Drug Development.

Background: The Neurovascular Unit is a multicellular structure of the CNS known to become dysfunctional in Alzheimer's Disease (AD) and cerebral amyloid angiopathy. Amyloidosis disrupts the function of cerebrovascular endothelial cells (cECs) via extrinsic and intrinsic apoptosis, and induction of blood brain barrier (BBB) permeability. Findings in our lab demonstrated that pan-Carbonic Anhydrase inhibitors (CAi's) prevent mitochondria-mediated apoptotic mechanisms in cECs.

Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis.

Introduction: Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes.

Methods: We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo MRI, to investigate early capillary dysfunction in Tg-SwDI mice without memory impairment.

Perinatal protein malnutrition alters maternal behavior and leads to maladaptive stress response, neurodevelopmental delay and disruption on DNA methylation machinery in female mice offspring.

Deficiencies in maternal nutrition have long-term consequences affecting brain development of the progeny and its behavior. In the present work, female mice were exposed to a normal-protein or a low-protein diet during gestation and lactation. We analyzed behavioral and molecular consequences of malnutrition in dams and how it affects female offspring at weaning.

Epigenetic mechanisms linking early-life adversities and mental health.

Early-life adversities, whether prenatal or postnatal exposure, have been linked to adverse mental health outcomes later in life increasing the risk of several psychiatric disorders. Research on its neurobiological consequences demonstrated an association between exposure to adversities and persistent alterations in the structure, function, and connectivity of the brain. Consistent evidence supports the idea that regulation of gene expression through epigenetic mechanisms are involved in embedding the impact of early-life experiences in the genome and mediate between social environments and later behavioral phenotypes.

Comparative analysis among different alternative fuels for ship propulsion in a well-to-wake perspective.

The shipping sector is required to give a significant contribution to the reduction of Green House Gas (GHG) emissions, according to the ambitious goals fixed by the International Maritime Organization (IMO). To achieve these targets, new technologies and measures are required, related to logistics, digitalization, hydrodynamics, machinery, energy, and aftertreatment. A large potential to reduce GHG emissions is offered by alternative fuels.

Homocysteine potentiates amyloid -induced death receptor 4- and 5-mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment.

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear.

Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors.

Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response.

Oxidative stress associated with spatial memory impairment and social olfactory deterioration in female mice reveals premature aging aroused by perinatal protein malnutrition.

Early-life adversity, like perinatal protein malnutrition, increases the vulnerability to develop long-term alterations in brain structures and function. This study aimed to determine whether perinatal protein malnutrition predisposes to premature aging in a murine model and to assess the cellular and molecular mechanisms involved. To this end, mouse dams were fed either with a normal (NP, casein 20%) or a low-protein diet (LP, casein 8%) during gestation and lactation.

FDA-approved carbonic anhydrase inhibitors reduce amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness.

Introduction: Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies.

Methods: Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness.

Results: Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice.

Cholesterol-Containing Liposomes Decorated With Au Nanoparticles as Minimal Tunable Fusion Machinery.

Membrane fusion is essential for the basal functionality of eukaryotic cells. In physiological conditions, fusion events are regulated by a wide range of specialized proteins, operating with finely tuned local lipid composition and ionic environment. Fusogenic proteins, assisted by membrane cholesterol and calcium ions, provide the mechanical energy necessary to achieve vesicle fusion in neuromediator release.

Early life stress induces visual dysfunction and retinal structural alterations in adult mice.

Early life stress (ELS) is defined as a period of severe and/or chronic trauma, as well as environmental/social deprivation or neglect in the prenatal/early postnatal stage. Presently, the impact of ELS on the retina in the adult stage is unknown. The long-term consequences of ELS at retinal level were analyzed in an animal model of maternal separation with early weaning (MSEW), which mimics early life maternal neglect.

Amphiphilic Gold Nanoparticles: A Biomimetic Tool to Gain Mechanistic Insights into Peptide-Lipid Interactions.

Functional peptides are now widely used in a myriad of biomedical and clinical contexts, from cancer therapy and tumor targeting to the treatment of bacterial and viral infections. Underlying this diverse range of applications are the non-specific interactions that can occur between peptides and cell membranes, which, in many contexts, result in spontaneous internalization of the peptide within cells by avoiding energy-driven endocytosis. For this to occur, the amphipathicity and surface structural flexibility of the peptides play a crucial role and can be regulated by the presence of specific molecular residues that give rise to precise molecular events.

Factors that contribute to disparities in time to acute leukemia diagnosis in young people: an in depth qualitative interview study.

Background: Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis.

Methods: This qualitative study utilized in-depth semi-structured interviews.

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke.

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology.

α-Synuclein interacts differently with membranes mimicking the inner and outer leaflets of neuronal membranes.

The toxicity of α-synuclein (α-syn), the amyloidogenic protein responsible for Parkinson's disease, is likely related to its interaction with the asymmetric neuronal membrane. α-Syn exists as cytoplasmatic and as extracellular protein as well. To shed light on the different interactions occurring at the different α-syn localizations, we have here modelled the external and internal membrane leaflets of the neuronal membrane with two complex lipid mixtures, characterized by phase coexistence and with negative charge confined to either the ordered or the disordered phase, respectively.

Impaired social cognition caused by perinatal protein malnutrition evokes neurodevelopmental disorder symptoms and is intergenerationally transmitted.

Nutritional inadequacy before birth and during postnatal life can seriously interfere with brain development and lead to persistent deficits in learning and behavior. In this work, we asked if protein malnutrition affects domains of social cognition and if these phenotypes can be transmitted to the next generation. Female mice were fed with a normal or hypoproteic diet during pregnancy and lactation.

Limited contextual memory and transcriptional dysregulation in the medial prefrontal cortex of mice exposed to early protein malnutrition are intergenerationally transmitted.

Memory contextualization is vital for the subsequent retrieval of relevant memories in specific situations and is a critical dimension of social cognition. The inability to properly contextualize information has been described as characteristic of psychiatric disorders like autism spectrum disorders, schizophrenia, and post-traumatic stress disorder. The exposure to early-life adversities, such as nutritional deficiency, increases the risk to trigger alterations in different domains of cognition related to those observed in mental diseases.

Impact of Tau on Neurovascular Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood.

Non-disruptive uptake of anionic and cationic gold nanoparticles in neutral zwitterionic membranes.

The potential toxicity of ligand-protected nanoparticles (NPs) on biological targets is crucial for their clinical translation. A number of studies are aimed at investigating the molecular mechanisms shaping the interactions between synthetic NPs and neutral plasma membranes. The role played by the NP surface charge is still widely debated.

Perinatal protein malnutrition results in genome-wide disruptions of 5-hydroxymethylcytosine at regions that can be restored to control levels by an enriched environment.

Maternal malnutrition remains one of the major adversities affecting brain development and long-term mental health outcomes, increasing the risk to develop anxiety and depressive disorders. We have previously shown that malnutrition-induced anxiety-like behaviours can be rescued by a social and sensory stimulation (enriched environment) in male mice. Here, we expand these findings to adult female mice and profiled genome-wide ventral hippocampal 5hmC levels related to malnutrition-induced anxiety-like behaviours and their rescue by an enriched environment.

Perinatal protein malnutrition induces the emergence of enduring effects and age-related impairment behaviors, increasing the death risk in a mouse model.

Background: Early-life adversity impacts on the offspring's brain development and is associated with a higher risk of developing age-associated diseases. In particular, perinatal protein malnutrition appears to be one of the most critical nutritional deficiencies affecting the individual's health and survival, but little is known about its effects on the persistence of behavioral alterations throughout life. Thus, the aim of the present study was to investigate how perinatal protein malnutrition impacts on age-related changes in the neuromuscular, cognitive and behavioral functions throughout life in a mouse model.

Amphiphilic gold nanoparticles perturb phase separation in multidomain lipid membranes.

Amphiphilic gold nanoparticles with diameters in the 2-4 nm range are promising as theranostic agents thanks to their spontaneous translocation through cell membranes. This study addresses the effects that these nanoparticles may have on a distinct feature of plasma membranes: lipid lateral phase separation. Atomic force microscopy, quartz crystal microbalance, and molecular dynamics are combined to study the interaction between model neuronal membranes, which spontaneously form ordered and disordered lipid domains, and amphiphilic gold nanoparticles having negatively charged surface functionalization.