High Receptor Density Research Articles

Noradrenergic system in the pathogenesis of age-dependent neurodegeneration

Ageing is a key factor in the development of cognitive decline and neurodegeneration, including Alzheimer’s disease (AD), the most common form of dementia diagnosed. In 2023 the US Federal Drug Administration (FDA) approved a new drug (Lecanemab, Leqembi) to treat AD that very moderately slows down cognitive decline in early-stage AD (van Dyck et al., 2023). Donanemab (Kisunla, Eli Lilley), acting similarly to lecanemab, was approved by the FDA in 2024 in the US, but not yet by the European Medicines Agency (EMA) in the EU. The mechanism of action of both of these monoclonal antibodies is similar to that of aducanumab (Aduhelm), conditionally approved for AD in 2021 (but subsequently discontinued by the producer), by acting on and reducing β-amyloid deposits (Sevigny et al., 2016; van Dyck et al., 2023). However, trials of all these monoclonal antibodies revealed significant adverse events (brain swelling or brain bleeding); hence treatment for AD and neurodegeneration in general remains an important unmet medical need, affecting millions of people worldwide. Here I discuss the role of the noradrenergic system innervating the brain and the spinal cord, consisting of the nucleus locus coeruleus (LC), which appears to be the most vulnerable structure in the central nervous system (CNS) to ageing-related factors, leading to early LC demise and cognitive impairments. Therefore, I propose that understanding the action of noradrenaline on the brain cells, in particular on astrocytes, homeostasis-providing cells, which exhibit a high density of adrenergic receptors, is a future strategy to develop new drugs to mitigate neurodegeneration and cognitive decline. Keywords: ageing; noradrenaline; adrenoceptors; locus coeruleus; neurodegeneration, neuroglia, astrocytes

Cyto-, gene, and multireceptor architecture of the early postnatal mouse hippocampal complex.

Neurotransmitter receptors are key molecules in signal transmission in the adult brain, and their precise spatial and temporal balance expressions also play a critical role in normal brain development. However, the specific balance expression of multiple receptors during hippocampal development is not well characterized. In this study, we used quantitative in vivo receptor autoradiography to measure the distributions and densities of 18 neurotransmitter receptor types in the mouse hippocampal complex at postnatal day 7, and compared them with the expressions of their corresponding encoding genes. We provide a novel and comprehensive characterization of the cyto-, gene, and multireceptor architecture of the developing mouse hippocampal and subicular regions during the developmental period, which typically differs from that in the adult brain. High-density receptor expressions with distinct regional and laminar distributions were observed for AMPA, Kainate, mGluR2/3, GABAA, GABAA/BZ, α2, and A1 receptors during this specific period, whereas NMDA, GABAB, α1, M1, M2, M3, nicotinic α4β2, 5-HT1A, 5-HT2, D1 and D2/D3 receptors exhibited relatively low and homogeneous expressions. This specific balance of multiple receptors aligns with regional cytoarchitecture, neurotransmitter distributions, and gene expressions. Moreover, contrasting with previous findings, we detected a high α2 receptor density, with distinct regional and laminar distribution patterns. A non-covariation differentiation phenomenon between α2 receptor distributions and corresponding gene expressions is also demonstrated in this early developmental period. The multimodal data provides new insights into understanding the hippocampal development from the perspective of cell, gene, and multireceptor levels, and contributes important resources for further interdisciplinary analyses.

Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea, and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine D2 receptor (D2R) signaling. However, AAb influence on dopamine D1 receptor (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia, a region of high dopamine receptor density. Here, we report a mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived monoclonal antibodies (mAbs), which induced both D1R G protein- and β-arrestin-transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.

Opposing actions of co-released GABA and neurotensin on the activity of preoptic neurons and on body temperature.

Neurotensin (Nts) is a neuropeptide acting as a neuromodulator in the brain. Pharmacological studies have identified Nts as a potent hypothermic agent. The medial preoptic area, a region that plays an important role in the control of thermoregulation, contains a high density of neurotensinergic neurons and Nts receptors. The conditions in which neurotensinergic neurons play a role in thermoregulation are not known. In this study, optogenetic stimulation of preoptic Nts neurons induced a small hyperthermia. In vitro, optogenetic stimulation of preoptic Nts neurons resulted in synaptic release of GABA and net inhibition of the preoptic pituitary adenylate cyclase-activating polypeptide (Adcyap1) neurons firing activity. GABA-A receptor antagonist or genetic deletion of Slc32a1 (VGAT) in Nts neurons unmasked also an excitatory effect that was blocked by a Nts receptor 1 antagonist. Stimulation of preoptic Nts neurons lacking Slc32a1 resulted in excitation of Adcyap1 neurons and hypothermia. Mice lacking Slc32a1 expression in Nts neurons presented changes in the fever response and in the responses to heat or cold exposure as well as an altered circadian rhythm of body temperature. Chemogenetic activation of all Nts neurons in the brain induced a 4-5°C hypothermia, which could be blocked by Nts receptor antagonists in the preoptic area. Chemogenetic activation of preoptic neurotensinergic projections resulted in robust excitation of preoptic Adcyap1 neurons. Taken together, our data demonstrate that endogenously released Nts can induce potent hypothermia and that excitation of preoptic Adcyap1 neurons is the cellular mechanism that triggers this response.

IMPACT OF STRESS ON EMOTIONAL HEALTH AND COGNITIVE FUNCTION

Background. Emotional stress can have both a positive effect, which is aimed at adaptation, and a negative one, which affects the higher integrative functions of the brain, and also leads to the development of numerous diseases. In this regard, the problem of establishing the influence of stress factors on the emotional state and cognitive function becomes relevant, which creates the prerequisites for a detailed analysis of the scientific data. Aim: to investigate the impact of chronic stress on emotional health and to determine the impact of stressful factors on human cognitive functions. Material and methods. The review included 63 articles, which have been selected using the following keywords: «chronic stress», «cortisol», «cognitive functions», «emotions», «memory», in the databases of scientific medical data PubMed, Scopus and Web of Science. An analysis of the existing research results on the impact of stress on emotional health and cognitive functions was carried out. Results. Stress causes a multiple effect on the human nervous system, leading to structural changes in different parts of the brain such as atrophy and reduction of brain volume and mass with long-term consequences for the nervous system resulting in impaired cognitive abilities and memory. Alteration of neuronal plasticity, caused by chronic stress, due to dendrite atrophy and decreased spinal density may underlie the depressive disorders. Additionally, chronic inflammation, which also results from prolonged stress, can develop depression and disturb cognitive functions. The hippocampus contains the high density of glucocorticoids receptors, thus increased basal concentration of cortisol may result in functional and structural changes in the hippocampus with atrophy and impaired neurogenesis. Chronic stress can affect cognitive function both acutely and chronically. The acute effect is caused by beta-adrenergic effects, while the chronic effect is caused by long-term changes in gene expression mediated by steroid hormones. Conclusion. Chronic stress with an increased basal concentration of glucocorticoids affects the hippocampus leading to impaired memory, cognition, and thinking, also increases risk of depression, anxiety disorders.

Ionic mechanisms involved in arginine vasopressin-mediated excitation of auditory cortical and thalamic neurons

The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and amygdala. A plethora amount of evidence indicates that activation of the V1a subtype of the vasopressin receptors facilitates anxiety-like and fear responses. As an essential structure involved in fear and anxiety responses, the amygdala, especially the lateral nucleus of amygdala (LA), receives glutamatergic innervations from the auditory cortex and auditory thalamus where high density of V1a receptors have been detected. However, the roles and mechanisms of AVP in these two important areas have not been determined, which prevents the understanding of the mechanisms whereby V1a activation augments anxiety and fear responses. Here, we used coronal brain slices and studied the effects of AVP on neuronal activities of the auditory cortical and thalamic neurons. Our results indicate that activation of V1a receptors excited both auditory cortical and thalamic neurons. In the auditory cortical neurons, AVP increased neuronal excitability by depressing multiple subtypes of inwardly rectifying K+ (Kir) channels including the Kir2 subfamily, the ATP-sensitive K+ channels and the G protein-gated inwardly rectifying K+ (GIRK) channels, whereas activation of V1a receptors excited the auditory thalamic neurons by depressing the Kir2 subfamily of the Kir channels as well as activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a persistent Na+ channel. Our results may help explain the roles of V1a receptors in facilitating fear and anxiety responses.Categories: Cell Physiology.

Multiscale Textile‐Based Haptic Interactions

Wearable haptic devices transmit information via touch receptors in the skin, yet devices located on parts of the body with high densities of receptors, such as fingertips and hands, impede interactions. Other locations that are well‐suited for wearables, such as the wrists and arms, suffer from lower perceptual sensitivity. The emergence of textile‐based wearable devices introduces new techniques of fabrication that can be leveraged to address these constraints and enable new modes of haptic interactions. This article formalizes the concept of “multiscale” interaction, an untapped paradigm for haptic wearables, enabling enhanced delivery of information via textile‐based haptic modules. In this approach, users choose the depth and detail of their haptic experiences by varying their interaction mode. Flexible prototyping methods enable multiscale haptic bands that provide both body‐scale interactions (on the forearm) and hand‐scale interactions (on the fingers and palm). A series of experiments assess participants’ ability to identify pressure states and spatial locations delivered by these bands across these interaction scales. A final experiment demonstrates the encoding of three‐bit information into prototypical multiscale interactions, showcasing the paradigm's efficacy. This research lays the groundwork for versatile haptic communication and wearable design, offering users the ability to select interaction modes for receiving information.

Smoking Progression and Nicotine-Enhanced Reward Sensitivity Predicted by Resting-State Functional Connectivity in Salience and Executive Control Networks.

The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity (NERS) and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC.) during smoking abstinence predicts NERS and smoking progression in young light smokers. We hypothesized that high rsFC between brain areas with high densities of nicotinic receptors (insula, anterior cingulate cortex [ACC], hippocampus, thalamus) and areas involved in reward-seeking (nucleus accumbens [NAcc], prefrontal cortex [PFC]) would predict NERS and smoking progression. Young light smokers (N = 64, age 18-24, M = 1.89 cigarettes/day) participated in the study. These individuals smoked between 5 and 35 cigarettes per week and lifetime use never exceeded 35 cigarettes per week. Their rsFC was assessed using functional magnetic resonance imaging after 14 hours of nicotine deprivation. Subjects also completed a probabilistic reward task after smoking a placebo on 1 day and a regular cigarette on another day. The probabilistic-reward-task assessed greater NERS was associated with greater rsFC between the right anterior PFC and right NAcc, but with reduced rsFC between the ACC and left inferior prefrontal gyrus and the insula and ACC. Decreased rsFC within the salience network (ACC and insula) predicted increased smoking progression across 18 months and greater NERS. These findings provide the first evidence that differences in rsFCs in young light smokers are associated with nicotine-enhanced reward sensitivity and smoking progression. NCT02129387 (preregistered hypothesis: www.clinicaltrials.gov). Weaker rsFC within the salience network predicted greater NERS and smoking progression. These findings suggest that salience network rsFC and drug-enhanced reward sensitivity may be useful tools and potential endophenotypes for reward sensitivity and drug-dependence research.

Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes

Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.

Distribution of insulin in primate brain following nose-to-brain transport.

Nose-to-brain (N2B) insulin delivery has potential for Alzheimer's disease (AD) therapy. However, clinical implementation has been challenging without methods to follow N2B delivery non-invasively. Positron emission tomography (PET) was applied to measure F-18-labeled insulin ([18F]FB-insulin) from intranasal dosing to brain uptake in non-human primates following N2B delivery. [18F]FB-insulin was prepared by reacting A1,B29-di(tert-butyloxycarbonyl)insulin with [18F]-N-succinimidyl-4-fluorobenzoate. Three methods of N2B delivery for [18F]FB-insulin were compared - delivery as aerosol via tubing (rhesus macaque, n = 2), as aerosol via preplaced catheter (rhesus macaque, n = 3), and as solution via preplaced catheter (cynomolgus macaque, n = 3). Following dosing, dynamic PET imaging (120 min) quantified delivery efficiency to the nasal cavity and whole brain. Area under the time-activity curve was calculated for 46 regions of the cynomolgus macaque brain to determine regional [18F]FB-insulin levels. Liquid instillation of [18F]FB-insulin by catheter outperformed aerosol methods for delivery to the subject (39.89% injected dose vs 10.03% for aerosol via tubing, 0.17% for aerosol by catheter) and subsequently to brain (0.34% injected dose vs 0.00020% for aerosol via tubing, 0.05% for aerosol by catheter). [18F]FB-insulin was rapidly transferred across the cribriform plate to limbic and frontotemporal areas responsible for emotional and memory processing. [18F]FB-insulin half-life was longer in olfactory nerve projection sites with high insulin receptor density compared to the whole brain. The catheter-based liquid delivery approach combined with PET imaging successfully tracked the fate of N2B [18F]FB-insulin and is thought to be broadly applicable for assessments of other therapeutic agents. This method can be rapidly applied in humans to advance clinical evaluation of N2B insulin as an AD therapeutic. [18F]FB-insulin passage across the cribriform plate was detected by PET.Intranasal [18F]FB-insulin reached the brain within 13 min.[18F]FB-insulin activity was highest in emotional and memory processing regions.Aerosol delivery was less efficient than liquid instillation by preplaced catheter.Insulin delivery to the cribriform plate was critical for arrival in the brain.

The First “Hit” to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children

BackgroundCannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). MethodsThis study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). ResultsPCE was associated with lower fractional anisotropy of the right (β = −0.005, p < .001) and left (β = −0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. ConclusionsIn sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

Leptin excites basolateral amygdala principal neurons and reduces food intake by LepRb-JAK2-PI3K-dependent depression of GIRK channels.

Leptin is an adipocyte-derived hormone that modulates food intake, energy balance, neuroendocrine status, thermogenesis, and cognition. Whereas a high density of leptin receptors has been detected in the basolateral amygdala (BLA) neurons, the physiological functions of leptin in the BLA have not been determined yet. We found that application of leptin excited BLA principal neurons by activation of the long form leptin receptor, LepRb. The LepRb-elicited excitation of BLA neurons was mediated by depression of the G protein-activated inwardly rectifying potassium (GIRK) channels. Janus Kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) were required for leptin-induced excitation of BLA neurons and depression of GIRK channels. Microinjection of leptin into the BLA reduced food intake via activation of LepRb, JAK2, and PI3K. Our results may provide a cellular and molecular mechanism to explain the physiological roles of leptin in vivo.

Elevated Insulin Levels Engage the Salience Network during Multisensory Perception

Introduction: Brain insulin reactivity has been reported in connection with systematic energy metabolism, enhancement in cognition, olfactory sensitivity, and neuroendocrine circuits. High receptor densities exist in regions important for sensory processing. The main aim of the study was to examine whether intranasal insulin would modulate the activity of areas in charge of olfactory-visual integration. Methods: As approach, a placebo-controlled double-blind within crossover design was chosen. The experiments were conducted in a research unit of a university hospital. On separate mornings, twenty-six healthy normal-weight males aged between 19 and 31 years received either 40 IU intranasal insulin or placebo vehicle. Subsequently, they underwent 65 min of functional magnetic resonance imaging whilst performing an odor identification task. Functional brain activations of olfactory, visual, and multisensory integration as well as insulin versus placebo were assessed. Regarding the odor identification task, reaction time, accuracy, pleasantness, and intensity measurements were taken to examine the role of integration and treatment. Blood samples were drawn to control for peripheral hormone concentrations. Results: Intranasal insulin administration during olfactory-visual stimulation revealed strong bilateral engagement of frontoinsular cortices, anterior cingulate, prefrontal cortex, mediodorsal thalamus, striatal, and hippocampal regions (p ≤ 0.001 familywise error [FWE] corrected). In addition, the integration contrast showed increased activity in left intraparietal sulcus, left inferior frontal gyrus, left superior frontal gyrus, and left middle frontal gyrus (p ≤ 0.013 FWE corrected). Conclusions: Intranasal insulin application in lean men led to enhanced activation in multisensory olfactory-visual integration sites and salience hubs which indicates stimuli valuation modulation. This effect can serve as a basis for understanding the connection of intracerebral insulin and olfactory-visual processing.

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe.

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker's areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

Resting-state functional connectivity in Autoimmune Addison's Disease

Patients with autoimmune Addison’s disease (AAD) are unable to produce glucocorticoids (GCs), mineralocorticoids (MCs) and androgens from the adrenal cortex and therefore require life-long treatment with GCs and MCs. Due to the sensitivity of the brain to cortisol and androgens, brain function might be affected in patients, as the replacement regime cannot mimic the natural rhythmicity of hormonal secretion. Alterations in brain function might predispose to cognitive or mood disturbances. The present study investigated resting-state functional connectivity (rs-fc) in patients with AAD. Resting-state fMRI data was collected from 57 (33 females) patients with AAD and 69 (39 females) control participants, aged 19-43 years. Resting-state brain networks were identified with independent component analysis (FSL MELODIC). Dual-regression analysis was applied to test for group differences in rs-fc in these networks. Within the patient group we tested the association between rs-fc and glucocorticoid replacement dose in mg/m2/day. Significant clusters were identified with threshold free cluster enhancement and considered to be significant at p<0.05. Patients with AAD had increased fc in the bilateral medial orbitofrontal cortex compared to controls. A higher glucocorticoid replacement dose was associated with stronger functional connectivity in several networks in the prefrontal cortex in patients. AAD seems to be associated with stronger fc at rest in an area known to contain a high density of GC receptors. Further research is needed to investigate if this increased activity is part of an adaptive mechanism or if it predisposes to disturbances in mood and executive functioning.

Receptor Density-Dependent Motility of Influenza Virus Particles on Surface Gradients.

Influenza viruses can move across the surface of host cells while interacting with their glycocalyx. This motility may assist in finding or forming locations for cell entry and thereby promote cellular uptake. Because the binding to and cleavage of cell surface receptors forms the driving force for the process, the surface-bound motility of influenza is expected to be dependent on the receptor density. Surface gradients with gradually varying receptor densities are thus a valuable tool to study binding and motility processes of influenza and can function as a mimic for local receptor density variations at the glycocalyx that may steer the directionality of a virus particle in finding the proper site of uptake. We have tracked individual influenza virus particles moving over surfaces with receptor density gradients. We analyzed the extracted virus tracks first at a general level to verify neuraminidase activity and subsequently with increasing detail to quantify the receptor density-dependent behavior on the level of individual virus particles. While a directional bias was not observed, most likely due to limitations of the steepness of the surface gradient, the surface mobility and the probability of sticking were found to be significantly dependent on receptor density. A combination of high surface mobility and high dissociation probability of influenza was observed at low receptor densities, while the opposite occurred at higher receptor densities. These properties result in an effective mechanism for finding high-receptor density patches, which are believed to be a key feature of potential locations for cell entry.

Modeling interaction of Glioma cells and CAR T-cells considering multiple CAR T-cells bindings

Chimeric antigen receptor (CAR) T-cell based immunotherapy has shown its potential in treating blood cancers, and its application to solid tumors is currently being extensively investigated. For glioma brain tumors, various CAR T-cell targets include IL13Rα2, EGFRvIII, HER2, EphA2, GD2, B7-H3, and chlorotoxin. In this work, we are interested in developing a mathematical model of IL13Rα2 targeting CAR T-cells for treating glioma. We focus on extending the work of Kuznetsov et al. (1994) by considering binding of multiple CAR T-cells to a single glioma cell, and the dynamics of these multi-cellular conjugates. Our model more accurately describes experimentally observed CAR T-cell killing assay data than the models which do not consider multi-cellular conjugates. Moreover, we derive conditions in the CAR T-cell expansion rate that determines treatment success or failure. Finally, we show that our model captures distinct CAR T-cell killing dynamics from low to high antigen receptor densities in patient-derived brain tumor cells.

Single-Particle Functionality Imaging of Antibody-Conjugated Nanoparticles in Complex Media.

The properties of nanoparticles (NPs) can change upon contact with serum components, occluding the NP surface by forming a biomolecular corona. It is believed that targeted NPs can lose their functionality due to this biological coating, thus losing specificity and selectivity toward target cells and leading to poor therapeutic efficiency. A better understanding of how the biomolecular corona affects NP ligand functionality is needed to maintain NP targeting capabilities. However, techniques that can quantify the functionality of NPs at a single-particle level in a complex medium are limited and often laborious in sample preparation, measurement, and analysis. In this work, the influence of serum exposure on the functionality of antibody-functionalized NPs was quantified using a straightforward total internal reflection fluorescence (TIRF) microscopy method and evaluated in cell uptake studies. The single-particle resolution of TIRF reveals the interparticle functionality heterogeneity and the substantial differences between NPs conjugated with covalent and noncovalent methods. Notably, only NPs covalently conjugated with a relatively high amount of antibodies maintain their functionality to a certain extent and still showed cell specificity and selectivity toward high receptor density cells after incubation in full serum. The presented study emphasizes the importance of single-particle functional characterization of NPs in complex media, contributing to the understanding and design of targeted NPs that retain their cell specificity and selectivity in biologically relevant conditions.

The effects of synthetic glucocorticoid treatment for inflammatory disease on brain structure, function, and dementia outcomes: A systematic review

Many regions of the brain have a high density of glucocorticoid receptors, and the prolonged elevation of endogenous glucocorticoids may cause neurotoxicity and increase risk for cognitive decline and dementia. However, despite synthetic glucocorticoids being the first line of treatment for many inflammatory diseases, few studies have addressed whether therapeutic glucocorticoids may have similar undesirable effects on the brain. Thus, our systematic review investigated the impact of long-term glucocorticoid usage on adult brain structure, cognitive function, and dementia risk. We identified 13 studies that met our eligibility criteria and found conflicting results dependent on the outcome studied. In particular, all but one study on hippocampal and amygdalar volumes found significant atrophy of both structures occurred in those who took glucocorticoids. Additionally, executive function, particularly working memory, and global cognitive function were significantly poorer in those taking long-term glucocorticoids. Notably, declines in episodic memory were not associated with long-term usage. Furthermore, most studies of dementia (all-cause) and Alzheimer’s disease, excluding vascular dementia, showed null to negative associations with glucocorticoids, suggesting a potential protective effect. Therefore, glucocorticoid therapy in those with inflammatory disease may impair certain brain structures and specific cognitive functions, but could lead to a significantly reduced risk of dementia.

The effects of a water-bound construction consolidation centre on off-site transport performance: the case of the Brussels-Capital Region

PurposeThe environmental logistics impact is significant in urban areas, characterised by high receptor densities, less accessible sites and limited storage space. With the aim to reduce negative externalities generated by urban construction transport and improve the use of existing inland waterway transport (IWT) infrastructure, the City of Brussels has implemented a water-bound Construction Consolidation Centre ((BCCC). While the concept of a CCC has been implemented in different European cities, limited impact studies are available. This paper assesses the environmental off-site road and IWT’s transport performance of the multimodal BCCC case. Design/methodology/approachThe sustainability impact is evaluated using economic external cost calculations, contextualised with transport planning indicators. Subsequently, findings are compared to business-as-usual (BAU) operations without a CCC as part of a scenario evaluation, for the 24 large construction sites supplied through the CCC between Sep-2019 and Dec-2020. FindingsImprovements in the IWT sector are necessary to tackle local emissions (NOx, PM) which rise significantly compared to BAU (+257 %), mainly attributable to less performant -yet ubiquitous- vessel engines and their long running life. In contrast, other externalities decrease, most noticeably on congestion costs (-91 %), climate change (-66 %), noise (-79 %) and infrastructure costs (-60 %). Overall, €49,404.67 of external costs are saved annually, a 58.72 % reduction compared to BAU. Additionally, improvements are observed on transport planning and efficiency, with 73 % timely deliveries and 93.32 % delivery compliance, hence respecting the Just-In-Time and Just-In-Place principles. Research limitations/implicationsPromising results are shown to incentivize industry and policy makers for adopting a CCC in light of alleviating the impact of urban construction logistics (CL), if the overall external costs and mobility impacts are considered. Results should be further compared to other logistic solutions to evaluate complementary measures, including more differentiated scenario evaluations. Practical implicationsAlthough IWT alleviates road network use, air pollution from vessels should be addressed. An IWT-CCC can offer decision-makers a transport planning solution to decrease urban nuisances and increase resource efficiency use, if specific IWT-CCC and CL applicability requirements are considered. Originality/valueThis paper adds knowledge to the sector’s impact mitigation potential using IWT-CCC, offering insights for decisional support and policy recommendations.