Until date, several machine learning approaches have been proposed for the dynamic modeling of temporal omics data. Although they have yielded impressive results in terms of model accuracy and ...predictive ability, most of these applications are based on "Black-box" algorithms and more interpretable models have been claimed by the research community. The recent eXplainable Artificial Intelligence (XAI) revolution offers a solution for this issue, were rule-based approaches are highly suitable for explanatory purposes. The further integration of the data mining process along with functional-annotation and pathway analyses is an additional way towards more explanatory and biologically soundness models. In this paper, we present a novel rule-based XAI strategy (including pre-processing, knowledge-extraction and functional validation) for finding biologically relevant sequential patterns from longitudinal human gene expression data (GED). To illustrate the performance of our pipeline, we work on in vivo temporal GED collected within the course of a long-term dietary intervention in 57 subjects with obesity (GSE77962). As validation populations, we employ three independent datasets following the same experimental design. As a result, we validate primarily extracted gene patterns and prove the goodness of our strategy for the mining of biologically relevant gene-gene temporal relations. Our whole pipeline has been gathered under open-source software and could be easily extended to other human temporal GED applications.
We examined the association of objectively measured sedentary time (ST) and physical activity (PA) levels with pain, fatigue, and the impact of the disease in women with fibromyalgia. Four hundred ...and nineteen (mean age ± SD = 51.7 ± 7.6 years old) women with fibromyalgia participated. ST and PA levels (light, moderate, and moderate‐to‐vigorous MVPA) were measured with triaxial accelerometry. We assessed experimental pain with algometry and clinical pain, fatigue, and impact of fibromyalgia with a number of questionnaires. The association of ST and light PA with most of the pain‐ and fatigue‐related outcomes and impact of fibromyalgia (all, P ≤ 0.019) was independent of moderate and vigorous PA. Furthermore, the association of vigorous PA with general and physical fatigue was independent of ST and light and moderate PA (all, P < 0.001). In conclusion, lower levels of ST or higher levels of light PA are associated with lower pain, fatigue, and the overall impact of the disease independent of moderate and vigorous PA in women with fibromyalgia. Interestingly, higher vigorous PA is independently associated with lower general and physical fatigue. These results are significant for future ST and PA intervention studies in this population.
Two oxoiron(IV) isomers (R2a and R2b) of general formula FeIV(O)(RPyNMe3)(CH3CN)2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ...ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.
The isomerization of pairs of electronically tuned oxoiron(IV) geometrical isomers is described, as a model for the “ferryl flip” observed in non‐heme enzymes. The position of the oxo ligand in the coordination sphere of the iron center has a strong impact on the hydrogen‐atom transfer (HAT) activity of the oxoiron(IV) compounds, while electronic effects do not play a significant role in HAT reactions.
Soil microbial communities are dominated by a relatively small number of taxa that may play outsized roles in ecosystem functioning, yet little is known about their capacities to resist and recover ...from climate extremes such as drought, or how environmental context mediates those responses. Here, we imposed an in situ experimental drought across 30 diverse UK grassland sites with contrasting management intensities and found that: (1) the majority of dominant bacterial (85%) and fungal (89%) taxa exhibit resistant or opportunistic drought strategies, possibly contributing to their ubiquity and dominance across sites; and (2) intensive grassland management decreases the proportion of drought-sensitive and non-resilient dominant bacteria-likely via alleviation of nutrient limitation and pH-related stress under fertilisation and liming-but has the opposite impact on dominant fungi. Our results suggest a potential mechanism by which intensive management promotes bacteria over fungi under drought with implications for soil functioning.
We aimed (1) to report age‐specific physical fitness levels in people with fibromyalgia of a representative sample from Andalusia; and (2) to compare the fitness levels of people with fibromyalgia ...with non‐fibromyalgia controls. This cross‐sectional study included 468 (21 men) patients with fibromyalgia and 360 (55 men) controls. The fibromyalgia sample was geographically representative from southern Spain. Physical fitness was assessed with the Senior Fitness Test battery plus the handgrip test. We applied the Generalized Additive Model for Location, Scale and Shape to calculate percentile curves for women and fitted mean curves using a linear regression for men. Our results show that people with fibromyalgia reached worse performance in all fitness tests than controls (P < 0.001) in all age ranges (P < 0.001). This study provides a comprehensive description of age‐specific physical fitness levels among patients with fibromyalgia and controls in a large sample of patients with fibromyalgia from southern of Spain. Physical fitness levels of people with fibromyalgia from Andalusia are very low in comparison with age‐matched healthy controls. This information could be useful to correctly interpret physical fitness assessments and helping health care providers to identify individuals at risk for losing physical independence.
The aim of the present study was to determine the reliability and feasibility of physical fitness tests in female fibromyalgia patients. 100 female fibromyalgia patients (aged 50.6±8.6 years) ...performed the following tests twice (7 days interval test-retest): chair sit and reach, back scratch, handgrip strength, arm curl, chair stand, 8 feet up and go, and 6-min walk. Significant differences between test and retest were found in the arm curl (mean difference: 1.25±2.16 repetitions, Cohen d=0.251), chair stand (0.99±1.7 repetitions, Cohen d=0.254) and 8 feet up and go (-0.38±1.09 s, Cohen d=0.111) tests. Intraclass correlation coefficients (ICC) range from 0.92 in the arm curl test to 0.96 in the back scratch test. The feasibility of the tests (patients able to complete the test) ranged from 89% in the arm curl test to 100% in the handgrip strength test. Therefore, the reliability and feasibility of the physical fitness tests examined is acceptable for female fibromyalgia patients.
Summary
Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal ...gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell‐free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele‐specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88‐mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88‐mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular‐based risk classification.
Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) ...play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA.
When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease.
We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.
•Early RA is difficult to diagnose due to the lack of specific biomarkers.•Patients with early RA show an overexpression of several miRNAs.•The predicted miRNA target genes were related to inflammation and T cell activation.•The mir-361-5p is overexpressed in early RA and has potential as a biomarker.
Parkinson's disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem ...histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.
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