Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPß, Aß40, Aß42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPß levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aß40, and Aß42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

Thallus hydrophobicity: A low-cost method for understanding lichen ecophysiological responses to environmental changes.

Premise: Methods to evaluate lichen thalli hydrophobicity have previously been described, but only recently has hydrophobicity been shown to be an important functional trait related to water regulation dynamics that could be used to predict future climate change effects. We describe a novel protocol to measure lichen thallus hydrophobicity that aims to be an easier and more affordable approach. Methods and Results: Our protocol requires only a micropipette, distilled water, a tripod, and a smartphone or camera. Hydrophobicity is inferred from multiple metrics associated with the absorption times of standardized droplets (initial and total absorption time). We used a data set of 93 lichen taxa with different growth forms and from different biomes and demonstrated that this method is well suited for capturing different levels of hydrophobicity, including very hydrophilic species. Conclusions: Our results show that this new protocol to measure lichen hydrophobicity is a rapid and low-cost method to assess an ecophysiologically based functional trait that can be used with almost no limitations, including in different climates, lichen species, and growth forms.

Premisa: En el pasado se han descrito métodos para evaluar la hidrofobicidad de los talos liquénicos, sin embargo, no fue hasta recientemente que se demostró la importancia de esta propiedad como rasgo funcional en relación a la dinámica de regulación hídrica de los talos, permitiendo utilizarla como herramienta para predecir futuros efectos del cambio climático. Describimos un nuevo protocolo para medir la hidrofobicidad de los talos liquénicos que pretende ser más fácil y asequible. Métodos y Resultados: Nuestro protocolo requiere solamente de una micropipeta, agua destilada, un trípode y un teléfono o una cámara. La hidrofobicidad es inferida a partir de múltiples métricas asociadas a los tiempos de absorción de gotas de un volumen estandarizado (tiempo de absorción inicial y tiempo de absorción total). Utilizamos datos de 93 taxones de líquenes con diferentes formas de crecimiento y provenientes de distintos biomas, lo que permitió demostrar que este método es adecuado para capturar diferentes niveles de hidrofobicidad, incluyendo a especies altamente hidrofílicas. Conclusiones: Nuestros resultados muestran que la medición de la hidrofobicidad de los talos es un método rápido y de bajo costo que permite evaluar un rasgo funcional basado en la ecofisiología de líquenes y que puede ser utilizado prácticamente sin limitaciones, incluyendo en diferentes climas, especies y formas de crecimiento.

Mass Spectrometry-Based Metabolomics Multi-platform for Alzheimer's Disease Research.

The integration of complementary analytical platforms is nowadays the most common strategy for comprehensive metabolomics analysis of complex biological systems. In this chapter, we describe methods and tips for the application of a mass spectrometry multi-platform in Alzheimer's disease research, based on the combination of direct mass spectrometry and orthogonal hyphenated approaches, namely, reversed-phase ultrahigh-performance liquid chromatography and gas chromatography. These procedures have been optimized for the analysis of multiple biological samples from human patients and transgenic animal models, including blood serum, various brain regions (e.g., hippocampus, cortex, cerebellum, striatum, olfactory bulbs), and other peripheral organs (e.g., liver, kidney, spleen, thymus).

A randomized controlled mHealth trial that evaluates social comparison-oriented gamification to improve physical activity, sleep quantity, and quality of life in young adults.

INTRODUCTION: The integration of gamification in mHealth interventions presents a novel approach to enhance user engagement and health outcomes. This study aims to evaluate whether comparison-oriented gamification can effectively improve various aspects of health and well-being, including physical activity, sedentary behavior, sleep, and overall quality of life among young adults. METHODS: Potential 107 young adults (from 19 to 28 years old) participated in an 8-week trial. Participants were assigned to either a gamified mHealth intervention (LevantApp) with daily leaderboards and progress bars (n = 53, 26 % dropped-out), or a control condition without gamification (n = 52, 29 % dropped-out). Physical activity (number of steps, moderate and moderate-to-vigorous physical activity -MVPA-) and sleep quantity were measured objectively via accelerometry and subjectively using the International Physical Activity Questionnaire(IPAQ), Pittsburgh Sleep Quality Index(PSQI), Sedentary Behavior Questionnaire(SBQ), and Short Form Health Survey(SF-36). RESULTS: This mHealth intervention with social comparison-oriented gamification significantly improved moderate physical activity to a greater extent than the control group. Additionally, the intervention group showed improvements in the number of steps, moderate physical activity, sedentary time, emotional wellbeing, and social functioning. However, no significant group by time interaction was observed. No significant differences were observed in sleep quality or quantity. CONCLUSION: s: The LevantApp gamified mHealth intervention was effective in improving moderate physical activity, physical functioning, and role-emotional in young adults. No significant effects were found on step counts, MVPA or sleep, suggesting that while gamification can enhance specific aspects of physical activity and quality of life, its impact may vary across different outcomes.

Parental obesity predisposes to exacerbated metabolic and inflammatory disturbances in childhood obesity within the framework of an altered profile of trace elements.

BACKGROUND: Family history of obesity is known to increase the odds of developing childhood obesity in the offspring, but its influence in underlying molecular complications remains unexplored. SUBJECTS/METHODS: Here, we investigated a population-based cohort comprising children with obesity, with and without parental obesity (PO+, N = 20; PO-, N = 29), and lean healthy children as controls (N = 30), from whom plasma and erythrocyte samples were collected to characterize their multi-elemental profile, inflammatory status, as well as carbohydrate and lipid metabolisms. RESULTS: We found parental obesity to be associated with unhealthier outcomes in children, as reflected in increased blood insulin levels and reduced insulin sensitivity, unfavorable lipid profile, and pro-inflammatory milieu. This was accompanied by moderate alterations in the content of trace elements, including increased copper-to-zinc ratios and iron deficiency in circulation, as well as metal accumulation within erythrocytes. CONCLUSIONS: Therefore, we hypothesize that family history of obesity could be an important risk factor in modulating the characteristic multi-elemental alterations behind childhood obesity, which in turn could predispose to boost related comorbidities and metabolic complications.

Metabolome biomarkers linking dietary fibre intake with cardiometabolic effects: results from the Danish Diet, Cancer and Health-Next Generations MAX study.

Biomarkers associated with dietary fibre intake, as complements to traditional dietary assessment tools, may improve the understanding of its role in human health. Our aim was to discover metabolite biomarkers related to dietary fibre intake and investigate their association with cardiometabolic risk factors. We used data and samples from the Danish Diet Cancer and Health Next Generation (DCH-NG) MAX-study, a one-year observational study with evaluations at baseline, six and 12 months (n = 624, 55% female, mean age: 43 years, 1353 observations). Direct associations between fibre intake and plasma concentrations of 2,6-dihydroxybenzoic acid (2,6-DHBA) and indolepropionic acid were observed at the three time-points. Both metabolites showed an intraclass-correlation coefficient (ICC) > 0.50 and were associated with the self-reported intake of wholegrain cereals, and of fruits and vegetables, respectively. Other metabolites associated with dietary fibre intake were linolenoyl carnitine, 2-aminophenol, 3,4-DHBA, and proline betaine. Based on the metabolites associated with dietary fibre intake we calculated predicted values of fibre intake using a multivariate, machine-learning algorithm. Metabolomics-based predicted fibre, but not self-reported fibre values, showed negative associations with cardiometabolic risk factors (i.e. high sensitivity C-reactive protein, systolic and diastolic blood pressure, all FDR-adjusted p-values <0.05). Furthermore, different correlations with gut microbiota composition were observed. In conclusion, 2,6-DHBA and indolepropionic acid in plasma may better link dietary fibre intake with its metabolic effects than self-reported values. These metabolites may represent a novel class of biomarkers reflecting both dietary exposure and host and/or gut microbiota characteristics providing a read-out that is differentially related to cardiometabolic risk.

QComics: Recommendations and Guidelines for Robust, Easily Implementable and Reportable Quality Control of Metabolomics Data.

The implementation of quality control strategies is crucial to ensure the reproducibility, accuracy, and meaningfulness of metabolomics data. However, this pivotal step is often overlooked within the metabolomics workflow and frequently relies on the use of nonstandardized and poorly reported protocols. To address current limitations in this respect, we have developed QComics, a robust, easily implementable and reportable method for monitoring and controlling data quality. The protocol operates in various sequential steps aimed to (i) correct for background noise and carryover, (ii) detect signal drifts and "out-of-control" observations, (iii) deal with missing data, (iv) remove outliers, (v) monitor quality markers to identify samples affected by improper collection, preprocessing, or storage, and (vi) assess overall data quality in terms of precision and accuracy. Notably, this tool considers important issues often neglected along quality control, such as the need of separately handling missing values and truly absent data to avoid losing relevant biological information, as well as the large impact that preanalytical factors may elicit on metabolomics results. Altogether, the guidelines compiled in QComics might contribute to establishing gold standard recommendations and best practices for quality control within the metabolomics community.

Immune and molecular landscape behind non-response to Mycophenolate Mofetil and Azathioprine in lupus nephritis therapy.

Lupus nephritis (LN) represents one of the most severe complications of systemic lupus erythematosus, leading to end-stage kidney disease in worst cases. Current first-line therapies for LN, including mycophenolate mofetil (MMF) and azathioprine (AZA), fail to induce long-term remission in 60-70% of the patients, evidencing the urgent need to delve into the molecular knowledge-gap behind the non-response to these therapies. A longitudinal cohort of treated LN patients including clinical, cellular and transcriptomic data, was analyzed. Gene-expression signatures behind non-response to different drugs were revealed by differential expression analysis. Drug-specific non-response mechanisms and cell proportion differences were identified. Blood cell subsets mediating non-response were described using single-cell RNASeq data. We show that AZA and MMF non-response implicates different cells and regulatory functions. Mechanistic models were used to suggest add-on therapies to improve their current performance. Our results provide new insights into the molecular mechanisms associated with treatment failures in LN.

A Mediterranean Diet-Based Metabolomic Score and Cognitive Decline in Older Adults: A Case-Control Analysis Nested within the Three-City Cohort Study.

SCOPE: Evidence on the Mediterranean diet (MD) and age-related cognitive decline (CD) is still inconclusive partly due to self-reported dietary assessment. The aim of the current study is to develop an MD- metabolomic score (MDMS) and investigate its association with CD in community-dwelling older adults. METHODS AND RESULTS: This study includes participants from the Three-City Study from the Bordeaux (n = 418) and Dijon (n = 422) cohorts who are free of dementia at baseline. Repeated measures of cognition over 12 years are collected. An MDMS is designed based on serum biomarkers related to MD key food groups and using a targeted metabolomics platform. Associations with CD are investigated through conditional logistic regression (matched on age, sex, and education level) in both sample sets. The MDMS is found to be inversely associated with CD (odds ratio [OR] [95% confidence interval (CI)] = 0.90 [0.80-1.00]; p = 0.048) in the Bordeaux (discovery) cohort. Results are comparable in the Dijon (validation) cohort, with a trend toward significance (OR [95% CI] = 0.91 [0.83-1.01]; p = 0.084). CONCLUSIONS: A greater adherence to the MD, here assessed by a serum MDMS, is associated with lower odds of CD in older adults.

Childhood obesity, metabolic syndrome, and oxidative stress: microRNAs go on stage.

The incidence of childhood obesity and metabolic syndrome has grown notably in the last years, becoming major public health burdens in developed countries. Nowadays, oxidative stress is well-recognized to be closely associated with the onset and progression of several obesity-related complications within the framework of a complex crosstalk involving other intertwined pathogenic events, such as inflammation, insulin disturbances, and dyslipidemia. Thus, understanding the molecular basis behind these oxidative dysregulations could provide new approaches for the diagnosis, prevention, and treatment of childhood obesity and associated disorders. In this respect, the transcriptomic characterization of miRNAs bares great potential because of their involvement in post-transcriptional modulation of genetic expression. Herein, we provide a comprehensive literature revision gathering state-of-the-art research into the association between childhood obesity, metabolic syndrome, and miRNAs. We put special emphasis on the potential role of miRNAs in modulating obesity-related pathogenic events, with particular focus on oxidative stress.

Exploring the interplay between climate, population immunity and SARS-CoV-2 transmission dynamics in Mediterranean countries.

The relationship between SARS-CoV-2 transmission and environmental factors has been analyzed in numerous studies since the outbreak of the pandemic, resulting in heterogeneous results and conclusions. This may be due to differences in methodology, considered variables, confounding factors, studied periods and/or lack of adequate data. Furthermore, previous works have reported that the lack of population immunity is the fundamental driver in transmission dynamics and can mask the potential impact of environmental variables. In this study, we aimed to investigate the association between climate variables and COVID-19 transmission considering the influence of population immunity. We analyzed two different periods characterized by the absence of vaccination (low population immunity) and a high degree of vaccination (high level of population immunity), respectively. Although this study has some limitations, such us the restriction to a specific climatic zone and the omission of other environmental factors, our results indicate that transmission of SARS-CoV-2 may increase independently of temperature and specific humidity in periods with low levels of population immunity while a negative association is found under conditions with higher levels of population immunity in the analyzed regions.

Integrative metabolomics science in Alzheimer's disease: Relevance and future perspectives.

Alzheimer's disease (AD) is determined by various pathophysiological mechanisms starting 10-25 years before the onset of clinical symptoms. As multiple functionally interconnected molecular/cellular pathways appear disrupted in AD, the exploitation of high-throughput unbiased omics sciences is critical to elucidating the precise pathogenesis of AD. Among different omics, metabolomics is a fast-growing discipline allowing for the simultaneous detection and quantification of hundreds/thousands of perturbed metabolites in tissues or biofluids, reproducing the fluctuations of multiple networks affected by a disease. Here, we seek to critically depict the main metabolomics methodologies with the aim of identifying new potential AD biomarkers and further elucidating AD pathophysiological mechanisms. From a systems biology perspective, as metabolic alterations can occur before the development of clinical signs, metabolomics - coupled with existing accessible biomarkers used for AD screening and diagnosis - can support early disease diagnosis and help develop individualized treatment plans. Presently, the majority of metabolomic analyses emphasized that lipid metabolism is the most consistently altered pathway in AD pathogenesis. The possibility that metabolomics may reveal crucial steps in AD pathogenesis is undermined by the difficulty in discriminating between the causal or epiphenomenal or compensatory nature of metabolic findings.

Development of ASTM International D8405-Standard Test Method for Evaluating PM2.5 Sensors or Sensor Systems Used in Indoor Applications.

Sensors and sensor systems for monitoring fine particles with aerodynamic diameters smaller than 2.5 µm can provide real-time feedback on indoor air quality and thus can help guide actions to manage indoor air pollutant concentrations. Standardized verification of the performance and accuracy of sensors and sensor systems is crucial for predicting the efficacy of such monitoring. A new ASTM International standard test method (ASTM D8405) was created for this need and is the most exacting laboratory protocol published to date for evaluating indoor air quality sensors and sensor systems measuring particles smaller than 2.5 µm in diameter. ASTM D8405 subjects sensors and sensor systems to five test phases: (1) an initial particle concentration ramp; (2) exposure to various temperature and humidity conditions; (3) exposure to interfering particles; (4) temperature cycling; and (5) a final particle concentration ramp to assess drift. This paper discusses the development of the standard test method, key aspects of the testing process, example evaluation results, and a comparison of this standard test method against peer evaluation protocols.

Metal Homeostasis and Exposure in Distinct Phenotypic Subtypes of Insulin Resistance among Children with Obesity.

BACKGROUND: Trace elements and heavy metals have proven pivotal roles in childhood obesity and insulin resistance. However, growing evidence suggests that insulin resistance could encompass distinct phenotypic subtypes. METHODS: Herein, we performed a comprehensive metallomics characterization of plasma samples from children and adolescents with obesity and concomitant insulin resistance, who were stratified as early (N = 17, 11.4 ± 2.4 years), middle (N = 16, 11.8 ± 1.9 years), and late (N = 33, 11.7 ± 2.0 years) responders according to the insulin secretion profile in response to an oral glucose tolerance test. To this end, we employed a high-throughput method aimed at determining the biodistribution of various essential and toxic elements by analyzing total metal contents, metal-containing proteins, and labile metal species. RESULTS: Compared with the early responders, participants with delayed glucose-induced hyperinsulinemia showed a worsened insulin resistance (HOMA-IR, 4.5 vs. 3.8) and lipid profile (total cholesterol, 160 vs. 144 mg/dL; LDL-cholesterol, 99 vs. 82 mg/dL), which in turn was accompanied by sharpened disturbances in the levels of plasmatic proteins containing chromium (4.8 vs. 5.1 µg/L), cobalt (0.79 vs. 1.2 µg/L), lead (0.021 vs. 0.025 µg/L), and arsenic (0.077 vs. 0.17 µg/L). A correlation analysis demonstrated a close inter-relationship among these multielemental perturbations and the characteristic metabolic complications occurring in childhood obesity, namely impaired insulin-mediated metabolism of carbohydrates and lipids. CONCLUSIONS: These findings highlight the crucial involvement that altered metal homeostasis and exposure may have in regulating insulin signaling, glucose metabolism, and dyslipidemia in childhood obesity.

Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones.

Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi-elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper-to-zinc ratios. More interestingly, obesity-related erythroid alterations were found to be sex-dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female-specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex-personalized approaches in the context of precision medicine.

Trace elements as potential modulators of puberty-induced amelioration of oxidative stress and inflammation in childhood obesity.

Although puberty is known to influence obesity progression, the molecular mechanisms underlying the role of sexual maturation in obesity-related complications remains largely unexplored. Here, we delve into the impact of puberty on the most relevant pathogenic hallmarks of obesity, namely oxidative stress and inflammation, and their association with trace element blood status. To this end, we studied a well-characterized observational cohort comprising prepubertal (N = 46) and pubertal (N = 48) children with obesity. From all participants, plasma and erythrocyte samples were collected and subjected to metallomics analysis and determination of classical biomarkers of oxidative stress and inflammation. Besides the expected raise of sexual hormones, pubertal children displayed better inflammatory and oxidative control, as reflected by lower levels of C-reactive protein and oxidative damage markers, as well as improved antioxidant defense. This was in turn accompanied by a healthier multielemental profile, with increased levels of essential elements involved in the antioxidant system and metabolic control (metalloproteins containing zinc, molybdenum, selenium, and manganese) and decreased content of potentially deleterious species (total copper, labile free iron). Therefore, our findings suggest that children with obesity have an exacerbated inflammatory and oxidative damage at early ages, which could be ameliorated during pubertal development by the action of trace element-mediated buffering mechanisms.

Load and muscle group size influence the ergogenic effect of acute caffeine intake in muscular strength, power and endurance.

INTRODUCTION: Although acute caffeine intake seems to improve muscular strength-power-endurance performance, there is scarce evidence evaluating upper vs lower-body exercises at different loads. Thus, this study aimed to examine the effects of acute caffeine intake on upper and lower-body muscular strength, power and endurance performance at different loads. METHODS: Twenty resistance-trained athletes (male/female: 10/10; age: 23 ± 4 years; body mass: 70.6 ± 15.1) participated in a double-blind, placebo-controlled, cross-over and randomized study. Participants were provided with either 3 mg/kg of body mass of caffeine or maltodextrin (placebo). Sixty minutes after ingestion, they performed muscular strength and power assessment for bench press and back squat exercise at 25%, 50%, 75% and 90% 1-repetition-maximum (1RM), performing 3, 2, 1 and 1 repetitions respectively, followed by muscular endurance assessment for both exercises at 65% and 85% 1RM performing until task failure. Isometric handgrip, isometric mid-thigh pull and vertical jump tests were also performed. RESULTS: In muscular strength and power, compared to placebo, caffeine improved mean velocity (P = 0.045; pη2 = 0.101), mean power (P = 0.049; pη2 = 0.189) and rate of force development (RFD, P = 0.032; pη2 = 0.216), particularly in back squat exercise at 75% and 90% 1RM where mean velocity increased by 5-7% (P = 0.48-0.038; g = 0.348-1.413), mean power by 6-8% (P = 0.050-0.032; g = 0.547-0.818) and RFD by 17-97% (P = 0.042-0.046; g = 1.436-1.196). No differences were found in bench press exercise. In muscular endurance, caffeine improved the number of repetitions in all exercises and loads (P = 0.003; pη2 = 0.206), but only in back squat exercise at 85% 1RM, caffeine increased mean and peak velocity (8-9%, P = 0.006-0.004; g = 2.029-2.075), mean and peak power (10-13%, P = 0.006-0.003; g = 0.888-1.151) and force peak (3%, P = 0.009; g = 0.247). CONCLUSIONS: Acute caffeine intake (3 mg/kg) improved muscular strength, power and endurance performance, revealing a more pronounced effect at high-loads (≥ 75% 1RM) and in lower-body (back squat) than in upper-body exercise (bench press) according to muscle group size.

Analysis and Annotation of Phospholipids by Mass Spectrometry-Based Metabolomics.

Phospholipids are essential components of membrane lipid bilayers and serve as precursors of multiple signaling molecules, so alterations in their homeostasis are associated with the pathogenesis of numerous diseases. In this context, the application of mass spectrometry-based metabolomics has demonstrated great potential to comprehensively characterize the human phospholipidome. In this chapter, we describe an untargeted method for the determination of phospholipids and other related metabolites in a variety of biological matrices, including plasma/serum, erythrocytes, and tissues, based on the combination of high-throughput direct mass spectrometry fingerprinting and subsequent profiling by ultra-high-performance reversed-phase liquid chromatography coupled to mass spectrometry. Furthermore, we also review the characteristic fragmentation patterns of phospholipids with the aim of providing simple guidelines for their straightforward annotation.

Direct health costs of amyotrophic lateral sclerosis in a multidisciplinary ALS unit in Catalonia (Spain).

Our research project computed the direct health costs of patients with amyotrophic lateral sclerosis (ALS) in a Spanish multidisciplinary unit and explored the main factors associated. Besides analyzing a context with universal health care provision, we used an administrative health care dataset from the most crucial center unit treating ALS in Catalonia (80% of total patients). Our results show that the direct health cost of caring for an ALS patient in our unit was 5,158€per patient/year. This cost was not influenced by the onset of the disease, sex or age, but it increased if the patient lived near our center since this facilitates the frequency of follow-up visits. Finally, the higher the educational level, the lower the direct health costs.