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Ticked Off: Allergic Effector Cells in the Pathogenesis of Alpha-gal Syndrome
Get PDFPurpose of Review Alpha-gal syndrome (AGS) is a novel allergic disease characterized by hypersensitivity responses following exposure to the glycan galactose-alpha-1,3-galactose (alpha-gal or α-Gal) attached to mammalian proteins and fats in food, supplements, and medications. Bites from hard-bodied ticks, including Amblyomma americanum (Aa or lone star tick) in the United States, have been identified as drivers of allergic sensitization to alpha-gal. Here, we review clinical presentation, epidemiology, diagnosis, and current understanding of the mechanistic drivers of AGS, with particular focus on the roles of allergic effector cells – mast cells (MCs) and basophils. We explore unique clinical characteristics of AGS through the lens of alpha-gal-specific IgE and MC activation in AGS. We propose potential explanations for delayed symptom onset, inconsistent symptom development, and persistence of allergic symptoms in some AGS patients despite removing all mammal products from the diet. Recent Findings Current evidence implicate bites from hard-bodied ticks as the primary sensitizing agent in AGS. However, there is emerging evidence that other ecto- and endoparasites may also induce alpha-gal-specific IgE. Multiparameter flow and mass cytometry and RNA sequencing have demonstrated an enrichment of unique populations of T, B, invariant natural killer T (iNKT), natural killer B (NKB) and MC progenitor cells in human volunteers with AGS. Recently developed mouse models of AGS will support future studies to identify which cells are critical for the development of AGS. In vitro models of the allergic effector phase of AGS using human sera and novel human alpha-gal-specific IgE monoclonal antibodies in humanized rat allergic effector cell lines, human basophils, human MC lines, and primary human MC cultures, confirm alpha-gal-induced allergic effector cell activation. They also provide a system to study potential alpha-gal-antigen-independent drivers of MC activation in AGS. Summary Efforts are ongoing to understand the epidemiology and immune mechanisms of AGS. Novel reagents (e.g. alpha-gal-specific monoclonal antibodies) and murine AGS models will facilitate deeper investigation of tick-driven, alpha-gal-specific IgE and allergic effector cell-induced pathology in AGS
Somatosensory restoration and neural control strategies in lower-limb prostheses
Get PDFPeople with lower-limb amputation cannot directly control or receive feedback from existing prostheses, but emerging technologies aim to address this gap. Some approaches focus on restoring somatosensation in the missing limb, while others record signals from residual muscles for prosthetic control. This review provides an overview of the current state of neuroprosthetics for somatosensory restoration and prosthetic control in lower-limb amputation, offering perspectives on integrating these technologies for bidirectional neuroprostheses
Cross-sectional associations of radiographic multiple joint osteoarthritis and symptoms, laboratory values and the gut microbiota: a multimodal study in humans and pet dogs
Get PDFObjective To describe the frequency of multiple joint osteoarthritis (MJOA) and symptoms, and associations with fecal microbial diversity and composition, in cohorts of humans and dogs. Design Human participants enrolled in the community-based Johnston County Health Study (JoCoHS), and an independent cohort of pet dogs, were included. Questionnaires, functional assessments, standardized multiple joint radiographs, and pain assessments, blood and fecal samples were obtained. Microbiome analysis was done by 16S rRNA amplicon sequencing. MJOA was defined as ≥3 unique joint sites involved; symptom burden was based on self-reported/proxy measures of pain. Descriptive statistics and Spearman correlations with Benjamini-Hochberg correction were used to determine relationships among lab tests, pain, and microbiome diversity measures. Results Human participants (n=100, 63% women, mean age 56 years, mean body mass index 34 kg/m2) and 115 pet dogs (40% spayed females, 57% neutered males, mean age 8 years, mean weight 27 kg) were included; 20% had radiographic MJOA (rMJOA). Microbial α-diversity did not differ between participants with or without rMJOA. However, lower levels of the Christensenellaceae R-7 group and Lachnoclostridium in humans, and the butyrate-producing bacterium, Faecalibacterium in dogs, were moderately correlated with greater pain severity, as were higher levels of Escherichia-Shigella in dogs. Faecalibacterium was more abundant in humans without rMJOA. Conclusions These two cohorts demonstrated remarkably similar frequencies of rMJOA (∼20%), supporting the use of dogs to model naturally occurring MJOA. Taxa potentially related to rMJOA and pain were identified in this preliminary analysis, providing new insights into links between dysbiosis and MJOA
Optimization, comparison and mechanism of ultrasound-assisted cellulase hydrolysis and ethanol extraction of quercetin, luteolin and apigenin from male inflorescences of Populus alba × berolinensis
Get PDFIn this study, we aimed to determine the optimal process parameters for extracting quercetin, luteolin and apigenin from the male inflorescences of Populus alba × berolinensis via the ultrasound-assisted cellulase hydrolysis and ethanol extraction (UACHEE) method and investigated the mechanism of cellulase action during the extraction process. The Box–Behnken design (BBD) was subsequently used to optimize the operating parameters. The optimal extraction parameters of ultrasound-assisted cellulase hydrolysis were as follows: ethanol volume fraction of 70 %, 40 mg/g of dose of cellulase, 50 °C of incubation temperature, 148 min of incubation time, pH of 5, mL/g of liquid‒solid ratio, duty cycle of 16.67 %, 200 W of ultrasound irradiation power in the incubation process, 200 W of ultrasound irradiation power in the extraction process, and 15 min of ultrasound irradiation time in the extraction process. Compared with other extraction methods, UACHEE presented an advantage in maintaining higher yields of quercetin, luteolin and apigenin (428.68, 549.65, 1136.20 μg/g). In addition, we used different characterization methods to clarify the extraction mechanism of this method to better improve the extraction yield and efficiency of the target components. This study will lay a theoretical foundation for the potential practical application of the male inflorescences of P. alba × berolinensis extracts in fields such as medicine, functional foods, cosmetics, environment and agriculture
A Descriptive Study of Hallucinogen and Inhalant Detoxification Admissions From 2006 to 2022
Get PDFBackground: Detoxification is often identified as treating drug withdrawal. All drug classes except hallucinogens and inhalants include withdrawal as diagnostic criteria for a substance use disorder diagnosis. This descriptive study provides an analysis of detoxification admissions for individuals with hallucinogens or inhalants as their primary substance. Objectives: This research aimed to explore the characteristics of these detoxification admissions, focusing on demographics, substance use patterns, and treatment characteristics.Design:This retrospective study used annual cross-sectional data. Methods: Using the Treatment Episode Dataset Admissions 2006 to 2022 file, data from 8919 detoxification admissions over a 17-year period from publicly funded treatment facilities in the United States were examined. Results: During the 17-year period, n = 6761 and n = 2158 detoxification treatment episode admissions had the primary substance hallucinogens and inhalants, respectively. Polysubstance use was prevalent among both samples, with 66% among the hallucinogen sample and 48% among the inhalant sample, with alcohol, cannabis, and cocaine/crack being the most commonly co-used substances. A total of 2872 cases were identified as only having hallucinogens and/or inhalants without other drug classes as reported substances during admission. Conclusion: These preliminary findings highlight detoxification admissions among individuals with primary substances that do not meet diagnostic criteria for withdrawal. More research is needed to better understand the context of detoxification among individuals with hallucinogens or inhalants as their primary substance
Outdoor ground surface influences spatiotemporal parameters of walking for individuals undergoing rehabilitation: An observational study
Get PDFClinical measures of walking capacity may differ from walking performed in outdoor environmental settings. This study assessed spatiotemporal aspects of gait in individuals undergoing rehabilitation when walking over various outdoor surfaces and compared them to a standard clinical gait measure. We sought to identify how spatiotemporal aspects of gait change across terrains commonly encountered in the community in individuals undergoing rehabilitation. Forty-six individuals with mobility deficits undergoing outpatient physical therapy completed the 10-meter walk test in clinic and walked over six standardized terrains (e.g., pavers, gravel, sand). We calculated gait speed, cadence, average step length, and walk ratio (calculated as cm/steps/min) from video recordings for all conditions and used repeated measures ANOVAs to assess differences between terrains compared to the 10-meter walk test. We then used multiple linear regressions to examine spatiotemporal mechanisms underlying gait speed changes across terrains. Gait speed and cadence were reduced when participants walked over sand, mulch, up sloping gravel, and down sloping gravel compared to the 10-meter walk test. Step length decreased in the sand, gravel upslope, and gravel downslope conditions compared to the 10-meter walk test. Walk ratio was decreased in the sloped gravel conditions. Cadence and step length changes explained 95-99% of the variance in gait speed changes across conditions with step length being more heavily weighted across conditions. Individuals undergoing physical therapy for mobility deficits walked slower, with smaller step lengths and cadence when faced with uneven outdoor terrain compared to an indoor 10-meter walk test while walk ratio remained consistent across level surfaces. Speed reductions were related to both step length and cadence. Walk ratio remained consistent across level terrains, indicating a consistent central control strategy, despite terrain changes. Although standardized measures like the 10-meter walk test provide critical information about gait capacity, they may not fully reflect performance in all real-world environments
The Erosion of Intelligibility: A Multi-Disciplinary Analysis of Linguistic Complexity and the Dilution of Meaning
Get PDFThis report investigates the pervasive linguistic paradox wherein increasing complexity in professional and academic discourse, often intended to signal intellectual rigor, systematically dilutes meaning and degrades communication efficacy. Drawing on a synthesis of research across cognitive psychology, psycholinguistics, organizational behavior, and signaling theory, the analysis demonstrates that the reliance on specialized jargon and convoluted syntax—the "complexity heuristic" is fundamentally counterproductive. We explore the cognitive mechanisms behind this failure, including the imposition of extraneous cognitive load on working memory (Cognitive Load Theory) and the negative impact of disfluency on reader trust and perception of competence (the "Oppenheimer Effect"). Furthermore, the report quantifies the economic and epistemic costs of obfuscation across key sectors, detailing how verbose communication leads to millions in lost productivity (business), non-adherence and errors (medicine), and barriers to justice (law). Finally, we argue that genuine epistemic authority is increasingly marked by the ability to distill complexity into clarity a form of "countersignaling" that differentiates mastery from mere linguistic posturing, particularly in an information environment saturated by algorithmically-generated, verbose text. The evidence overwhelmingly supports the conclusion that simplicity is the most valuable and functional currency of modern professional communication
Differential Expression of One‐Carbon Pathway Enzyme ALDH1L1 Is Linked to Tumorigenicity of Low‐Grade Bladder Cancer Cells Through Metabolic Reprogramming
Get PDFRT4 bladder cancer cell line, derived from a nonmuscle‐invasive low‐grade subtype, is one of the few neoplastic cell lineages that maintain high expression of the candidate tumor suppressor ALDH1L1. Here, we investigated how differential ALDH1L1 expression affects cellular characteristics and tumorigenicity of RT4 cells as well as tumor metabotypes. We characterized RT4 cells and two shRNA clones (sh506/low ALDH1L1 expression; sh572/ALDH1L1 is lost) for proliferation, migration, clonogenic capacity, and mitochondrial respiration. We have further evaluated the tumorigenic potential of RT4 cells and the two clones in nude mice and compared metabotypes of derived tumors using untargeted metabolomics. Both clones with diminished ALDH1L1 expression exhibited increased proliferation rates with doubling times of 19.4 h (sh506) and 23.2 h (sh572) versus 36.3 h for RT4 cells. Downregulation of ALDH1L1 expression also enhanced motility and clonogenic capacity. Proliferation and clonogenic capacity were highest for the sh506 clone (low ALDH1L1 expression), while motility was strongest for the sh572 clone (complete ALDH1L1 loss). Both clones showed altered energy metabolism, as indicated by a reduced basal oxygen consumption rate and enhanced maximal respiration rate following oligomycin treatment. Mouse xenograft tumors derived from ALDH1L1‐deficient RT4 clones were significantly larger than RT4 cell‐derived tumors. Of note, complete ALDH1L1 loss (sh572 clone) was less advantageous for tumor growth than the partial loss of the protein (sh506 clone). Untargeted metabolomics has shown that tumors with downregulated ALDH1L1 have altered the metabolism of fatty acids, amino acids, CoA, and acylcarnitines. Alterations in several key pathways, including glutathione metabolism (sh506), and TCA cycle (sh572), depend on the extent of ALDH1L1 downregulation. Our study underscores ALDH1L1 as a key metabolic regulator of proliferation, migration, and tumorigenicity in RT4 bladder cancer cells, suggesting that retaining low ALDH1L1 expression can provide a metabolic advantage for growth of aggressive tumors
Preserved Cognitive Function After Statin Administration During Cancer Treatment With Doxorubicin
Get PDFImportance: Receipt of anthracycline-based chemotherapy and statin therapy have been found to be associated with deterioration of cognitive function in patients with cancer. Objective: To assess the association of statins with attention, verbal fluency, and executive function in patients receiving doxorubicin treatment for cancer. Design, Setting, and Participants: This secondary analysis of the Preventing Anthracycline Cardiovascular Toxicity With Statins randomized clinical trial, conducted across 31 US community and academic sites from February 5, 2014, through September 24, 2020, involved participants with stage I to IV lymphoma or stage I to III breast cancer undergoing doxorubicin treatment. The data analysis was conducted between August 1, 2024, and April 4, 2025. Interventions: Participants were randomized (1:1) to receive a daily 40-mg dose of atorvastatin or placebo before initiating doxorubicin treatment and then continued for 24 months. Main Outcomes and Measures: Attention, executive function, and verbal fluency were assessed using the Trail Making Test part A (TMT-A) and part B (TMT-B) and the Controlled Oral Word Association test, respectively. Time to complete the assessments were modeled using a linear mixed model, while errors (counts) were modeled using a generalized linear mixed model assuming a Poisson distribution. Results: A total of 238 participants (mean [SD] age, 49 [12] years; 217 female [91.2%]) were randomized to the statin (n = 118) or placebo (n = 120) groups. Values for TMT-A at 6 and 24 months were similar between the statin group (mean, 32.5 seconds [95% CI, 29.4-35.7 seconds] and 29.8 seconds [95% CI, 26.4-33.2 seconds], respectively) and the placebo group (mean, 28.4 seconds [95% CI, 25.2-31.5 seconds] and 27.8 seconds [95% CI, 24.5-31.0 seconds], respectively). From before treatment to 24 months after treatment, statin recipients had a significant mean improvement of 10.2 seconds for TMT-B (95% CI, 1.9-18.5 seconds), whereas placebo recipients had a nonsignificant improvement of only 0.2 seconds for TMT-B (95% CI, -8.5 to 8.1 seconds). Analysis of the time-by-treatment interaction showed no significant difference between groups. For Controlled Oral Word Association scores in the same period, both the placebo and statin groups showed a mean improvement of 3.62 points (95% CI, 1.71-5.54 points) and 4.74 points (95% CI, 2.69-6.79 points), respectively, with no difference between groups. Conclusions and Relevance: This secondary analysis of a randomized clinical trial suggests that the receipt of statins during doxorubicin therapy for lymphoma or breast cancer was not associated with worsening cognitive functions over 24 months. Within-group analyses suggested that statins may have contributed to better executive function on the TMT-B. Trial Registration: ClinicalTrials.gov Identifier: NCT01988571
A General Approach to the Estimation of Variance Components
Get PDFA general method of estimation of variance components in random-effects models of the nested and/or classification type is considered. If a given parameter is estimable with respect to some particular experimental design (i. e., an unbiased estimate of the parameter may be obtained from the experiment), then the suggested estimator may be readily computed with only the aid of a desk calculator. The estimates are always unbiased and consistent (with respect to the structure of the experimental design); in the case of balanced experiments, they coincide with those obtained from the analysis of variance. Secondly, the problem of designing experiments to estimate variance components is briefly discussed from the point-of-view of the suggested estimation procedure. As a result, certain non-balanced designs are seen to yield more efficient estimators of particular parameters in specified situations than the corresponding balanced design using the same number of observations. Finally, the method of estimation is shown to be applicable to models more general than the variance component one. Again it is readily computed and is unbiased and consistent