Search Results (312)

Obesity is a multifactorial condition that influences metabolic, endocrine, inflammatory, circadian, and behavioral systems. These disruptions can adversely affect the initiation of lactogenesis II—the critical process marking the onset of copious milk secretion following childbirth. In mothers with obesity, prolonged inflammation within the mammary gland, a blunted hormonal response (notably of prolactin), altered progesterone and estrogen dynamics, high leptin levels, and misaligned circadian rhythms contribute significantly to delayed lactogenesis. In addition, mechanical difficulties and psychological factors further hinder effective breastfeeding. This report synthesizes evidence from human epidemiological studies and animal models that elucidate the diverse mechanisms linking maternal obesity to delayed lactogenesis. We review the role of obesity-associated inflammatory mediators in impairing mammary tissue remodeling, the endocrine aberrations that impair lactogenic signaling, the consequences of circadian disruption on hormonal rhythmicity, and the behavioral influences that challenge effective breastfeeding. Finally, we discuss the clinical implications of these findings and propose future research directions targeting endocrine modulation, anti-inflammatory therapy, circadian interventions, and enhanced lactation support strategies for mothers with obesity. Full article

Background/Objectives: To assess the optical performance of two refractive premium IOLs across pupil sizes and values of corneal spherical aberration (SA). Methods: Two refractive IOLs were evaluated in this study: Tecnis Eyhance and Mini Well. The surface profiles were obtained to calculate the through-object MTF (TO MTF) curves and simulate optotype images. Entrance pupil sizes ranging from 2 to 5.5 and three corneal models were analyzed in the simulation: an average population aberrated cornea, an aberration-free cornea and a post-Lasik myopic cornea. Results: For Model 1 and pupil sizes between 3.0 and 3.5 mm, Mini Well provided acceptable visual quality from far to near distances, whereas Eyhance struggled to maintain visual quality at distances closer than intermediate. For patients with lower-than-normal corneal SA (i.e., more prolate corneas, such as post-hyperopic LASIK) both IOLs exhibited a hyperopic shift in far focus. Conversely, for patients with higher-than-normal corneal SA (i.e., more oblate corneas, such as post-myopic LASIK), the shift occurred in the myopic direction. Despite the implementation of an optimized IOL power to circumvent any shift, the TO MTF nevertheless reflected the interaction between corneal and IOL SA. Furthermore, the Mini Well demonstrated increased tolerance to less negative SA values, while Eyhance exhibited behavior consistent with a monofocal lens for more positive SA values. Conclusions: Surgeons should consider each patient’s corneal asphericity and typical pupil diameter when selecting and calculating the power of the premium IOLs studied, particularly in patients with a history of refractive surgery. Full article

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article

Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article

The study’s aim was to evaluate electroretinographic (ERG) alterations in Fragile X syndrome (FXS), FMR1 premutation carriers, and controls, and to explore correlations with peripheral blood FMRP expression levels and behavioral outcomes. ERG recordings were obtained using a handheld device across three stimulus protocols in 43 premutation carriers, 39 individuals with FXS, and 23 controls. Peripheral blood FMRP expression levels were quantified using TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer). Correlations were assessed with cognitive and behavioral measures including IQ (Intelligence Quotient), ABC_FX (Aberrant Behavior Checklist for Fragile X Syndrome), SNAP-IV (Swanson, Nolan, and Pelham Teacher and Parent Rating Scale), SEQ (Sensory Experiences Questionnaire), ADAMS (Anxiety, Depression, and Mood Scale), and the Vineland III Adaptive Behavior Scale standard score. Significant group differences were observed in multiple ERG parameters, particularly in 2 Hz b-wave amplitude (p = 0.0081), 2 Hz b-wave time to peak (p = 0.0164), 28.3 Hz flash combined amplitude (p = 0.0139), 3.4 Hz red/blue flash b-wave amplitude (p = 0.0026), and PhNR amplitude (p = 0.0026), indicating both outer and inner retinal dysfunction in FXS and premutation groups. Despite high test–retest reliability for ERG (ICC range = 0.71–0.92) and FMRP (ICC = 0.70), no correlation was found between ERG metrics and FMRP or behavioral measures. However, FMRP levels strongly correlated with IQ (ρ = 0.69, p < 0.0001) and inversely with behavioral impairment [ABC_FX (ρ = −0.47, p = 0.0041), SNAP-IV (ρ = −0.48, p = 0.0039), SEQ (ρ = −0.43, p = 0.0146), and the Vineland III standard score (ρ = 0.56, p = 0.0019)]. ERG reveals distinct retinal functional abnormalities in FMR1-related conditions but does not correlate with peripheral FMRP expression levels, highlighting the need for multimodal biomarkers integrating radiological, physiological, behavioral, and molecular measures. Full article

Asthma is defined as a chronic respiratory disease, the processes of which are mainly related to the hyperreactivity of the immune system. Airway hyperresponsiveness and remodeling are other hallmarks of asthma that are strongly involved in the progression of the disease. Moreover, asthma is associated with the occurrence of atopic dermatitis, chronic sinusitis, allergic rhinitis, and a high profile of T2-type cytokines, such as IL-4, IL-5 and IL-13. The hyperresponsiveness of the immune system is a consequence of aberrant levels of alarmins, endogenous molecules that induce pro-inflammatory responses. They are released as a result of a defect or cell death, leading to the initiation of an inflammatory reaction. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and IL-25 bind to various receptors, influencing the behavior of immune cells, resulting in stimulated migration and activation of these cells. In this review, we will discuss the potential role of alarmins in the pathogenesis of asthma. Full article

Aberrant or non-standard operations by ship drivers are a leading cause of water traffic accidents, making the development of real-time and reliable behavior detection systems critically important. However, the environment within a ship’s bridge is significantly more complex than typical scenarios, such as vehicle driving or general security monitoring, which results in poor performance when applying generic algorithms. In such settings, both the accuracy and efficiency of existing methods are notably limited. To address these challenges, this paper proposes a cross-modal behavioral intelligence framework designed specifically for a ship’s bridge, integrating multi-target tracking, behavior recognition, and feature object association. The framework employs ByteTrack, a high-performance multi-object tracker that maintains stable tracking even when subject to occlusions or motion blur through its novel association mechanism, using both high and low confidence detection boxes, for multi-driver tracking. Combined with an improved Temporal Shift Module (TSM) algorithm for behavior recognition, which effectively resolves issues concerning target association and action ambiguity in complex environments, the proposed framework achieves a Top-1 accuracy of 82.1%, based on the SCA dataset. Furthermore, the method incorporates a multi-modal decision optimization strategy, based on spatiotemporal correlation rules, leveraging YOLOv7-e6 for simultaneous personnel and small object detection, and introduces the Accuracy of Focused Anomaly Recognition (AFAR) metric to enhance the anomaly detection performance. This approach improves the anomaly detection rate, up to 81.37%, with an overall accuracy of 80.66%, significantly outperforming single-modality solutions. Full article

Background: Schizotypal traits are considered to be clinical and cognitive features of Schizotypal Disorder in children (SDc). These traits are also seen in children and adolescents with high-functioning Autism Spectrum Disorder (ASD). This study examines the influence of schizotypal traits (and their severity) on the capacity of children with ASD to manage emotions, develop relationships with others, and adapt in school and family life. Methods: The Schizotypal traits of 63 children (6–12 years old) with High Functioning ASD were measured by the Melbourne Assessment of Schizotypy in Kids (MASK). Parents and teachers of the participating children completed the Child Behavior Checklist (CBCL) and Teachers’ Report Form (TRF) from the Achenbach System of Empirically Based Assessment and the Aberrant Behavior Checklist (ABC). Results: Overall, the results indicated correlations between the MASK scores and problems recorded by teachers, such as Internalizing problems (i.e., Anxious/Depressed, Withdrawn/Depressed, and Other problems score) according to TRF and Inappropriate speech scores, according to teacher’s ABC scales. Schizotypal traits impact the social, emotional, and behavioral functioning of children with ASD at home and school environments. Conclusions: The assessment of schizotypal traits in children with ASD provides critical information about a child’s functionality and cognitive development, also leading to the identification of potential cognitive-neuropsychological endophenotypes within ASD with characteristics of both Autism and Schizophrenia spectra. Τhe development of a valid assessment tool is required, as well as the design of targeted interventions to prevent the loss of functionality. Full article

Purpose: A novel enhanced monofocal intraocular lens (IOL) has been developed to improve functional intermediate vision, maintaining a distance vision comparable to a standard monofocal lens and avoiding the drawbacks of multifocal IOLs. The aim of this study is to perform optical bench analysis and to evaluate refractive and visual outcomes and patient satisfaction. Methods: This prospective comparative single-center study was conducted in Careggi Hospital, University of Florence (Italy). We included 100 eyes from 50 patients who underwent bilateral cataract surgery. One group received the standard monofocal Tecnis GCB00 IOL, while the other group received the novel enhanced monofocal Evolux IOL. We evaluated binocular visual and refractive outcomes at 6 months after surgery. Binocular defocus curves and contrast sensitivity (CS) were also assessed. Optical quality was also analyzed in terms of higher-order aberrations (HOAs), modulation transfer function (MTF), objective scatter index (OSI), Strehl ratio, effective lens position (ELP), and halo analysis. A Patient-Reported Spectacle Independence Questionnaire (PRSIQ) was performed to assess spectacle independence outcomes. Finally, we analyzed the optical bench of both lenses. Results: All eyes implanted with Evolux achieved excellent distance vision, comparable to that achieved with GCB00. Evolux showed better intermediate and near vision, without any loss of visual quality, contrast sensitivity, or the presence of halos and photic phenomena. The optical bench analysis confirmed the different optical properties of the two lenses and supported the behavior obtained with the clinical defocus curve. Conclusions: These preliminary results show good refractive accuracy and visual outcomes for the enhanced monofocal IOL Evolux after cataract surgery. Further studies are needed to confirm our findings in terms of the number of patients and the period of follow-up. Full article

Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation. Full article

Aberrant salience, defined as the inappropriate attribution of significance to neutral stimuli, is increasingly recognized as a critical mechanism in the onset of psychotic disorders. In young individuals at ultra-high risk (UHR) for psychosis, abnormal salience processing may serve as a precursor to full-blown psychotic symptoms, contributing to distorted perceptions and the onset of psychotic ideation. This review examines current literature on aberrant salience among UHR youth, exploring its neurobiological, psychological, and behavioral dimensions. Through a comprehensive analysis of studies involving neuroimaging, cognitive assessments, and symptomatology, we assess the consistency of findings across diverse methodologies. Additionally, we evaluate factors contributing to aberrant salience, including neurochemical imbalances, dysregulation in dopamine pathways, and environmental stressors, which may jointly increase psychosis vulnerability. Identifying aberrant salience as a measurable trait in UHR populations could facilitate earlier identification and targeted interventions. Implications for clinical practice are discussed, highlighting the need for specialized therapeutic approaches that address cognitive and emotional dysregulation in salience attribution. Recent research underscores the importance of aberrant salience in early psychosis research and advocates for further studies on intervention strategies to mitigate progression to psychosis among UHR individuals. Full article

Myosin-binding protein C (MyBP-C) comprises a family of myofilament proteins that maintain sarcomeric structure and regulate actomyosin crossbridge cycling. Pathogenic variants in MYBPC1, the gene encoding the slow skeletal isoform (sMyBP-C), lead to a dominant congenital myopathy, termed Myotrem, characterized by muscle weakness, hypotonia, and a distinctive tremor of myogenic origin, in the absence of neuropathy. However, the molecular mechanism(s) of myogenic tremorgenesis is largely unknown. One potential mechanism is aberrant myofilament stretch activation, which is defined as a delayed increase in force after a rapid stretch. We utilized the Myotrem murine model harboring the pathogenic MYBPC1 E248K variant to test the hypothesis that stretch activation is augmented in permeabilized Myotrem E248K soleus fibers. We found that stretch activation was significantly increased in E248K soleus muscle fibers. Interestingly, once submaximally Ca²⁺ activated, a subpopulation of slow-twitch E248K fibers exhibited spontaneous pulsatile sarcomere oscillations. This pulsing behavior generated a sinusoidal waveform pattern in sarcomere length, which often persisted on a timescale of minutes. These results align with sMyBP-C as key regulator of the synchronous activation of myofilaments by dampening both spontaneous oscillatory activity and stretch-dependent activation. We propose that the presence of sMyBP-C-E248K disrupts this regulation, thereby driving pathogenic myogenic tremors. Full article

Hyaluronan (HA) is essentially secreted by every cell and plays a critical role in maintaining normal cell physiology. While the structure and function of HA have been extensively investigated, questions regarding the sizes and conformation of HA under physiological and inflamed conditions, in relevance to its functions, remain elusive. In this article, we update our knowledge of the HA functional properties, including binding proteins and their signaling networks, as well as matrix formation, which can potentially induce phase separation and affect the mobility and behavior of small molecules, proteins, and cells. We detail the striking differences regarding the biological outcomes of signaling pathways for HA and membrane receptors versus HA and GPI-linked hyaluronidase Hyal-2. We describe: (1) the native, large-sized HA is not proapoptotic but signals with an overexpressed HYAL-2/WWOX/SMAD4 complex to induce apoptosis, which is likely to occur in an inflamed microenvironment; (2) HA-binding proteins are connected via signal pathway networks. The competitive binding of HA and TGF-β to the membrane HYAL-2 and the downstream HYAL-2/WWOX/SMAD4 signaling is addressed; (3) the phase-separated proteins or small molecules in the HA matrices may contribute to the aberrant interactions, leading to inflammation and disease progression; (4) the role of HA and complement C1q in Alzheimer’s disease via connection with a risk factor for Alzheimer’s disease WWOX is also discussed; (5) a hidden function is the inducible HA conformational changes that confer cancer suppression and, probably, retardation of neurodegeneration. Full article

The homozygous Leu100Pro amino acid substitution in SPRED2, a protein negatively controlling RAS function, has recently been identified to be causally linked to a recessive form of Noonan syndrome. The amino acid substitution was documented to affect protein stability and cause a decreased and/or less stable interaction with neurofibromin, a RAS-specific GTPase activating protein negatively regulating RAS function. To further investigate the structural and functional impact of Leu100Pro, we structurally characterized the consequences of this change on the interaction of SPRED2 with neurofibromin, by 1 µn-long molecular dynamics (MD) simulations. Our analyses failed in identifying local perturbations predicted to disrupt or dramatically affect SPRED2 binding to neurofibromin, though a rearrangement of their interaction was observed. On the other hand, MD simulations also identified long-range structural rearrangements of the SPRED2 EVH-1 domain, which might be relevant for an aberrant folding of the mutant driving the previously documented accelerated degradation. Overall, the performed MD simulations suggest the occurrence of multiple intramolecular and intermolecular structural perturbations driven by the Leu100Pro change that likely contribute to its LoF behavior. Full article

Janus kinase 2 (JAK2) is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV) and essential thrombocythemia (ET), while aberrant JAK2 activity is also associated with a number of immune diseases. The acquired somatic mutation JAK2 V617F (95% of cases of PV and in 55–60% of cases of ET), which constitutively activates the JAK2, is the most common molecular event in MPN. The development of specific JAK2 inhibitors is therefore of considerable clinical importance. Ruxolitinib is a JAK inhibitor recently approved by the FDA/EMA and effective in relieving symptoms in patients with MPN. Ruxolitinib binds to the JAK2 last domain, namely JH1; its action on the dynamics of the domain is still only partially known. Using Molecular Dynamics simulations, we have analyzed the JH1 domain in four different states as follows: (i) alone, (ii) with one phosphorylation, (iii) adding Ruxolitinib, and (iv) with five phosphorylations and Ruxolitinib. The ligand induces a dynamic behavior similar to the inactive form of JH1, with a less flexible state than the phosphorylated active form of JH1. This study highlights the inhibitory effect of Ruxolitinib on the JH1 domain, demonstrating the importance of dynamics in regulating JH1 activation. Full article