Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures

Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness

Seismic Behaviour of Cable-Stayed Bridges: A Review

Cable-stayed bridges represent backbones in the infrastructure networks and their adequate seismic response must be ensured. These structures present complex interactions between the deck, the cables, the towers and their foundation. This, in combination with the reduced damping and the outstanding slenderness of cable-stayed bridges, renders a unique dynamic response. A complete review on the state of knowledge about the seismic behaviour of cable-stayed bridges is presented here, with special attention to the analysis techniques. The current design trends in the seismic design and control of cable-stayed bridges are also presented

Age at first episode modulates diagnosis-related structural brain abnormalities in psychosis

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12–35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15–20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18–20 y). The AFP group also had age-constant (12–35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis

Fornix degeneration in risk factors of Alzheimer's disease, possible trigger of cognitive decline

Risk factors of late-onset Alzheimer's disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of cognitive decline and dementia by triggering cerebrovascular pathology and neuroinflammation.White matter (WM) microstructure and function are especially vulnerable to these conditions. Microstructural WM changes, assessed with diffusion weighted magnetic resonance imaging, can already be detected at preclinical stages of AD, and in the presence of the aforementioned risk factors. Particularly, the limbic system and cortico-cortical association WM tracts, which myelinate late during brain development, degenerate at the earliest stages. The fornix, a C-shaped WM tract that originates from the hippocampus, is one of the limbic tracts that shows early microstructural changes. Fornix integrity is necessary for ensuring an intact executive function and memory performance. Thus, a better understanding of the mechanisms that cause fornix degeneration is critical in the development of therapeutic strategies aiming to prevent cognitive decline in populations at risk. In this literature review, i) we deepen the idea that partial loss of forniceal integrity is an early event in AD, ii) we describe the role that common risk factors of AD can play in the degeneration of the fornix, and iii) we discuss some potential cellular and physiological mechanisms of WM degeneration in the scenario of cerebrovascular disease and inflammation

Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures

Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness

Is the cerebellum the optimal reference region for intensity normalization of perfusion MR studies in early Alzheimer's disease?

The cerebellum is the region most commonly used as a reference when normalizing the intensity of perfusion images acquired using magnetic resonance imaging (MRI) in Alzheimer's disease (AD) studies. In addition, the cerebellum provides unbiased estimations with nuclear medicine techniques. However, no reports confirm the cerebellum as an optimal reference region in MRI studies or evaluate the consequences of using different normalization regions. In this study, we address the effect of using the cerebellum, whole-brain white matter, and whole-brain cortical gray matter in the normalization of cerebral blood flow (CBF) parametric maps by comparing patients with stable mild cognitive impairment (MCI), patients with AD and healthy controls. According to our results, normalization by whole-brain cortical gray matter enables more sensitive detection of perfusion abnormalities in AD patients and reveals a larger number of affected regions than data normalized by the cerebellum or whole-brain white matter. Therefore, the cerebellum is not the most valid reference region in MRI studies for early stages of AD. After normalization by whole-brain cortical gray matter, we found a significant decrease in CBF in both parietal lobes and an increase in CBF in the right medial temporal lobe. We found no differences in perfusion between patients with stable MCI and healthy controls either before or after normalization

A functional cerebral endothelium is necessary to protect against cognitive decline

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included Nemo(Fl) controls and three Nemo(beKO) groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in Nemo(beKO) mice and were not countered by treatments. Cerebrovascular function was compromised in Nemo(beKO) groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. Nemo(beKO) mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts