Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Real-time label-free detection of dynamic aptamer-small molecule interactions using a nanopore nucleic acid conformational sensor.

Nucleic acids can undergo conformational changes upon binding small molecules. These conformational changes can be exploited to develop new therapeutic strategies through control of gene expression or triggering of cellular responses and can also be used to develop sensors for small molecules such as neurotransmitters. Many analytical approaches can detect dynamic conformational change of nucleic acids, but they need labeling, are expensive, and have limited time resolution. The nanopore approach can provide a conformational snapshot for each nucleic acid molecule detected, but has not been reported to detect dynamic nucleic acid conformational change in response to small -molecule binding. Here we demonstrate a modular, label-free, nucleic acid-docked nanopore capable of revealing time-resolved, small molecule-induced, single nucleic acid molecule conformational transitions with millisecond resolution. By using the dopamine-, serotonin-, and theophylline-binding aptamers as testbeds, we found that these nucleic acids scaffolds can be noncovalently docked inside the MspA protein pore by a cluster of site-specific charged residues. This docking mechanism enables the ion current through the pore to characteristically vary as the aptamer undergoes conformational changes, resulting in a sequence of current fluctuations that report binding and release of single ligand molecules from the aptamer. This nanopore tool can quantify specific ligands such as neurotransmitters, elucidate nucleic acid-ligand interactions, and pinpoint the nucleic acid motifs for ligand binding, showing the potential for small molecule biosensing, drug discovery assayed via RNA and DNA conformational changes, and the design of artificial riboswitch effectors in synthetic biology.

Characterizing Interest in and Uptake of Preexposure Prophylaxis for HIV Prevention Among Men in a US State Correctional System.

BACKGROUND: People experiencing incarceration are disproportionately impacted by HIV and are potential candidates for HIV preexposure prophylaxis (PrEP). We explored factors associated with PrEP interest and PrEP uptake and described barriers to PrEP uptake among incarcerated men in a state correctional system. METHODS: From September 2019 to July 2022, incarcerated men at the Rhode Island Department of Corrections were screened for PrEP eligibility and referred to a PrEP initiation study. We used bivariate analyses and multivariable logistic regression models to explore factors associated with PrEP interest and uptake in the screening sample. RESULTS: Of the men screened and determined to be eligible for PrEP, approximately half (50%) were interested in taking PrEP. Individuals identifying as men who have sex with men (adjusted odds ratio, 4.46; 95% confidence interval, 1.86-11.4) and having multiple female sex partners (adjusted odds ratio, 2.98; 95% confidence interval, 1.47-6.27) were more likely to express interest in PrEP (interested/not interested) than those not reporting these behavioral factors. Preexposure prophylaxis uptake (yes/no) was 38%. Lack of PrEP interest, low self-perceived risk of HIV acquisition, and unpredictable lengths of incarceration were the most frequently encountered barriers to PrEP uptake. CONCLUSIONS: Men reporting sexual transmission behaviors were more interested in PrEP and had higher uptake than other men. Preexposure prophylaxis interest and HIV risk factors were both moderately high, which suggests that men experiencing incarceration should be screened for and offered PrEP as part of standard clinical care. Study findings have important implications for research and practice to adapt PrEP care to correctional systems.

Prurigo nodularis: new insights into pathogenesis and novel therapeutics.

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. Patients with PN suffer from an intractable itch-scratch cycle leading to impaired sleep, psychosocial distress and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines [such as interleukin (IL)-4, -13, -17, -22 and -31] and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to T-helper (Th)17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibres that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of patients with PN and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centred around degrees of type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences, with African Americans having densely fibrotic skin lesions. Dupilumab became the first US Food and Drug Administration-approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31 receptor A inhibitor nemolizumab is in late-stage development with positive phase III data reported. In addition, the oral Janus kinase (JAK) 1 inhibitors, abrocitinib and povorcitinib, are in phase II trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase III studies.

Prurigo nodularis (PN) is a chronic skin condition featuring extremely itchy nodules on the skin of the legs, arms and trunk of the body. PN affects approximately 72 per 100 000 people and the severe itch associated with the condition can negatively impact a person's sleep, work and social life. However, the cause of PN remains unclear. Current understanding of PN is based on imbalances in the immune system leading to widespread inflammation as well as dysregulation of the nerves in the skin. Immune molecules released from T cells [such as interleukin (IL)-4, -13, -31, -17, -22 and -31] increase systemic inflammation and are elevated in people with PN. Activated inflammatory cells (such as mast cells or eosinophils) may also release factors that promote inflammation, itch and neural changes within the skin. Neural dysregulation in PN features a lower density of itch-sensing nerve fibres in the epidermis (upper layer of the skin) and a higher density of itch-sensing nerve fibres in the dermis (lower layer of the skin). Because the pathogenesis of PN is not fully understood, the therapies available for PN have had limited success in reducing itch and nodules. The only drug currently approved for PN in the USA and Europe is dupilumab, an IL-4Rα inhibitor that blocks signalling through IL-4 and IL-13, which is undergoing post-marketing surveillance. Other new drugs are being assessed in various phases of clinical trials, including nemolizumab, vixarelimab, barzolvolimab, ruxolitinib, abrocitinib, povorcitinib and nalbuphine.

Atopic dermatitis, cognitive function and psychiatric comorbidities across early childhood and adolescence in a population-based UK birth cohort.

BACKGROUND: Atopic dermatitis (AD) may affect cognitive function, but studies are limited and inconsistent. The effect of AD severity on cognition remains underexplored and few previous studies have examined clinically validated or repeated measures of cognition throughout childhood. OBJECTIVES: To evaluate the relationship of AD activity and severity with validated measures of general cognition in a longitudinal birth cohort. METHODS: We conducted cross-sectional analyses using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK cohort of 14 975 individuals followed prospectively since their birth in 1991-92. AD was assessed 11 times between the age of 6 and 166 months. Mothers were asked if their child had an 'itchy, dry skin rash in the joints and creases', and AD status was time-updated accordingly as 'never', 'maybe', 'inactive', 'active/mild' or 'active/moderate-severe'. General cognition [i.e. intelligence quotient (IQ)] was measured at 18, 49, 103 and 186 months of age using the Griffiths Mental Development Scales (GMDS), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC) and Wechsler Abbreviated Scale of Intelligence (WASI), respectively. Multivariable linear regression was used to compare IQ with respect to nearest time-updated AD status. Secondary analyses were stratified by the presence or absence of psychiatric or learning disorders. An exploratory longitudinal analysis of IQ across all four outcome assessments was conducted using generalized estimating equations. RESULTS: No significant associations between AD status and full-scale IQ scores on the GMDS, WPPSI, WISC and WASI were observed after adjustment for sociodemographic factors, atopic comorbidities and sleep characteristics. However, at 8 years of age, WISC Performance IQ was slightly, although statistically significantly, lower among children with active/moderate-severe AD [ß coefficient -2.16, 95% confidence interval (CI) -4.12 to -0.19] and Verbal IQ was slightly, but statistically significantly, higher among those with inactive AD (ß coefficient 1.31, 95% CI 0.28-2.34) compared with those without AD. Analyses stratified by psychiatric or learning disorders, and exploratory longitudinal analyses of cognition revealed similar findings. CONCLUSIONS: We did not find any clinically meaningful associations between AD activity and severity and general cognitive function during early childhood and adolescence. Future studies should incorporate objective measures of AD severity and investigate outcomes beyond IQ.

Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype.

Sulforaphane (SFN) is a promising cancer prevention and treatment agent that strongly suppresses the cutaneous squamous cell carcinoma (CSCC) cell cancer phenotype. We previously showed that yes-associated protein 1 (YAP1)/TEAD signaling is a key procancer stimulator of the aggressive CSCC cell cancer phenotype. However, SFN-responsive upstream regulators of YAP1/TEAD signaling are not well characterized and so there is a pressing need to identify these factors. We show that CD44v6 knockdown reduces YAP1/TEAD-dependent transcription and target gene expression, and that this is associated with reduced spheroid formation, invasion and migration. CD44v6 knockout cell lines also display reduced YAP1/TEAD activity and target gene expression and attenuated spheroid formation, invasion, migration and tumor formation. An important finding is that SFN treatment suppresses CD44v6 level leading to a reduction in YAP1/TEAD signaling and marker gene expression. Sox2 level and epithelial-mesenchymal transition (EMT) are also reduced. Forced expression of constitutive active YAP1 in CD44v6 knockdown cells partially restores the aggressive cancer phenotype. These important findings suggest that CD44v6 drives YAP1/TEAD signaling to enhance the CSCC cell cancer phenotype and that SFN treatment reduces CD44v6 level/function which, in turn, reduces YAP1/TEAD signaling leading to reduced stemness, EMT and tumor growth.

The transglutaminase 2 cancer cell survival factor maintains mTOR activity to drive an aggressive cancer phenotype.

Transglutaminase 2 (TG2) is an important cancer stem-like cell survival protein that is highly expressed in epidermal squamous cell carcinoma and drives an aggressive cancer phenotype. In the present study, we show that TG2 knockdown or inactivation results in a reduction in mammalian target of rapamycin (mTOR) level and activity in epidermal cancer stem-like cells which are associated with reduced spheroid formation, invasion, and migration, and reduced cancer stem cell and epithelial-mesenchymal transition (EMT) marker expression. Similar changes were observed in both cultured cells and tumors. mTOR knockdown or treatment with rapamycin phenocopies the reduction in spheroid formation, invasion, and migration, and cancer stem cell and EMT marker expression. Moreover, mTOR appears to be a necessary mediator of TG2 action, as a forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and cancer stem cell and EMT marker expression. Tumor studies show that rapamycin reduces tumor growth and cancer stem cell marker expression and EMT. These studies suggest that TG2 stimulates mTOR activity to stimulate cancer cell stemness and EMT and drive aggressive tumor growth.

Quantification of Stern Layer Water Molecules, Total Potentials, and Energy Densities at Fused Silica:Water Interfaces for Adsorbed Alkali Chlorides, CTAB, PFOA, and PFAS.

We have employed amplitude- and phase-resolved second-harmonic generation spectroscopy to investigate ion-specific effects of monovalent cations at the fused silica:water interface maintained under acidic, neutral, and alkaline conditions. We find a negligible dependence of the total potential (as negative as -400 mV at pH 14), the second-order nonlinear susceptibility (as large as 1.5 × 10-21 m2 V-1 at pH 14), the number of Stern layer water molecules (1 × 1015 cm-2 at pH 5.8), and the energy associated with water alignment upon going from neutral to high pH (ca. -24 kJ mol-1 to -48 kJ mol-1 at pH 13 and 14, close to the cohesive energy of liquid water but smaller than that of ice) on chlorides of the alkali series (M+ = Li+, Na+, K+, Rb+, and Cs+). Attempts are presented to provide estimates for the molecular hyperpolarizability of the cations and anions in the Stern layer at high pH, which arrive at ca. 20-fold larger values for αtotal ions(2) = αM+(2) + αOH-(2) + αCl-(2) when compared to water's molecular hyperpolarizability estimate from theory and point to a sizable contribution of deprotonated silanol groups at high pH. In contrast to the alkali series, a pronounced dependence of the total potential and the second-order nonlinear susceptibility on monovalent cationic (cetrimonium bromide, CTAB) and anionic (perfluorooctanoic and perfluorooctanesulfonic acid, PFOA and PFOS) surfactants was quantifiable. Our findings are consistent with a low surface coverage of the alkali cations and a high surface coverage of the surfactants. Moreover, they underscore the important contribution of Stern layer water molecules to the total potential and second-order nonlinear susceptibility. Finally, they demonstrate the applicability of heterodyne-detected second-harmonic generation spectroscopy for identifying perfluorinated acids at mineral:water interfaces.

Water Structure in the Electrical Double Layer and the Contributions to the Total Interfacial Potential at Different Surface Charge Densities.

The electric double layer governs the processes of all charged surfaces in aqueous solutions; however, elucidating the structure of the water molecules is challenging for even the most advanced spectroscopic techniques. Here, we present the individual Stern layer and diffuse layer OH stretching spectra at the silica/water interface in the presence of NaCl over a wide pH range using a combination of vibrational sum frequency generation spectroscopy, heterodyned second harmonic generation, and streaming potential measurements. We find that the Stern layer water molecules and diffuse layer water molecules respond differently to pH changes: unlike the diffuse layer, whose water molecules remain net-oriented in one direction, water molecules in the Stern layer flip their net orientation as the solution pH is reduced from basic to acidic. We obtain an experimental estimate of the non-Gouy-Chapman (Stern) potential contribution to the total potential drop across the insulator/electrolyte interface and discuss it in the context of dipolar, quadrupolar, and higher order potential contributions that vary with the observed changes in the net orientation of water in the Stern layer. Our findings show that a purely Gouy-Chapman (Stern) view is insufficient to accurately describe the electrical double layer of aqueous interfaces.

Divalent Ion Specific Outcomes on Stern Layer Structure and Total Surface Potential at the Silica:Water Interface.

The second-order nonlinear susceptibility, χ(2), in the Stern layer and the total interfacial potential drop, Φ(0)tot, across the oxide:water interface are estimated from SHG amplitude and phase measurements for divalent cations (Mg2+, Ca2+, Sr2+, and Ba2+) at the silica:water interface at pH 5.8 and various ionic strengths. We find that interfacial structure and total potential depend strongly on ion valency. We observe statistically significant differences between the experimentally determined χ(2) value for NaCl and that of the alkali earth series but smaller differences between ions of the same valency in that series. These differences are particularly pronounced at intermediate salt concentrations, which we attribute to the influence of hydration structure in the Stern layer. Furthermore, we corroborate the differences by examining the effects of anion substitution (SO42- for Cl-). Finally, we identify that hysteresis in measuring the reversibility of ion adsorption and desorption at fused silica in forward and reverse titrations manifests itself both in Stern layer structure and in total interfacial potential for some of the salts, most notably for CaCl2 and MgSO4 but less so for BaCl2 and NaCl.

COVID-19 impacts, coping strategies, and management reflection: A lodging industry case.

The COVID-19 pandemic has hit the global tourism and hospitality industry with drastic results. Hotels have been experiencing unprecedented challenges, leaving many to temporarily or permanently closed. Employing a case study approach supported by both quantitative and qualitative analysis, this study examined how two hotels in Oklahoma City had coped with challenges presented by the COVID-19 pandemic, from day to day operations, health and safety measures to marketing, human resources and cost-saving strategies. The study contributes to the tourism crisis and disaster literature by providing micro-level coping strategies, a literature gap that needs to be addressed, particularly under the current pandemic.

Hotel employees' fun climate at work: Effects on work-family conflict and employee deep acting through a collectivistic perspective.

Although the importance of workplace fun in hospitality organizations has been emphasized by scholars, discussion of the mechanism of a workplace fun climate in collectivistic cultural contexts is still rare in current literature. Therefore, based on a collectivistic perspective, this study aims to examine the effects of a three-component fun climate at work (socializing with coworkers, celebrating at work, and global fun at work) on employee deep acting and work-family conflict. A total of 389 usable survey responses were collected from full-time hotel employees in China. The results of this study reveal that socializing with coworkers and celebrating at work enhance global fun at work. Moreover, global fun at work significantly reduces employees' work-family conflict and strengthens their deep acting at work. Findings of this study not only contribute to knowledge of understanding workplace fun climate in hospitality literature but also offer valuable practical implications to the hospitality industry.

A multiplexed analysis approach identifies new association of inflammatory proteins in patients with overactive bladder.

Overactive bladder (OAB) is a common debilitating bladder condition with unknown etiology and limited diagnostic modalities. Here, we explored a novel high-throughput and unbiased multiplex approach with cellular and molecular components in a well-characterized patient cohort to identify biomarkers that could be reliably used to distinguish OAB from controls or provide insights into underlying etiology. As a secondary analysis, we determined whether this method could discriminate between OAB and other chronic bladder conditions. We analyzed plasma samples from healthy volunteers (n = 19) and patients diagnosed with OAB, interstitial cystitis/bladder pain syndrome (IC/BPS), or urinary tract infections (UTI; n = 51) for proinflammatory, chemokine, cytokine, angiogenesis, and vascular injury factors using Meso Scale Discovery (MSD) analysis and urinary cytological analysis. Wilcoxon rank-sum tests were used to perform univariate and multivariate comparisons between patient groups (controls, OAB, IC/BPS, and UTI). Multivariate logistic regression models were fit for each MSD analyte on 1) OAB patients and controls, 2) OAB and IC/BPS patients, and 3) OAB and UTI patients. Age, race, and sex were included as independent variables in all multivariate analysis. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic potential of a given analyte. Our findings demonstrate that five analytes, i.e., interleukin 4, TNF-α, macrophage inflammatory protein-1ß, serum amyloid A, and Tie2 can reliably differentiate OAB relative to controls and can be used to distinguish OAB from the other conditions. Together, our pilot study suggests a molecular imbalance in inflammatory proteins may contribute to OAB pathogenesis.

Malignant melanoma arising in a burn scar.

Secondary malignancies are rare but devastating complications of longstanding burn scars. Squamous cell carcinoma is the most common, followed by basal cell carcinoma and melanomas. There are fewer than 50 total reported cases of malignant melanomas arising in burn scars. We report a case of malignant melanoma arising within a longstanding burn scar confirmed by histology, FISH, and PRAME staining to further characterize melanomas arising in burn scars and to illustrate the diagnostic challenges they present.

Progressive Skull Osteolysis in the Setting of Endotine Implantation: A Case Report.

OBJECTIVES: To report a case of a 71-year-old woman who presented 8 years following 2 endoscopic brow lift procedures for evaluation of bony irregularities of her frontoparietal skull. To highlight a novel complication of Endotine fixation following an endoscopic brow lift procedure. METHODS: A chart review, bicoronal cranioplasty and a review of literature. RESULTS: The patient was satisfied with her post-surgical outcome and no complications were observed at the 1-month follow-up visit. A review of the literature revealed no previous reports of focal skull osteolysis relating to Endotine implants. CONCLUSION: We believe that our patient's focal calvarial osteolysis is a direct complication of Endotine fixation. Future research into the long-term effects of endoscopic brow lift procedures using Endotine implants is necessary to help ensure patient safety and guide future practices.