Glymphatic inhibition exacerbates tau propagation in an Alzheimer's disease model.

BACKGROUND: The aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer's and Parkinson's disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. METHODS: In this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. RESULTS: Our findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the alterations were attenuated. CONCLUSIONS: These results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.

Fragrance Encapsulates: Effect of Polymeric Shell Purification Method on the Accuracy of Biodegradability Testing.

Fragrance encapsulates are widely used in consumer care applications such as fabric softeners or other liquid laundry products; they provide multiple benefits, from fragrance protection in the commercial product to a controlled release and improved sensorial experience for the consumers. Polymeric fragrance encapsulates are in the scope of the EU regulation restricting the use of intentionally added microplastic particles, and industry is actively working on innovation programs to find biodegradable alternatives. However, particular attention needs to be paid to claims that a fragrance encapsulation system is biodegradable, because biodegradation test results can vary considerably depending on how a test material is prepared, which can even lead to false-positive biodegradation test results, as shown in our study. We demonstrate the importance of the sample preparation phase of the process. We show how the biodegradation level can fluctuate from 0% to 91%, depending on how the test material is isolated from a given microcapsule slurry system, and we present a method that can be used to obtain trustworthy biodegradation results. Environ Toxicol Chem 2024;00:1-8. © 2024 Givaudan France SAS. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

High molecular weight hyaluronic acid vectorised with clay provides long-term hydration and reduces skin brightness.

BACKGROUND: Hyaluronic acid (HA) is a widely used active cosmetic ingredient. Its multiple skin care benefits are modulated by its molecular weight. Low molecular weight (LMW) HA can penetrate the skin, but high molecular weight (HMW) HA remains at the surface. Here, we assessed how vectorization of HMW HA with bentonite clay-achieved with an innovative technology-enhances its cosmetic and hydrating properties. MATERIALS AND METHODS: The two HA forms were applied to skin explants; their penetration and smoothing effects were monitored by Raman spectroscopy and scanning electron microscopy. The two forms were biochemically characterised by chromatography, enzyme sensitivity assays, and analysis of Zeta potential. Cosmetics benefits such as, the smoothing effect of vectorised-HA was assessed in ex vivo experiments on skin explants. A placebo-controlled clinical study was finally conducted applying treatments for 28 days to analyse the final benefits in crow's feet area. RESULTS: Raman spectroscopy analysis revealed native HMW HA to accumulate at the surface of skin explants, whereas vectorised HMW HA was detected in deeper skin layers. This innovative vectorisation process changed the zeta potential of vectorised HMW HA, being then more anionic and negative without impacting the biochemical structure of native HA. In terms of cosmetic benefits, following application of vectorised HMW HA ex vivo, the skin's surface was visibly smoother. This smoothing was clinically confirmed, with a significant reduction in fine lines. CONCLUSION: The development of innovative process vectorising HMW HA allowed HMW HA penetration in the skin. This enhanced penetration extends the clinical benefits of this iconic cosmetic ingredient.

Microcanonical treatment of HCl dissociative chemisorption on Au(111): Reactive dampening through inefficient translational energy coupling and an active surface.

Microcanonical unimolecular rate theory is applied to Shirhatti and Wodtke's recent supersonic molecular beam experiments examining the activated dissociative chemisorption of HCl on Au(111). A precursor mediated microcanonical trapping (PMMT) model (where the surface vibrates and HCl rotations, vibration, and translation directed along the surface normal are treated as active degrees of freedom) gave dissociative sticking coefficient predictions that are several orders of magnitude higher than experimental values but in good accord with prior quantum and molecular dynamics simulations. Density functional theory (DFT) electronic structure calculations using the Perdew-Burke-Ernzerhof (PBE) functional served to fix the vibrational frequencies of the reactive transition state and the threshold energy for dissociation, E0 = 72.9 kJ/mol. To explore the possibilities of varying threshold energy, coupling to phonons, and dynamics, a three-parameter [E0, s, ɛn] dynamically biased (d-) PMMT model was fit to the experiments. A dynamical bias was introduced using an efficiency, ɛn, of normal translational energy to contribute to the active exchangeable energy capable of promoting reactivity. To achieve the low sticking probabilities observed in experiment, severe normal translational energy dampening (ɛn → 0.26) was imposed, leading to a large vibrational efficacy of ηv = εv/εn = 3.85. The optimal threshold energy for dissociation was E0 = 30.88 kJ/mol, some 40 kJ/mol below the PBE-DFT prediction, and the optimal number of Au surface oscillators was s = 1. The d-PMMT modeling indicates that HCl/Au(111) reactivity can be consistent with electronically adiabatic passage across a relatively low and late transition state that dynamically disfavors normal translational energy.

The heterogeneity and complexity of skin surface lipids in human skin health and disease.

The outermost epidermal layer of the skin, the stratum corneum, is not simply a barrier that safeguards skin integrity from external insults and invaders, it is also a delicately integrated interface composed of firm, essentially dead corneocytes and a distinctive lipid matrix. Together, the stratum corneum lipid matrix and sebum lipids derived from sebaceous glands give rise to a remarkably complex but quite unique blend of skin surface lipids that demonstrates tremendous heterogeneity and provides the skin with its indispensable protective coating. The stratum corneum lipid matrix is composed primarily of three major lipid classes: ceramides, non-esterified fatty acids and cholesterol, whereas sebum is a waxy mixture predominantly composed of acylglycerols, wax esters, non-esterified fatty acids, squalene, cholesterol and cholesterol esters. The balance of these skin surface lipids in terms of their relative abundance, composition, molecular organisation and dynamics, and their intricate interactions play a crucial role in the maintenance of healthy skin. For that reason, even minuscule alterations in skin surface lipid properties or overall lipid profile have been implicated in the aetiology of many common skin diseases including atopic dermatitis, psoriasis, xerosis, ichthyosis and acne. Novel lipid-based interventions aimed at correcting the skin surface lipid abnormalities have the potential to repair skin barrier integrity and the symptoms associated with such skin diseases, even though the exact mechanisms of lipid restoration remain elusive.

Changes in cardiac-driven perivascular fluid movement around the MCA in a pharmacological model of acute hypertension detected with non-invasive MRI.

Perivascular spaces mediate a complex interaction between cerebrospinal fluid and brain tissue that may be an important pathway for solute waste clearance. Their structural or functional derangement may contribute to the development of age-related neurogenerative conditions. Here, we employed a non-invasive low b-value diffusion-weighted ECG-gated MRI method to capture perivascular fluid movement around the middle cerebral artery of the anaesthetised rat brain. Using this method, we show that such MRI estimates of perivascular fluid movement directionality are highly sensitive to the cardiac cycle. We then show that these measures of fluid movement directionality are decreased in the angiotensin-II pharmacological model of acute hypertension, with an associated dampening of vessel pulsatility. This translational MRI method may, therefore, be useful to monitor derangement of perivascular fluid movement associated with cardiovascular pathologies, such as hypertension, in order to further our understanding of perivascular function in neurology.

Representativeness of whole-genome sequencing approaches in England: the importance for understanding inequalities associated with SARS-CoV-2 infection.

Whole-genome sequencing (WGS) information has played a crucial role in the SARS-CoV-2 (COVID-19) pandemic by providing evidence about variants to inform public health policy. The purpose of this study was to assess the representativeness of sequenced cases compared with all COVID-19 cases in England, between March 2020 and August 2021, by demographic and socio-economic characteristics, to evaluate the representativeness and utility of these data in epidemiological analyses. To achieve this, polymerase chain reaction (PCR)-confirmed COVID-19 cases were extracted from the national laboratory system and linked with WGS data. During the study period, over 10% of COVID-19 cases in England had WGS data available for epidemiological analysis. With sequencing capacity increasing throughout the period, sequencing representativeness compared to all reported COVID-19 cases increased over time, allowing for valuable epidemiological analyses using demographic and socio-economic characteristics, particularly during periods with emerging novel SARS-CoV-2 variants. This study demonstrates the comprehensiveness of England's sequencing throughout the COVID-19 pandemic, rapidly detecting variants of concern, and enabling representative epidemiological analyses to inform policy.

Development of Novel High-Affinity Antagonists for the Relaxin Family Peptide Receptor 1.

H2 relaxin is a peptide hormone that exerts its biological actions through the G protein-coupled receptor, RXFP1. The numerous important biological functions of H2 relaxin, including potent renal, vasodilatory, cardioprotective, and anti-fibrotic actions, have resulted in considerable interest in its use as a therapeutic for various cardiovascular diseases and other fibrotic indications. Interestingly though, H2 relaxin and RXFP1 have been shown to be overexpressed in prostate cancer, allowing for the downregulation or blocking of relaxin/RXFP1 to decrease prostate tumor growth. These findings suggest the application of an RXFP1 antagonist for the treatment of prostate cancer. However, these therapeutically relevant actions are still poorly understood and have been hindered by the lack of a high-affinity antagonist. In this study, we chemically synthesized three novel H2 relaxin analogues that have complex insulin-like structures with two chains (A and B) and three disulfide bridges. We report here the structure-activity relationship studies on H2 relaxin that resulted in the development of a novel high-affinity RXFP1 antagonist, H2 B-R13HR (∼40 nM), that has only one extra methylene group in the side chain of arginine 13 in the B-chain (ArgB13) of H2 relaxin. Most notably, the synthetic peptide was shown to be active in a mouse model of prostate tumor growth in vivo where it inhibited relaxin-mediated tumor growth. Our compound H2 B-R13HR will be an important research tool to understand relaxin actions through RXFP1 and may be a potential lead compound for the treatment of prostate cancer.

Autophagy is the key to making chronic wounds acute in skin wound healing.

As a highly regulated and dynamically balanced intracellular degradation mechanism, macroautophagy/autophagy plays an essential housekeeping role in different successive stages of skin wound healing; from the homeostasis and inflammatory stages to the proliferative and remodeling stages. Under both progressive and defective skin wound healing conditions, autophagy operates at different levels with a precise extent of activity, at the interface of inflammation, stress signaling and cell metabolism through a complex spatiotemporal cascade of molecular and cellular events. Depending on the wound healing conditions autophagic activity is fine-tuned and differentially modulated at each stage of skin wound healing in order to cope with stage-specific requirements. Here, we postulate that under favorable conditions autophagy may act as the key modulator of skin wound healing by making chronic wounds acute. Enhancing autophagy through the topical application of pro-autophagy biologics in an appropriate hydrating vehicle/moisturizing base such as hydrogels, onto a chronic skin wound may provide moisture and immune modulation, thus contributing to rapid and efficient skin wound healing. A moist environment is more conducive to skin wound healing as it helps to not only accelerate cell proliferation and migration, and extracellular matrix reorganization, but also promotes autophagy and reduces the incidence of inflammation.Abbreviation: AKT: AKT serine/threonine protein kinase; ECM: extracellular matrix; FN1: fibronectin 1; LAM: laminin; MMPs: matrix metallopeptidases; MMP2: matrix metallopeptidase 2; MRSA: methicillin-resistant Staphylococcus aureus; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; TNF/TNF-α: tumor necrosis factor.

Emerging Trends in the Use of Topical Antifungal-Corticosteroid Combinations.

A broad range of topical antifungal formulations containing miconazole or terbinafine as actives are commonly used as efficacious choices for combating fungal skin infections. Their many benefits, owing to their specific mechanism of action, include their ability to target the site of infection, enhance treatment efficacy and reduce the risk of systemic side effects. Their proven efficacy, and positioning in the treatment of fungal skin infections, is enhanced by high patient compliance, especially when appropriate vehicles such as creams, ointments and gels are used. However, inflammation as a result of fungal infection can often impede treatment, especially when combined with pruritus (itch), an unpleasant sensation that elicits an urge to scratch. The scratching that occurs in response to pruritus frequently accelerates skin damage, ultimately aggravating and spreading the fungal infection. To help overcome this issue, a topical antifungal-corticosteroid combination consisting of miconazole or terbinafine and corticosteroids of varying potencies should be used. Due to their inherent benefits, these topical antifungal-corticosteroid combinations can concomitantly and competently attenuate inflammation, relieve pruritus and treat fungal infection.

Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system.

Many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system; however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined; however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.

Skin Cleansing without or with Compromise: Soaps and Syndets.

Products designed to cleanse the skin commonly do so through surfactant action, which leads to the lowering of the surface tension of the skin to facilitate the removal of dirt from its surface. Skin cleansers generally come in one of two types: soap-based and synthetic detergents, or syndets. While the latter can effectively maintain the native skin structure, function and integrity, the former tends to negatively affect the skin by causing barrier disruption, lipid dissolution and pH alteration. Despite this, soap is still often preferred, possibly due to the negative connotations around anything that is not perceived as 'natural'. It is, therefore, important that the science behind cleansers, especially those designed for the maintenance of healthy skin and the management of common skin conditions such as eczema, be understood by both formulators and end-users. Here, we carefully weigh the advantages and disadvantages of the different types of surfactant-the key ingredient(s) in skin cleansers-and provide insight into surfactants' physicochemical properties, biological activity and potential effects. Fine-tuning of the complex characteristics of surfactants can successfully lead to an 'optimal' skin cleanser that can simultaneously be milder in nature, highly effective and beneficial, and offer minimal skin interference and environmental impact.

Image-Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR-compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.

Vehicles for Drug Delivery and Cosmetic Moisturizers: Review and Comparison.

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined.

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Recruitment of adults with moderate eczema for a randomised trial: Comparison of traditional versus modern methods.

BACKGROUND: Clinical trial recruitment is challenging for investigators who often overestimate the pool of qualified, willing subjects. Moreover, there is a paucity of literature, particularly in dermatology, regarding recruitment and the comparative success of advertising strategies. METHODS: Both 'traditional' (physician referral, newspaper and radio advertisements, letterbox drops, posters/flyers, word-of-mouth) and 'modern' (patient recruitment services, social media, Google advertisements, websites, email) recruitment methods were used to enrol 100 patients (>18 years) diagnosed with moderate eczema for a randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of a topical eczema treatment over 4 weeks. The relationships between recruitment method and patient age, sex, race, study completion and costs were analysed. RESULTS: The majority of patients recruited were young, with millennials and Gen Z comprising 77% of the study population. Both traditional and modern recruitment methods were equally successful in recruiting younger patients, with older patients predominately recruited by traditional methods. Eighty per cent more men were recruited by traditional compared to modern methods, whilst 67% more women than men were recruited by modern methods. Recruitment method neither appeared to be influenced by race, nor did it effect whether patients completed the study. Costs per enrolment were similar for both methods. CONCLUSIONS: This study shows that despite the high proportion of young patients and the rising popularity of social media and increased internet use, a combination of both traditional and modern recruitment methods was required to successfully meet the trial enrolment target of 100 adult patients with moderate eczema.

Pharmacological MRI with Simultaneous Measurement of Cerebral Perfusion and Blood-Cerebrospinal Fluid Barrier Function using Interleaved Echo-Time Arterial Spin Labelling.

Pharmacological MRI (phMRI) studies seek to capture changes in brain haemodynamics in response to a drug. This provides a methodological platform for the evaluation of novel therapeutics, and when applied to disease states, may provide diagnostic or mechanistic information pertaining to common brain disorders such as dementia. Changes to brain perfusion and blood-cerebrospinal fluid barrier (BCSFB) function can be probed, non-invasively, by arterial spin labelling (ASL) and blood-cerebrospinal fluid barrier arterial spin labelling (BCSFB-ASL) MRI respectively. Here, we introduce a method for simultaneous recording of pharmacological perturbation of brain perfusion and BCSFB function using interleaved echo-time ASL, applied to the anesthetized mouse brain. Using this approach, we capture an exclusive decrease in BCSFB-mediated delivery of arterial blood water to ventricular CSF, following anti-diuretic hormone, vasopressin, administration. The commonly used vasodilatory agent, CO2, induced similar increases (~21%) in both cortical perfusion and the BCSFB-ASL signal. Furthermore, we present evidence that caffeine administration triggers a marked decrease in BCSFB-mediated labelled water delivery (41%), with no significant changes in cortical perfusion. Finally, we demonstrate a marked decrease in the functional response of the BCSFB to, vasopressin, in the aged vs adult brain. Together these data, the first of such kind, highlight the value of this translational approach to capture simultaneous and differential pharmacological modulation of vessel tone at the blood brain barrier and BCSFB and how this relationship may be modified in the ageing brain.

A daily regimen of a ceramide-dominant moisturizing cream and cleanser restores the skin permeability barrier in adults with moderate eczema: A randomized trial.

The dysfunctional skin barrier in eczema patients may be attributed to decreased levels of ceramides in the stratum corneum. The aim of this study was to determine whether a two-part system consisting of a ceramide-dominant physiological lipid-based moisturizing cream and cleanser could ameliorate the signs and symptoms of moderate eczema in adults over 28 days compared to placebo. Assessments were conducted at baseline and every 7 days thereafter. Eczema area severity index score decreased significantly across all time points in both groups compared to baseline (P < .0001), however, this decrease was not significant between groups at day 28 (P = .7804). In contrast, transepidermal water loss and skin hydration significantly improved over time in the active group, while it either stayed the same or worsened in the placebo group (P = .0342 and P < .0001, respectively). There was no difference in the use of mometasone furoate as rescue medication over time between groups (P = .1579). Dermatology life quality index scores improved significantly in both groups (P < .0001), with no difference between groups (P = .5256). However, patient satisfaction was greater in the active compared to the placebo group for several parameters including relief of itch, dry skin, skin softness and smoothness (all P < .05). No patients withdrew from the study due to adverse events (AEs) and there were no serious AEs. The ceramide-dominant moisturizing cream and cleanser safely restores skin permeability and improves the signs and symptoms of eczema in adults.