests. MIP and MEP correlated with creatine phosphokinase and creatinine levels, and FVC correlated with serum level of transaminases. Conclusions: This longitudinal study shows a progressive decline of spirometric data throughout life in patients with SBMA. Spirometric measures relative to maximal strength of the respiratory muscles (MIP and MEP) may have a better predictive value for pulmonary and muscular decline than FVC.

We have shown that Newton’s third law does not strictly hold in a system with remote elements, due the finite speed of signal propagation and thus force imbalance occurs at the system’s center of mass. As the said system is affected by a total force for a finite duration, mechanical energy and momentums are gained by the system. In early works we assumed that the bodies were macroscopically charge neutral. Later we removed this restriction, thus analyzing the consequences on a possible electric charged relativistic motor. On the first published paper on this subject we studied this phenomena in general but gave only an example of a system reaching a stationary state, in this paper we shall analyze a charged retarded electromagnetic motor in a more general time dependent setting giving specific examples in which the system never reaches a stationary state yet produces steady linear momentum non the less.

Hamman’s syndrome is a rare condition that mostly affects young males, often with a predisposition of asthma. It includes the presence of free air in the mediastinum and subcutaneous emfysema with no other underlying cause such as trauma or infection. It occurs spontanously and often in association with prolonged valsalva manouvre. This might explain why there are some cases of Hamman syndrome among young females giving birth. Here we present a case report of a 24-year- old primigravida with Hamman’s syndrome. She presented with symptoms a few hours after an uncomplicated vaginal delivery at 40+1 pregnancy week. The symptoms resolved spontanously after a few days of observation. We also give a systemic review of reported cases since 2000 to provide overview on pathomechanism, symptoms, diagnostics, treatment and management of this condition. Hamman’s syndrome is a rare, usually benign, but potentially serious complication that can occur during the second stage of labour. Diagnostics include inquiring about typical symptoms, clinical examination and chest x-ray or CT scan. Treatment is usually conservative with oxygen, bronchodilators and pain relief. The reccurence rate is low and there is no contraindication to vaginal delivery in future pregnancies. However, it is suggested that physicians and midwives be cautious and consider low threshold for instrumental delivery or caesarean section to avoid excessive valsalva manoeuvre.

Malocclusions have a continuously increasing prevalence from a generation to another as a result of climate changes, soil, atmosphere and water pollution. All of these aspects have unfavorable consequences on the nutritional scheme. Thus, nutrition together with other etiopathogenic factors contribute to complex alterations in the somatic development of the entire organism and, implicitly, of the cephalic extremity. The study group included 4147 children from randomly selected schools from Vâlcea County, Romania. The aim of this study is to determine the prevalence of malocclusions in schoolchildren from Vâlcea County, Romania, according to the three main classes of malocclusions (according to Angle’s classification), age groups (from 6 to 10 years old and from 11 to 14 years old), gender (male and female) and place of origin (rural and urban). For Angle class I malocclusions we recorded the highest prevalence (48,78% from the total number of schoolchildren with malocclusions), followed by Angle class II malocclusions (45,85% from the total number of schoolchildren with malocclusions) and for Angle class III malocclusions we found the lowest prevalence (5,37% from the total number of schoolchildren with malocclusions).According to gender, we found the highest prevalence in female gender (29,90% from the total number of female subjects), while in male gender we recorded a prevalence of 27,70% from the total number of male subjects. Regarding the place of origin, there is a higher prevalence of malocclusions in the urban areas (29,16%). The study subgroup included 140 children randomly selected from the total number of subjects from the study group. They were included in a more advanced study. The aim is to find potential associations between the presence of malocclusions and various oral variables. Categorical variables were expressed as numerical values and percentages, and their association was evaluated with either the Chi-square test of association or homogeneity, or the Fisher Exact test. The acquired data were incorporated into a binomial logistic regression model to assess the likelihood of developing malocclusions in relation to the following variables: defective phonation, bruxism, frequency of teeth brushing, onychophagia, oral respiration, infantile deglutition, placing objects between the maxillaries, thumb sucking and salivary aspects. It is also aimed to compare the results obtained with similar ones from the specialized literature.

Driver’s distractions are more prone to occur with automated driving vehicles, which might turn into cancelling some of their advantages. Traffic reports, naturalistic observations and in-lab tests are carried out to determine the influence of driver’s distractions in car crashes and to develop technology to detect and prevent them from happening. One of the best strategies to cope with this problem is education. In this work we propose a simulation environment to design laboratory experiments to study driver’s distractions as well as simple games to train drivers to take over the control of the vehicle when required. The result framework enables drivers to experience driving highly automated cars in their neighborhoods or in places of their choice with different levels of events to check their ability in taking over the control when required.

Background:Caregiving for individuals with neurological disease involves providing physical, emotional, and social support, which can be a challenging and stressful experience. This study aims to compare the caregivers' burden, including the impact on mental and physical health, social support, and quality of life, in different neurodegenerative disorders. Methods:Fifty-five primary caregivers (F=41;mean age=53.07±12.29) of patients with Parkinson's Disease (PD=26), Multiple System Atrophy (MSA=16), and Amyotrophic Lateral Sclerosis (ALS=13), took part in the study. Standardized screening scales for the quality of life (EQ-5D/EQ-VAS and PQoL), levels of the caregiving burden (CBI and FSQ), and the assessment of the anxiety-depressive axis (HADS) were administered. Results: The mean CBI score was higher for caregivers of MSA patients (28.81±21.90) and ALS (25.15±16.23) than for caregivers of PD patients (16.08±10.34; p=0.036). Critical burden (cut-off>36) was present in the caregivers of MSA (31.3%), ALS (23.1%), and PD (19.2%) patients. Caregivers of patients with ALS had a worse perception of quality of life (EQ-5D total score) than caregivers of patients with MSA and PD (p

In this paper, we propose an extension of the Planck distribution function derived from the Boltzmann principle. That is, we consider extending Planck's law with new distribution functions. In addition, using ideas applied to the expansion of the Planck distribution function, Von Koch's inequality is derived without using the Riemann hypothesis, showing that the abc conjecture is negated. We also describe some challenges for the future. Namely, we will discuss that Entropy is related to dynamical systems described by logistic function models, such as the bacterial and the population growth.

This study explores the intricate relationship between the angle of vehicle-to-vehicle (V2V) conflicts and the severity of conflicts at signalized intersections during traffic signal failures, leveraging the advanced capabilities of LiDAR sensor technology. The research delves into the impact of conflict angles on collision outcomes and introduces LiDAR as a novel and precise tool for capturing spatial dynamics during unregulated traffic movements. Findings reveal that as the angle of V2V conflicts increases, indicating a wider approach between vehicles, the severity of conflicts tends to decrease. This reduction in severity is attributed to the detailed spatial data provided by LiDAR, enabling the identification of glancing impacts rather than direct head-on collisions. The mitigation of forces involved in collisions at increased angles contributes to a decreased likelihood of severe consequences, such as extensive vehicle damage and serious injuries to occupants.Conversely, as the angle of V2V conflicts decreases, signifying a narrower approach between vehicles, the potential for severe collisions tends to increase. LiDAR technology facilitates precise measurements of spatial coordinates and temporal dynamics, revealing that collisions occurring at smaller angles involve more direct and concentrated impact forces. This heightened risk of extensive damage to vehicles and increased injury severity is crucially captured by LiDAR, providing valuable insights into the relationship between conflict angles and collision outcomes during traffic signal failures. This study underscores the efficacy of LiDAR sensor technology in understanding the nuanced dynamics of V2V conflicts and highlights its role in developing targeted safety interventions. The integration of LiDAR data into traffic safety analyses offers a sophisticated approach to mitigating the impact of conflicts and enhancing overall safety at signalized intersections during signal failures. The research also highlighted that as the angle of V2P conflicts widens, PET experiences a proportional increase. A larger conflict angle signifies a more complex interaction between vehicles and pedestrians, leading to prolonged PET values. Conversely, a decrease in the angle of V2P conflicts is associated with a reduction in PET during traffic signal failures.The study commences with an examination of traffic characteristics at the E Cold Spring Ln – Hillen Rd intersection in Baltimore City, MD, utilizing a deployed LiDAR sensor. When the signal at this intersection experienced a temporary malfunction on a regular working day in September 2023, the LiDAR captured data related to vehicle and pedestrian volumes, as well as V2V and V2P conflicts. The primary objective of the research is to evaluate the repercussions of traffic signal failures on both traffic flow and safety, specifically V2V and V2P conflicts, occurring during periods of improper signal functionality. Additionally, this investigation delves into various factors that impact traffic signal performance, encompassing traffic demand, geometric layout, pedestrian interactions, and the incorporation of emerging technologies.

We are interested in studying alterations in the regulatory circuitry that controls mRNA stability and function, and more specifically in the interactions among miRNAs and mRNAs. We have previously reported transcriptome-wide changes in mRNA expression in an animal model of atherosclerosis (ATS) progression, and reversion upon treatment with an αCD40 specific siRNA. In this work, we have used our data on mRNAs downregulated during these processes to study length dynamics as an adaptive mechanism to thwart miRNA activity. We show that ATS progression was characterized by the lengthening of the 5’UTR and 3’UTR regions of these mRNAs. Furthermore, 3’UTR lengthening (but not that of the 5’UTR) was shown to be partially reversed by the treatment with the αCD40 specific siRNA. Study of the exonic composition of the transcriptome of these mRNAs suggested a role for alternative/cryptic/latent splicing in the generation of length variants. This was confirmed by the detection, during ATS progression, of a transcript variant switching process in which specific isoforms were replaced by others that differed in their pattern of alternative splicing, mainly at their 5’ or 3’UTRs. This work highlights alternative splicing as a mechanism contributing to the generation of 5’/3’UTR length and sequence variability during ATS progression and calls attention on factors regulating alternative splicing as possible targets of therapeutical intervention.

This paper focuses on the long-standing issue of galactic rotation, i.e. the discrepancy between observed rotation rates and predictions based on Newtonian gravity. While Newton's law holds within the solar system, it fails to explain the higher-than-expected rotation speeds of galaxies, particularly at greater distances from their centers. This study finds that Newton's gravitational formula applies only when gravitational lensing has a negligible impact. We examine the gravitational force on objects farther from the galactic center, where the lensing effect of a supermassive black hole becomes significant. This lensing causes the actual gravitational force to exceed Newtonian predictions, with the discrepancy increasing with distance. This effect offers an alternative explanation for the galactic rotation curve without the need for dark matter. Our findings suggest that Newton's formula requires revision to account for gravitational lensing, a key factor in understanding galactic dynamics and its broader cosmic implications.

This review aimed to identify the risks of cosmetics during the sensitive period of pregnancy. Pregnancy causes many hormonal changes and skin issues, such as red stretch marks, cellulite, and more. These aesthetic concerns can impact both the appearance and health of the pregnant woman. Cosmetics and aesthetic treatments can help improve these problems and positively affect the mental well-being of these women. However, the lack of clinical trials regarding the safety of such treatments during pregnancy has led to the recommendation of only the mildest aesthetic applications. Additionally, professional aestheticians and dermatologists who provide cosmetics and other aesthetic treatments (e.g., laser, ultrasound, radiofrequency) during pregnancy face challenging and sometimes adverse working conditions. They should be treated with respect for their situation, with careful consideration of all the peculiarities associated with pregnancy. Further research and additional recorded data are crucial for better understanding the use of cosmetics and aesthetic treatments during pregnancy.

A 64-year-old woman with primary Sjogren’s syndrome which was not treated, was admitted to our hospital for nasal bleeding, oral bleeding, and purpura on her entire body. On this admission, laboratory findings were as follows: WBC counts, 8,910 /μL; hemoglobin, 9.9 g/dL; and platelet counts, 0.1×10⁴/μL. Although the anti-PLT antibody was positive, other autoimmune antibodies such as anti-DNA were negative. Moreover, cytomegalovirus IgM, Parbovirus B19 IgM, and Helicobacter pyroli IgG antibodies were not detected. No abnormal findings suggestive of infection were identified in the systemic examination. A bone marrow aspiration smear revealed normal bone marrow. Based on these findings, the patient was diagnosed with primary Sjogren’s syndrome-related immune thrombocytopenia. The patient initially received intravenous immunoglobulin, methyl prednisolone pulse therapy, and subsequent high dose prednisolone without significant improvement. Therefore, eltrombopag, a thrombopoietin-receptor agonist, was added. Subsequently, erythromycin was also added, considering its immunomodulatory effects. After initiating the erythromycin treatment, the platelet counts increased. Therefore, add-on eltrombopag and erythromycin treatment was effective; however, the platelet counts gradually decreased with reducing the prednisolone dosage. Instead of increasing the prednisolone dosage again, tacrolimus, a calcineurin inhibitor, was successfully added. Consequently, the prednisolone dosage could be reduced. This case shows that treatment with erythromycin and tacrolimus may be efficacious when conventional immunosuppressants show limited effectiveness in primary Sjogren’s syndrome-related immune thrombocytopenia.

Crohn’s disease (CD) is a progressive, multifactorial, immune-mediated disease characterized by chronic inflammation of any part of the gastrointestinal (GI) tract. Pediatric patients present with a more extensive form of the disease, especially in the upper GI tract with various histopathological inflammatory patterns. Our study aims to analyze the endoscopic and histopathological findings in children with diagnosed CD and compare results on the initial and follow-up tests. Our study included 100 children and adolescents with CD, with performed endoscopic and histopathological (HP) procedures. The results of multiple biopsies performed in these 8 years were matched and compared. We found a statistically significant decrease in stool changes, weight loss, and abdominal pain as presenting symptoms, and in the fecal calprotectin levels. On esophagogastroduodenoscopy and ileo-colonoscopy 36.59% and 64.86% patients had specific findings, respectively. Non-caseating granulomas were found on 9% of oesophageal, 18% of gas-tric, and 12% of duodenal biopsies. In the lower GI tract, we have observed a disease progression in the rectum and descending colon between the first and second biopsies. Our study showed that more than a third of patients had specific endoscopic (36.59%) and histopathologic (32%) findings in the upper GI tract, and an additional 23% had HP findings highly suggestive of CD. We demonstrated the importance of regular endoscopic and histopathological assessments of pediatric CD patients.

Introduction and Purpose: Nurses are expected to be competent in practice based on the domain of standards and interpersonal soft skills (ISS). Nurses are faced with inadequate physical assessment 28%, formulating diagnoses 56%, plans 34%, implementation 31%, evaluation 37,5%, and communication skills 41%. Aims to develop an ISS learning model based on transformative learning theory and digitalization (TLTD) to improve nurses’ competencies. Method: Used Explanatory cross-sectional involved 190 practitioner nurses. Variables of individual characters (X1), facilities (X2), Social environment support/SES (X3), TLTD (X4), ISS (X5), and nursing competencies (Y) were measured. Data was collected using a checklist questionnaire, conducted on 6 June to 10 August 2022 at Dili, Baucau, and Maliana hospitals. Used descriptive and inferential analysis with SEM-PLS. Result: Five of the 11 hypotheses of statistical p-value < 0,05 and T-Test > 1,96, including X2>X4, X3>X5, X4>X5, and X5>y, to form ISS learning model. The characteristic of respondents were 81,8% young adults, 67,9% women, 57,8% undergraduates, judging the previous training 35% was unsuccessful, and 45,8% did not meet expectations. Learning facilities that are still lacking include policies 23,7%, curriculum 23,4%, guideline 22,7%, modules 27,9%, infrastructure 20,3%, social environment support 24,2% low, organizational support, 30,0% low peer support and 26,3% low family support. The average TLTD is 25,3% to 34,2%, ISS 22,1% to 30,5%, and nurse competence 25,3% to 30,5%.Suggestion: Result of the study become base to improve nurse’s competencies. Conclusion: Learning model was formed by facilities, SES, TLTD, ISS, and nurses’ competencies.

Background: Takayasu’s arteritis is a rare type of vasculitis, with severe complications like stroke, ischemic heart disease, pulmonary hypertension, secondary hypertension, aneurysms. Diagnosis is conducted by clinical and angiographic criteria. Treatment is medical and surgical, but unfortunately, the outcome is reserved. Case presentation: A 34- year- old Caucasian women had an ischemic stroke (2009). She was diagnosed with Takayasu’s arteritis and she received treatment with methotrexate, prednisolone, antiplatelet agents, with a mild improvement of clinical state. After 5 years (2014) she associated ascending aorta aneurysm, pulmonary hypertension, mild aortic regurgitation. The surgical treatment solved both ascending aorta aneurysm and left carotid artery stenosis (ultrasound in 2009 and computed tomography angiogram in 2014). Morphopathology revealed typical appearance for Takayasu’s arteritis. Tumor necrosis factor inhibitors (TNF-inhibitors) were associated to methotrexate. At 48 years (2023) she developed coronary heart disease (angina, electrocardiogram); echocardiography revealed severe pulmonary hypertension; angiography described normal coronary arteries, abdominal aorta pseudoaneurysm and arterial-venous fistula, with origin in right coronary artery and drainage on medium pulmonary artery. The patient refused surgical/ interventional treatment; she received again TNF- inhibitors, methotrexate, antiplatelet agents, statins. Conclusions: This case report presents us a severe form of Takayasu’s arteritis. We consider that morphopathology had a great importance in revealing to clinicians the typical appearance and the stadialization of inflammatory arterial process: acute or chronic. The verdict of morphopathologist was chronic phase, with acute relapses, so we decided that immunosuppressive treatment was still necessary.

his quantitative study investigates teachers' perceptions of self-efficacy during the COVID-19 pandemic and explores the correlation between these perceptions and the preservice training they received. The research addresses the cognitive connection between teachers' current self-efficacy, particularly their satisfaction with and appreciation of preservice lecturers. Utilizing a retrospective lens, the study reveals a significant correlation between teachers' evaluation of their preservice training, especially their appreciation of lecturers, and their present self-efficacy. The findings highlight that teachers, amidst the challenges of the pandemic, evaluated their self-efficacy at a remarkably high level. This underscores their resilience during a period of unprecedented uncertainty, demanding substantial personal and professional adaptability. The nuanced interplay observed suggests that teachers' sense of self-efficacy serves as a predictive variable of their mental and professional resilience when confronting uncertainty and navigating rapid and profound changes, as exemplified by the exigencies of the COVID-19 pandemic.

Keywords: Parkinson’s disease; sleep disorders; GBA; Parkin

Variable-Angle Tow (VAT) laminates can improve straight fiber composites mechanical properties thanks to the application of curvilinear fibers. This characteristic allows to achieve ambitious objectives for design and performance purposes. Nevertheless, the wider design space and the higher number of parameters result in a more complex structural problem. Among the various approaches that have been used for VATs study, Carrera’s Unified Formulation (CUF) allows to obtain multiple theories within the same framework, guaranteeing a good compromise between the results accuracy and the computational cost. In this article, the linear buckling behavior of VAT laminates is analyzed through the extension of CUF 2D plate models within the Reissner’s Mixed Variational Theorem (RMVT). Results show that RMVT can better approximate the prebuckling non-uniform stress field of the plate when compared to standard approaches, thus improving the prediction of the linear buckling loads of VAT composites.

The United Nations Global Sustainability Agenda 2030 introduces a transformative framework through its Sustainable Development Goals (SDGs), which are designed to achieve equitable, prosperous, and sustainable development globally. Unlike the incremental Millennium Development Goals (MDGs), the SDGs aim for systemic changes across economic, social, and environmental dimensions, ensuring that no one is left behind. This research paper provides a comprehensive examination of Pakistan's progress towards achieving the SDGs under the UN Global Sustainability Agenda 2030. Specifically, it includes an analysis of the prioritization of SDGs in Pakistan, highlights federal and institutional initiatives aimed at promoting sustainable development, and explores the role of the China-Pakistan Economic Corridor (CPEC) in advancing these goals. Additionally, the paper critically analyzes the SDGs in Pakistan’s annual status report, identifies the key challenges faced by the nation in implementing these goals, and offers recommendations for enhancing the effectiveness of SDG implementation. Overall, the focus is primarily on the detailed analysis of the annual status report, the challenges encountered, and strategic recommendations for achieving excellence in SDGs in Pakistan.

Recent research has implicated the gut microbiota in the development of lymphoma. Dysbiosis of the gut microbial community can disrupt the production of gut microbial metabolites, thereby impacting host physiology and potentially contributing to lymphoma. Dysbiosis-driven release of gut microbial metabolites such as lipopolysaccharides can promote chronic inflammation, potentially elevating the risk of lymphoma. In contrast, gut microbial metabolites, such as short-chain fatty acids, have shown promise in preclinical studies by promoting regulatory T-cell function, suppressing inflammation, and preventing lymphoma. Another metabolite, urolithin A, exhibited immunomodulatory and antiproliferative properties against lymphoma cell lines in vitro. While research on the role of gut microbial metabolites in lymphoma is limited, this article emphasizes the need to comprehend their significance, including therapeutic applications, molecular mechanisms of action, and interactions with standard chemotherapies. The article also suggests promising directions for future research in this emerging lymphoma and gut microbiome investigation field.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition, yet its alignment with a specific host immunological pathway remains unclear. The THαβ host immunological pathway, recognized for its defense against viruses and prions, has recently emerged as a response to DNA, RNA, and protein pathogens. SLE patients often produce anti-double strand DNA antibodies and anti-nuclear antibodies, suggesting a potential association with the THαβ host immune reaction. Throughout the course of SLE, elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 are commonly observed. These cytokines and antibody isotypes are indicative of the THαβ host immunological pathway. Similarly, Myasthenia gravis, Grave’s disease, Graft versus host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjogren’s syndrome are also linked to THαβ-related type 2 hypersensitivities. Considering the potential association of these diseases with dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferons α/β could be explored to manage these disorders effectively.

In this paper, we consider the synchronization of chaotic oscillators interconnected via a second order dynamic coupling. The design of the proposed coupling is inspired in the ancient synchronization experiment of synchronized pendulum clocks, as described by the Dutch scientist Christiaan Huygens more than three centuries ago. It is demonstrated that the coupled chaotic systems may exhibit not only complete synchronization, but also mixed synchronization—some states synchronize in anti-phase whereas other states synchronize in-phase. In fact, a transition from complete synchronization to mixed synchronization or viceversa can be induced by just changing a single parameter in the coupling. Additionally, the stability of the synchronous solution is investigated by using the Master Stability Function approach and the largest transverse Lyapunov exponent. The Lorenz system is considered as particular application example. Finally, the performance of the proposed synchronization scheme is illustrated with computer simulations and validated by means of experiments using electronic circuits.

This paper presents a biologically inspired flocking-based aggregation behaviour of a swarm of mobile robots. Aggregation behaviour is essential to many swarm systems, such as swarm robotics systems, in order to accomplish complex tasks that are impossible for a single agent. We developed a robot controller using Reynolds’ flocking rules to coordinate the movements of multiple e-puck robots during the aggregation process. To improve aggregation behaviour among these robots and address the scalability issues in current flocking-based aggregation approaches, we used a K-means algorithm to identify clusters of agents. Using the developed controller, we simulated the aggregation behaviour among the swarm of robots. Five experiments were conducted using Webots simulation software. The performance of the developed system was evaluated under a variety of environments and conditions, such as various obstacles, agent failure, different numbers of robots and arena sizes. The results of the experiments demonstrated that the proposed algorithm is robust and scalable. Moreover, we compared our proposed algorithm with another implementation of the flocking-based self-organizing aggregation behaviour based on Reynolds’ rules in a swarm of e-puck robots. Our algorithms outperformed this method in terms of cohesion performance and aggregation completion time.

Background/Objectives: It is known that balance disorders involve occupational hazards. However, the inverse relationship (between certain occupations and an increased incidence of vertigo or dizziness) has been scarcely studied. The objective of this work was to analyze the occupation of a group of patients with vertigo, compared to economically active general population, and to evaluate the prevalence of occupational noise and/or vibration-exposure in both groups. Methods: A cross-sectional, observational, case-control study was carried out including 461 patients (220: Meniere’s disease; 73: vestibular migraine; 28: vestibular neuritis; 140: BPPV) (310 women and 151 men). These patients were compared to a control group from the general population, obtained from 6th EWCS-Spain (2015). Possible differences regarding sex, age, occupation, exposure to noise, and exposure to mechanical vibrations were analyzed. Results: Differences in distribution of occupations between patients with vertigo and general population were observed (Chi-square, p=6.142 e-30). Patients with vertigo were significantly more exposed to noise (p=8.19 e-12; OR=2,127, CI95% (1.720;2.630)) and vibrations (p=1.11 e-12; OR=2.288, CI95% (1.835;2.853)) than the control group. These differences were observed both between men and women. Conclusions: A relationship between occupational exposure to noise and/or vibrations and the presence of vertigo was observed. Protective and preventive measures could help prevent the occurrence of some diseases involving vertigo.

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients, and healthy subjects with (GBA-C) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn &amp; Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-C and HC were also considered. Clinical assessment included the MDS-UPDRS and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-C (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p&lt;0.05, Fisher’s exact test) and higher MDS-UPDRS part-II (p&lt;0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-DHP. Allopregnanolone was the only neurosteroid significantly lower (p&lt;0.01, Dunn’s test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.

Falls are a frequent and serious problem for older adults and especially those living with Parkinson’s. The relationship between falls and physical activity is complex and people often restrict activity following a fall. Exercise is an important aspect of re-ducing further risk of a fall and a key component of the management of Parkinson’s. The aim of this study was to understand the types of activity that are engaged in, the environments in which they take place and the experience of people with and without Parkinson’s who have fallen. 17 people with Parkinson’s and 13 older adults, who had experienced at least one fall in the previous year, were recruited to this mixed methods study. Activity levels were captured over one week using accelerometers and body worn cameras, allowing the type and location of activity to be recorded and analysed. This information informed an interview. Findings showed that although both groups often achieved up to 10,000 steps per day, this was in very short bouts of activity. Sedentary activity such as watching television dominated the findings. Participants were aware of the benefits of being active but described many barriers to achieving the level of activity they would like to.

The field of epigenetics, which explores how heritable traits or stable alterations of cell functions occur without changes to the DNA sequence and how environmental factors affect gene expression, is rapidly advancing. Epigenetics plays a critical role in memory formation, learning, and cognitive functioning, effectively bridging genetics with environmental influence. Maternal behavior in rats, for instance, can modify the stress response of their offspring through epigenetic mechanisms such as histone acetylation and DNA methylation. Understanding neurodegenerative diseases like Parkinson's disease (PD) depends on comprehending the mechanisms of epigenetic regulation. Epigenetic modifications, which alter proteins and DNA structure without changing the DNA sequence, can activate or suppress gene expression, assisting organisms in adapting to environmental changes. These modifications may influence genes involved in inflammation, synaptic plasticity, and neuroprotection, potentially contributing to cognitive deficits in PD patients. MicroRNAs (miRNAs), histone modifications, and DNA methylation are the epigenetic mechanisms that significantly influence cell differentiation and maintain normal cellular activity. Understanding the intricate molecular processes of epigenetics could lead to more targeted and effective therapies. Despite numerous findings on how epigenetics affects cognitive alterations in PD patients, only some studies coordinate and integrate these results. Here, we summarize recent findings on how epigenetic changes impact gene expression linked to cognitive impairments in PD.

Introduction: While preparing for dive exams, divers are trained to perform rescue exercises. Currently, divers think they will manage and control their body at any time.Methods: At the bottom of the water, the student takes the instructor who simulates a sickness, up to the surface, by controlling the going up. Then, if the exercise is wrong, both divers go down and exercise again. If the exercise is successful, both divers go down to perform another exercise until they are tired or until they have no more air. Results: I discovered that there was a mistake in the preparation of divers for rescue training due to Descartes’ error, “I think, thus I am”, which is part of our collective memory. Going up and going down after a sickness simulation is a repetitive action of the body and going down is therefore part of the automatisms of rescue, which is very dangerous. Conclusions: The body is not necessarily controlled by the present thinking, and if divers forget sickness while going up in a real rescue situation, they will go down automatically because their bodies were trained like this. In addition, it is very easy to forget sickness. Divers should not go down after rescue, they should be on the dive boat or on the land. Descartes’ error has to be reversed: “I am, thus I think” is right. The divers’ rescue exercises must be simplified and divers should never go down after the simulation of a sickness.