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Ferrari, A.

Publications and source records attributed to Ferrari, A..

At least 19 recordsLinked to original sources

Cortical long-range dynamics track excitation-inhibition balance across cognitive states and organizational principles

A fundamental question in systems neuroscience is how the brain's excitation-inhibition (E/I) balance shapes the temporal structure of neural activity and whether we can non-invasively recover this relationship from neural scaling properties. We show that MRS-derived E/I balance is expressed in long-range temporal dynamics and constrained by cytoarchitecture. The laminar organisation of inhibitory circuits, spanning agranular to granular cortex, determines how faithfully regional dynamics reflect E/I balance. This neurochemical signature is state-dependent: its relationship with cortical dynamics reverses during task engagement, consistent with traversal of dynamical regimes around a critical point. It extends beyond fMRI to arousal-linked dynamics, indexed by pupil diameter and microsaccades, indicating a global mode of cortical state rather than a regionally isolated property. The imprint of E/I balance on long-range dynamics follows the sensory-association axis at rest, and is reconfigured during task engagement. These findings establish E/I balance as a neurochemical quantity with structured, scalable signatures across the temporal and spatial organization of the human cortex.

neuroscience↗

Feeling the music: Audiotactile encoding of temporal structure in the human brain

In everyday situations, like a rock party or an organ concert, we feel music vibrating through our bodies. How do these vibrotactile signals influence music processing? How do they aid auditory scene analysis? Combining psychophysics, fMRI and time-resolved EEG decoding, this work reveals how the brain encodes the temporal structure of music (beat and envelope) across audition and touch and uses this information to guide multisensory integration and segregation in simple and more complex perceptual scenes. Participants experienced monophonic and polyphonic piano pieces through auditory, vibrotactile and audiotactile stimulation. Vibrotactile signals improved the detection of a brief target embedded in music, establishing the functional relevance of audiotactile integration in naturalistic settings. fMRI and EEG multivariate decoding revealed that auditory and tactile beat information converged in planum temporale and parietal operculum, albeit through distinct neural dynamics and representations. Superior temporal cortices reliably encoded envelope information from audition, but only weakly from touch. Nevertheless, vibrotactile signals significantly enhanced neural encoding of auditory beat as early as 100 ms, and envelope representations from 250 ms onward. These encoding benefits were associated with superadditive interactions in primary auditory cortex, where tactile signals sharpen and amplify auditory envelope representations. In complex polyphonic music, touch further amplified the segregation and encoding of temporally coherent auditory streams. Our findings highlight the important, yet largely unexplored influence of touch on auditory processing, enriching music perception and supporting auditory scene analysis in real-world environments.

neuroscience↗

NK2R signaling governs intestinal lipid mobilization and mucosal inflammation

Neuropeptidergic control of lipid metabolism is conserved and increasingly implicated in metabolic diseases, but receptor-level mechanisms remain unclear. Here we identify the neurokinin-2 receptor (NK2R) as a central node linking tachykinin signals to intestinal lipid mobilization, epithelial composition, and mucosal inflammation. Across complementary genetic and pharmacological perturbations, modulation of NK2R drives bidirectional effects. Loss or blockade of NK2R increases postprandial triglyceridemia and expands intestinal lipid stores, whereas agonism suppresses chylomicron output, reduces adiposity, and improves glycemia in diet-induced obesity. Transcriptomic and cellular analyses indicate coordinated upregulation of lipid-metabolic programs with a concomitant dampening of immune pathways in the absence of NK2R, accompanied by sex-specific remodeling of secretory lineages and male-biased protection from colitis. NK2R signaling also shaped the fecal microbiota in a genotype- and diet-dependent manner, highlighting crosstalk among neuropeptide signaling, epithelial physiology, and host-microbe interactions. These findings position NK2R as a molecular switch for intestinal lipid handling and mucosal inflammation and suggest that NK2R-targeted agonists or antagonists could be deployed as context- and sex-dependent therapeutic strategies for metabolic disease and inflammatory bowel disease.

physiology↗

snATAC-Express infers Gene Expression from Prioritized Chromatin Accessibility Peaks using Machine Learning

BackgroundSingle cell multi-omic investigation opens-up new opportunities to understand mechanisms of gene regulation. Existing methods for inferring transcript abundance from chromatin accessibility fail to prioritize the most relevant peaks and tend to assume positive associations between ATAC peaks and RNA counts. We hypothesize that gene regulation can be modeled as a function of combined positive and negative interactions among peaks and that causal regulatory variants are enriched in the vicinity of the most critical peaks. ResultsA machine learning pipeline leveraging single nuclear multiomic transcriptome and chromatin accessibility data is developed to model gene expression as a function of ATAC peak intensity. Multiome data was available for 18 immune cell types from 29 donors, 19 with Crohns disease. The pipeline aggregates results from three machine learning approaches (random forest regression, XGBoost, and Light GBM) as well as linear regression to identify which ATAC peaks contribute to explaining variation among donors and cell types in pseudobulk gene expression. The coefficient of determination with cross-validation was used to identify robust models which typically explain between 5% and 40% of transcript abundance, utilizing on average 47% of the ATAC peaks, representing a significant gain in predictive accuracy. The most important peaks are enriched in GWAS variants for inflammatory bowel disease and the autoimmune disease systemic lupus erythematosus, but not for rheumatoid arthritis. ConclusionAtlanta Plots visualize the proportion of ATAC peaks contributing to a predictive model of gene expression as well as the proportion of variance explained by the model. Software implementing our pipeline, "snATAC-Express", is freely available on GitHub.

bioinformatics↗

Cholesterol Metabolism in a Murine Model of Vertical Sleeve Gastrectomy

The most effective and durable treatment for obesity is metabolic bariatric surgery. Currently, vertical sleeve gastrectomy (VSG) has become the preferred surgical method to achieve sustained weight loss and reverse obesity-related disease, including dyslipidemias. Human studies indicate that 40% of VSG patients can discontinue statin treatment by 6 months, while alterations in plasma bile acids and synthesis have been observed after bariatric surgery. Although it is well known that cholesterol is the precursor for all bile acids, the link between changes in plasma cholesterol and bile acids remains unclear in the context of VSG. Here, we present a murine model of VSG that leads to a marked decrease in plasma cholesterol levels despite no difference in body weight compared to sham surgery. Our results demonstrate that gastric resection lowers systemic cholesterol burden by promoting the hepatobiliary elimination of cholesterol through the upregulation of bile acid synthesis. These observations imply that gastric resection impacts overall hepatic physiology and cholesterol homeostasis independent of weight loss.

physiology↗

The epigenetic regulator TRIM24 controls melanoma cell dedifferentiation and resistance to treatment in melanoma

Cancer cell plasticity plays a key role in tumor progression and treatment resistance in melanoma. While the transcriptional programs enabling adaptative switching between melanocytic and mesenchymal phenotypes are well characterized, unravelling druggable epigenetic regulators that sustain melanoma cell adaptation and resistance remains crucial. Herein, we identified TRIM24, a bromodomain protein frequently upregulated during melanoma metastatic progression, as a crucial regulator of melanoma cell plasticity towards invasive/resistant states. shRNA-mediated knock-down of TRIM24 or degradation using a TRIM24-specific PROTAC decrease the migratory capacities and increase the sensitivity to BRAF inhibitors of melanoma cells. Integration of transcriptomic (RNA-seq) and epigenomic (ATAC-seq, CUT&Tag) analyses reveals that TRIM24 reprograms the epigenome of melanoma cells, promoting mesenchymal and repressing melanocytic transcriptional programs. We further define a TRIM24-specific transcriptional signature, that is consistently enriched in treatment-resistant mesenchymal subpopulations in melanoma single-cell RNA-seq datasets. Accordingly, analysis of TRIM24 protein expression in melanoma patients highlights that high TRIM24 expression correlates with relapse to adjuvant immunotherapy. Finally, TRIM24 knock-down in immunocompetent mouse models synergises with immune checkpoint inhibitors. Overall, our findings spotlight TRIM24 as a major epigenetic regulator driving melanoma cell dedifferentiation and resistance to therapy, representing a promising druggable target to reverse phenotype switching and resensitize to treatment.

cancer biology↗

Prior expectations guide multisensory integration during face-to-face communication

Face-to-face communication relies on the seamless integration of multisensory signals, including voice, gaze, and head movements, to convey meaning effectively. This poses a fundamental computational challenge: optimally binding signals sharing the same communicative intention (e.g. looking at the addressee while speaking) and segregating unrelated signals (e.g. looking away while coughing), all within the rapid turn-taking dynamics of conversation. Critically, the computational mechanisms underlying this extraordinary feat remain largely unknown. Here, we cast face-to-face communication as a Bayesian Causal Inference problem to formally test whether prior expectations arbitrate between the integration and segregation of vocal and bodily signals. Moreover, we asked whether there is a stronger prior tendency to integrate audiovisual signals that show the same communicative intention, thus carrying a crossmodal pragmatic correspondence. In a spatial localization task, participants watched audiovisual clips of a speaker where the audio (voice) and the video (bodily cues) were sampled either from congruent positions or at increasing spatial disparities. Crucially, we manipulated the pragmatic correspondence of the signals: in a communicative condition, the speaker addressed the participant with their head, gaze and speech; in a non-communicative condition, the speaker kept the head down and produced a meaningless vocalization. We measured audiovisual integration through the ventriloquist effect, which quantifies how much the perceived audio position is misplaced towards the video position. Bayesian Causal Inference outperformed competing models in explaining participants behaviour, demonstrating that prior expectations guide multisensory integration during face-to-face communication. Remarkably, participants showed a stronger prior tendency to integrate vocal and bodily information when signals conveyed congruent communicative intent, suggesting that pragmatic correspondences enhance multisensory integration. Collectively, our findings provide novel and compelling evidence that face-to-face communication is shaped by deeply ingrained expectations about how multisensory signals should be structured and interpreted. Author summaryFace-to-face communication is complex: what we say is coupled with bodily signals, offset in time, which may or may not work in concert to convey meaning. Yet, the brain rapidly determines which multisensory signals belong together and which, instead, must be kept apart, suggesting that prior expectations play a crucial role in this decision-making process. Here, we directly tested this hypothesis using Bayesian computational modelling, which allows for isolating the contribution of prior expectations and sensory uncertainty on the final perceptual decision. We found that people have a stronger prior tendency to combine vocal and bodily signals when they convey the same communicative intent (i.e. the speaker addresses the observer concurrently with their head, gaze and speech) relative to when this correspondence is absent. Thus, the brain uses prior expectations to bind multisensory signals that carry converging communicative meaning. These findings provide key insight into the sophisticated mechanisms underpinning efficient multimodal communication.

neuroscience↗

Multiscale excitation-inhibition balance dynamics: integrating metabolite kinetics with time-varying executive networks

The balance between neural excitation and inhibition (EIB) is an essential mechanism supporting cognitive processes. Yet, little is understood about how EIB shifts with cognitive load and its impact on functional connectivity dynamics. In this study, we investigate temporal profiles of the reciprocal modulation between EIB and functional network dynamics during working memory tasks, revealing that EIB prefrontal kinetics scale with increasing cognitive load. Notably, prefrontal EIB kinetics correlated with cognitive load, impacting stability of networks crucial for cognitive function. On one hand, brain dynamics adapt to meet increasing cognitive challenges with a shift towards more focused and sustained neural activity patterns in terms of connectivity. On the other, imbalances favouring excitation may hinder cognitive adaptability. Importantly, this experimental approach demonstrates a link between EIB kinetics, brain network dynamics and cognitive performance, defining the groundwork for exploring healthy and aberrant cognitive states. TeaserHighly focused or less responsive? Chemical signalling and network dynamics are coupled to produce persistent cognitive states.

neuroscience↗

WTools: a MATLAB-based toolbox for time-frequency analysis

Electroencephalography (EEG) is an established method for investigating neurocognitive functions during human development. In cognitive neuroscience, time-frequency analysis of the EEG is a widely used analytical approach. This paper introduces WTools, a new MATLAB-based toolbox capable of performing time-frequency analysis of EEG signals using complex wavelet transformation. WTools features an intuitive GUI that guides users through the analysis steps, focusing on essential parameters. Being free and open-source, it can be integrated and expanded with new features, making it a handy tool that is growing its popularity in developmental cognitive neuroscience. Here, we provide a detailed description of the WTools algorithm for wavelet transformation and we compare it with state-of-the-art methods implemented in EEGLAB. Alongside the official tool release, we also offer a comprehensive illustrated tutorial to enhance accessibility and promote the transparent and reproducible usage of WTools by the scientific community. HighlightsO_LIWTools is a new MATLAB-based toolbox for time-frequency analysis of the EEG signal C_LIO_LIIt uses wavelet transformation and the algorithm is fully described C_LIO_LIIt is designed to be very user friendly through its simple GUI C_LIO_LIIt is open source and flexible as the code is freely available C_LIO_LIWe provide a step-by-step tutorial and an example dataset to learn the toolbox C_LI

neuroscience↗

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling

Complex genetic and dietary cues contribute to the development of obesity, but how these are integrated on a molecular level is incompletely understood. Here, we show that PPAR{gamma} supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, a membrane-bound O-acyltransferase that enriches diet-derived omega-6 (n-6) polyunsaturated fatty acids (PUFAs) in the phospholipidome. In high-fat diet-fed mice, lowering membrane n-6 PUFA levels by adipocyte-specific Lpcat3 knockout (Lpcat3AKO) or by dietary lipid manipulation leads to dysfunctional triglyceride (TG) storage, ectopic fat deposition and insulin resistance. Aberrant lipolysis of stored TGs in Lpcat3AKO adipose tissues instigates a non-canonical adaptive response that engages a futile lipid cycle to increase energy expenditure and limit further body weight gain. Mechanistically, we find that adipocyte LPCAT3 activity promotes TG storage by selectively enriching n-6 arachidonoyl-phosphatidylethanolamine at the ER-lipid droplet interface, which in turn favours the budding of large droplets that exhibit greater resistance to ATGL-dependent hydrolysis. Thus, our study highlights the PPAR{gamma}-LPCAT3 pathway as a molecular link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.

physiology↗

Long-term Immunity of a Microneedle Array Patch of SARS-CoV-2 S1 Protein Subunit Vaccine Irradiated by Gamma Rays in Mice

COVID-19 vaccines effectively prevent symptomatic infection and severe disease, including hospitalization and death. However, unequal vaccine distribution during the pandemic, especially in low- and middle-income countries, has led to the emergence of vaccine-resistant strains. This underscores the need for alternative, safe, and thermostable vaccine platforms, such as dissolved microneedle array patches (MAP) delivering a subunit vaccine, which eliminate the need for cold chain and trained healthcare personnel. This study demonstrates that the SARS-CoV-2 S1 monomer with RS09, a TLR-4 agonist peptide, serves as an optimal protein subunit immunogen. This combination stimulates a stronger S1-specific immune response, resulting in binding to the membrane-bound spike on the cell surface and ACE2-binding inhibition, compared to the monomer S1 alone or trimer S1, regardless of RS09. MAP delivery of the rS1RS09 subunit vaccine elicited higher and longer-lasting immunity compared to conventional intramuscular injection. S1-specific IgG levels remained significantly elevated for up to 70 weeks post-administration. Additionally, different doses of 5, 15, and 45 g of MAP vaccines induced robust and sustained Th2-prevalent immune responses, suggesting a dose-sparing effect and inducing significantly high neutralizing antibodies against the Wuhan, Delta, and Omicron variants at 15 and 45 g dose. Moreover, gamma irradiation as a terminal sterilization method did not significantly affect immunogenicity, with irradiated vaccines maintaining comparable efficacy to non-irradiated ones. The stability of MAP vaccines was evaluated after long-term storage at room temperature and refrigeration for 19 months, showing minimal protein degradation. Further, after an additional one-month of storage at elevated temperature (42{degrees}C), rS1RS09 in both non-irradiated and irradiated MAP degraded less than 3%, while the liquid subunit vaccine degraded over 23%. Overall, these results indicate that gamma irradiation sterilized MAP-rS1RS09 vaccines maintain stability during extended storage without refrigeration, supporting their potential for mass production and widespread use in global vaccination efforts.

microbiology↗

Cholesterol binding to VCAM-1 promotes vascular inflammation

Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endothelium in vivo dampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.

physiology↗

Glacier retreat decreases plant-pollinator network robustness over space-time

Glaciers are retreating worldwide at an ever-increasing rate, exposing new ice-free areas to ecological succession. This process leads to changes in biodiversity and potentially to species interactions. However, we still have a limited understanding of how glacier retreat influences species interaction networks, particularly the structure and robustness of mutualistic networks. After reconstructing plant-pollinator networks along a glacier foreland, we address the effects of glacier retreat on pollination network structure and robustness. Our results show that the prevalence of different network motifs changes over space-time. With glacier retreat, pollination networks shift from being highly connected with specialist interactions to loosely connected with generalist interactions. Furthermore, network robustness decreased with glacier retreat. Despite the turnover of plant species, we find that structural roles played by different plant species stay constant over space-time. Our findings suggest that glacier retreat pushes pollination networks towards a loss of specialist interactions and low robustness, leading to increased fragility in the long term. Monitoring network motifs may provide valuable insights into the ability of novel pollination networks to withstand disturbances and preserve functionality in the face of glacier extinction.

ecology↗

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

The nuclear receptor Liver X Receptor- (LXR) activates lipogenic gene expression in hepatocytes. Its inhibition has therefore been proposed as a strategy to treat metabolic-dysfunction-associated steatotic liver disease (MASLD). In order to understand the impact of reducing LXR activity on human health we first examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXR) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXR in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXR, carriers of damaging mutations in LXR had reduced serum triglycerides ({beta}=-0.13 s.d. {+/-}0.03, P=2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated concentrations of serum liver enzymes (e.g. ALT: {beta}=0.17s.d. {+/-}0.03, P=1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P=1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Homozygous knock-in mice rapidly developed severe hepatitis and fibrotic liver injury following exposure to western diet despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was completely rescued by viral over-expression of wildtype LXR specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXR knockout mice showed some evidence of hepatocyte injury under similar dietary conditions, the phenotype of the LXRW441R/W441R mouse was much more severe, suggesting that dominant negative mutations that actively co-repress target genes can result in pathological impacts significantly more severe than those seen with simple absence of the receptor. In summary, our results show that loss of function mutations in LXR occur in at least 1/450 people and are associated with evidence of liver dysfunction. These findings implicate LXR in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.

genetics↗

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption

The intrinsic pathways that control membrane organization in immune cells and the impact of such pathways on cellular function are not well defined. Here we report that the non-vesicular cholesterol transporter Aster-A links plasma membrane (PM) cholesterol availability in T cells to immune signaling and systemic metabolism. Aster-A is recruited to the PM during T-cell receptor (TCR) activation, where it facilitates the removal of newly generated "accessible" membrane cholesterol. Loss of Aster-A leads to excess PM cholesterol accumulation, resulting in enhanced TCR nano-clustering and signaling, and Th17 cytokine production. Finally, we show that the mucosal Th17 response is restrained by PM cholesterol remodeling. Ablation of Aster-A in T cells leads to enhanced IL-22 production, reduced intestinal fatty acid absorption, and resistance to diet-induced obesity. These findings delineate a multi-tiered regulatory scheme linking immune cell lipid flux to nutrient absorption and systemic physiology.

physiology↗

Second Boost of Omicron SARS-CoV-2 S1 Subunit Vaccine Induced Broad Humoral Immune Responses in Elderly Mice

Currently approved COVID-19 vaccines prevent symptomatic infection, hospitalization, and death from the disease. However, repeated homologous boosters, while considered a solution for severe forms of the disease caused by new SARS-CoV-2 variants in elderly individuals and immunocompromised patients, cannot provide complete protection against breakthrough infections. This highlights the need for alternative platforms for booster vaccines. In our previous study, we assessed the boost effect of the SARS-CoV-2 Beta S1 recombinant protein subunit vaccine (rS1Beta) in aged mice primed with an adenovirus-based vaccine expressing SARS-CoV-2-S1 (Ad5.S1) via subcutaneous injection or intranasal delivery, which induced robust humoral immune responses (1). In this follow-up study, we demonstrated that a second booster dose of a non-adjuvanted recombinant Omicron (BA.1) S1 subunit vaccine with Toll-like receptor 4 (TLR4) agonist RS09 (rS1RS09OM) was effective in stimulating strong S1-specific immune responses and inducing significantly high neutralizing antibodies against the Wuhan, Delta, and Omicron variants in 100-week-old mice. Importantly, the second booster dose elicits cross-reactive antibody responses, resulting in ACE2 binding inhibition against the spike protein of SARS-CoV-2 variants, including Omicron (BA.1) and its subvariants. Interestingly, the levels of IgG and neutralizing antibodies correlated with the level of ACE2 inhibition in the booster serum samples, although Omicron S1-specific IgG level showed a weaker correlation compared to Wuhan S1-specific IgG level. Furthermore, we compared the immunogenic properties of the rS1 subunit vaccine in young, middle-aged, and elderly mice, resulting in reduced immunogenicity with age, especially an impaired Th1-biased immune response in aged mice. Our findings demonstrate that the new variant of concern (VOC) rS1 subunit vaccine as a second booster has the potential to offer cross-neutralization against a broad range of variants and to improve vaccine effectiveness against newly emerging breakthrough SARS-CoV-2 variants in elderly individuals who were previously primed with the authorized vaccines.

immunology↗

3-O-methyltolcapone and Its Lipophilic Analogues are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinsons disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation which is responsible of the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore, in-vitro toxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover, in-vitro permeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.

biochemistry↗

Fourth dose of Microneedle Array Patch of SARS-CoV-2 S1 Protein Subunit Vaccine Elicits Robust Long-lasting Humoral Responses in mice

The COVID-19 pandemic has underscored the pressing need for safe and effective booster vaccines, particularly in considering the emergence of new SARS-CoV-2 variants and addressing vaccine distribution inequalities. Dissolving microneedle array patches (MAP) offer a promising delivery method, enhancing immunogenicity and improving accessibility through the skins immune potential. In this study, we evaluated a microneedle array patch-based S1 subunit protein COVID-19 vaccine candidate, which comprised a bivalent formulation targeting the Wuhan and Beta variant alongside a monovalent Delta variant spike proteins in a murine model. Notably, the second boost of homologous bivalent MAP-S1(WU+Beta) induced a 15.7-fold increase in IgG endpoint titer, while the third boost of heterologous MAP-S1RS09Delta yielded a more modest 1.6-fold increase. Importantly, this study demonstrated that the administration of four doses of the MAP vaccine induced robust and long-lasting immune responses, persisting for at least 80 weeks. These immune responses encompassed various IgG isotypes and remained statistically significant for one year. Furthermore, neutralizing antibodies against multiple SARS-CoV-2 variants were generated, with comparable responses observed against the Omicron variant. Overall, these findings emphasize the potential of MAP-based vaccines as a promising strategy to combat the evolving landscape of COVID-19 and to deliver a safe and effective booster vaccine worldwide.

immunology↗