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Time Series Classification (TSC) is essential in fields like medicine, environmental science, and finance, enabling tasks such as disease diagnosis, anomaly detection, and stock price analysis. While machine learning models like Recurrent Neural Networks and InceptionTime are successful in numerous applications, they can face scalability issues due to computational requirements. Recently, ROCKET has emerged as an efficient alternative, achieving state-of-the-art performance and simplifying training by utilizing a large number of randomly generated features from the time series data. However, many of these features are redundant or non-informative, increasing computational load and compromising generalization. Here we introduce Sequential Feature Detachment (SFD) to identify and prune non-essential features in ROCKET-based models, such as ROCKET, MiniRocket, and MultiRocket. SFD estimates feature importance using model coefficients and can handle large feature sets without complex hyperparameter tuning. Testing on the UCR archive shows that SFD can produce models with better test accuracy using only 10% of the original features. We named these pruned models Detach-ROCKET. We also present an end-to-end procedure for determining an optimal balance between the number of features and model accuracy. On the largest binary UCR dataset, Detach-ROCKET improves test accuracy by 0.6% while reducing features by 98.9%. By enabling a significant reduction in model size without sacrificing accuracy, our methodology improves computational efficiency and contributes to model interpretability. We believe that Detach-ROCKET will be a valuable tool for researchers and practitioners working with time series data, who can find a user-friendly implementation of the model at https://github.com/gon-uri/detach_rocket.

Cell viability and motility comprise ubiquitous mechanisms involved in a variety of (patho)biological processes including cancer. We report a technical comparative analysis of the novel impedance-based xCELLigence Real-Time Cell Analysis detection platform, with conventional label-based endpoint methods, hereby indicating performance characteristics and correlating dynamic observations of cell proliferation, cytotoxicity, migration and invasion on cancer cells in highly standardized experimental conditions. Dynamic high-resolution assessments of proliferation, cytotoxicity and migration were performed using xCELLigence technology on the MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. Proliferation kinetics were compared with the Sulforhodamine B (SRB) assay in a series of four cell concentrations, yielding fair to good correlations (Spearman's Rho 0.688 to 0.964). Cytotoxic action by paclitaxel (0-100 nM) correlated well with SRB (Rho>0.95) with similar IC(50) values. Reference cell migration experiments were performed using Transwell plates and correlated by pixel area calculation of crystal violet-stained membranes (Rho 0.90) and optical density (OD) measurement of extracted dye (Rho>0.95). Invasion was observed on MDA-MB-231 cells alone using Matrigel-coated Transwells as standard reference method and correlated by OD reading for two Matrigel densities (Rho>0.95). Variance component analysis revealed increased variances associated with impedance-based detection of migration and invasion, potentially caused by the sensitive nature of this method. The xCELLigence RTCA technology provides an accurate platform for non-invasive detection of cell viability and motility. The strong correlations with conventional methods imply a similar observation of cell behavior and interchangeability with other systems, illustrated by the highly correlating kinetic invasion profiles on different platforms applying only adapted matrix surface densities. The increased sensitivity however implies standardized experimental conditions to minimize technical-induced variance.

DNA methylation alterations have already been linked to cancer, and their usefulness for therapy and diagnosis has encouraged research into the human epigenome. Several biomarker studies have focused on identifying cancer types individually, yet common cancer and multicancer markers are still underexplored. We used The Cancer Genome Atlas (TCGA) to investigate genome‐wide methylation profiles of 14 different cancer types and developed a three‐step computational approach to select candidate biomarker CpG sites. In total, 1991 pan‐cancer and between 75 and 1803 cancer‐specific differentially methylated CpG sites were discovered. Differentially methylated blocks and regions were also discovered for the first time on such a large scale. Through a three‐step computational approach, a combination of four pan‐cancer CpG markers was identified from these sites and externally validated (AUC = 0.90), maintaining comparable performance across tumor stages. Additionally, 20 tumor‐specific CpG markers were identified and made up the final type‐specific prediction model, which could accurately differentiate tumor types (AUC = 0.87–0.99). Our study highlights the power of the methylome as a rich source of cancer biomarkers, and the signatures we identified provide a new resource for understanding cancer mechanisms on the wider genomic scale with strong applicability in the context of new minimally invasive cancer detection assays. We used The Cancer Genome Atlas to study genome‐wide methylation profiles of 14 different cancer types. We identified and validated a combination of four candidate pan‐cancer methylation CpG biomarkers and 20 candidate cancer type‐specific markers. This highlights the methylome as a rich source of biomarkers which can be used in the context of new minimally invasive cancer detection assays.

Atmospheric deposition is an important component of the nutrient cycles of terrestrial ecosystems, but field measurements are especially scarce in tropical regions. In this study we analysed 15 months of precipitation chemistry collected in an old growth tropical forest located in French Guiana. We measured nutrient inputs via bulk precipitation and throughfall and used the canopy budget model to estimate nutrient fluxes via canopy exchange and dry deposition. Based on this method we quantified net fluxes of macronutrients and compared their contribution to internal cycling rates via litterfall. Our results suggest that while atmospheric deposition of nitrogen was relatively high (13 kg ha⁻¹ year⁻¹), and mainly in organic forms, the N inputs via litterfall were an order of magnitude higher. In contrast to nitrogen, we found that atmospheric deposition of phosphorus (0.5 kg ha⁻¹ year⁻¹) supplied up to one third of the annual litterfall input to the forest floor. Most strikingly, combined annual inputs of potassium via atmospheric deposition (14 kg ha⁻¹ year⁻¹) and canopy leaching (22 kg ha⁻¹ year⁻¹) were three times larger than internal nutrient recycling via litterfall (11 kg ha⁻¹ year⁻¹). We conclude that atmospheric deposition of phosphorus and especially potassium may play an important role in sustaining the productivity of this old-growth tropical rainforest.

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6 , a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders. Brain-wide mapping of synapse molecular composition in Pax6 mutant mice shows remodelling and restoration of synaptome architecture during development, a possible means of conferring resilience to genetic disorders.

Nonischaemic myocardial fibrosis is associated with cardiac dysfunction, malignant arrhythmias and sudden cardiac death. In the absence of a specific aetiology, its finding as late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging is often attributed to preceding viral myocarditis. Athletes presenting with ventricular arrhythmias often have nonischaemic LGE. Previous studies have demonstrated an adverse effect of exercise on the course of acute viral myocarditis. In this study, we have investigated, for the first time, the impact of endurance training on longer-term outcomes such as myocardial fibrosis and arrhythmogenicity in a murine coxsackievirus B3 (CVB)-induced myocarditis model. Male C57BL/6J mice (n = 72) were randomly assigned to 8 weeks of forced treadmill running (EEX) or no exercise (SED). Myocarditis was induced 2 weeks later by a single intraperitoneal injection with CVB, versus vehicle in the controls (PBS). In a separate study, mice (n = 30) were subjected to pretraining for 13 weeks (preEEX), without continuation of exercise during myocarditis. Overall, continuation of exercise resulted in a milder clinical course of viral disease, with less weight loss and better preserved running capacity. CVB-EEX and preEEX-CVB mice tended to have a lower mortality rate. At sacrifice (i.e. 6 weeks after inoculation), the majority of virus was cleared from the heart. Histological assessment demonstrated prominent myocardial inflammatory infiltration and cardiomyocyte loss in both CVB groups. Inflammatory lesions in the CVB-EEX group contained higher numbers of pro-inflammatory cells (iNOS-reactive macrophages and CD8 + T lymphocytes) compared to these in CVB-SED. Treadmill running during myocarditis increased interstitial fibrosis [82.4% (CVB-EEX) vs. 56.3% (CVB-SED); P  = 0.049]. Additionally, perivascular and/or interstitial fibrosis with extensive distribution was more likely to occur with exercise [64.7% and 64.7% (CVB-EEX) vs. 50% and 31.3% (CVB-SED); P  = 0.048]. There was a numerical, but not significant, increase in the number of scars per cross-section (1.9 vs. 1.2; P  = 0.195), with similar scar distribution and histological appearance in CVB-EEX and CVB-SED. In vivo electrophysiology studies did not induce sustained monomorphic ventricular tachycardia, only nonsustained (usually polymorphic) runs. Their cumulative beat count and duration paralleled the increased fibrosis between CVB-EEX and CVB-SED, but the difference was not significant ( P  = 0.084 for each). Interestingly, in mice that were subjected to pretraining only without continuation of exercise during myocarditis, no differences between pretrained and sedentary mice were observed at sacrifice (i.e. 6 weeks after inoculation and training cessation) with regard to myocardial inflammation, fibrosis, and ventricular arrhythmogenicity. In conclusion, endurance exercise during viral myocarditis modulates the inflammatory process with more pro-inflammatory cells and enhances perivascular and interstitial fibrosis development. The impact on ventricular arrhythmogenesis requires further exploration.

The World Health Organization (WHO) endorsed diagnosis of leprosy (also known as Hansen’s disease) entirely based on clinical cardinal signs, without microbiological confirmation, which may lead to late or misdiagnosis. The use of slit skin smears is variable, but lacks sensitivity. In 2017–2018 during the ComLep study, on the island of Anjouan (Union of the Comoros; High priority country according to WHO, 310 patients were diagnosed with leprosy (paucibacillary = 159; multibacillary = 151), of whom 263 were sampled for a skin biopsy and fingerstick blood, and 260 for a minimally-invasive nasal swab. In 74.5% of all skin biopsies and in 15.4% of all nasal swabs, M . leprae DNA was detected. In 63.1% of fingerstick blood samples, M . leprae specific antibodies were detected with the quantitative αPGL-I test. Results show a strong correlation of αPGL-I IgM levels in fingerstick blood and RLEP-qPCR positivity of nasal swabs, with the M . leprae bacterial load measured by RLEP-qPCR of skin biopsies. Patients with a high bacterial load (≥50,000 bacilli in a skin biopsy) can be identified with combination of counting lesions and the αPGL-I test. To our knowledge, this is the first study that compared αPGL-I IgM levels in fingerstick blood with the bacterial load determined by RLEP-qPCR in skin biopsies of leprosy patients. The demonstrated potential of minimally invasive sampling such as fingerstick blood samples to identify high bacterial load persons likely to be accountable for the ongoing transmission, merits further evaluation in follow-up studies.

Athletes often exhibit unexplained non-ischemic myocardial fibrosis, which is associated with malignant arrhythmias. Given the prevalent (over)use of NSAIDs among athletes and their harmful effects during viral myocarditis, this study examined the effects of combined NSAIDs and endurance exercise on the disease progression. To this end, male C57BL/6J mice underwent eight weeks of treadmill running (60 min/day; 18 cm/s) or no exercise. After two weeks, mice were implanted with mini-pumps delivering ibuprofen (70 mg/kg bw/day) or vehicle. Myocarditis was induced via intraperitoneal coxsackievirus inoculation. Mice were sacrificed six weeks post-inoculation for ventricular arrhythmogenicity evaluation and cardiac histopathological and molecular analysis. Exercising coxsackievirus-infected mice receiving ibuprofen recovered faster from weight loss. Mortality was low and similar across groups. Histopathology revealed abating inflammation and cell loss, without significant group differences. While exercise tended to increase extensive myocardial fibrosis, statistical analyses indicated no significant differences—with or without NSAIDs—in perivascular fibrosis, interstitial fibrosis, or myocardial scarring. NSAIDs—irrespective of exercise—did not increase arrhythmogenicity. In conclusion, ibuprofen in exercising mice with viral myocarditis resulted in faster weight loss recovery, without significant differences in inflammation, fibrosis, or arrhythmogenesis compared to exercise-only mice.

Gait characteristics measured at usual pace may allow profiling in patients with cognitive problems. The influence of age, gender, leg length, modified speed or dual tasking is unclear. Cross-sectional analysis was performed on a data registry containing demographic, physical and spatial-temporal gait parameters recorded in five walking conditions with a GAITRite® electronic carpet in community-dwelling older persons with memory complaints. Four cognitive stages were studied: cognitively healthy individuals, mild cognitive impaired patients, mild dementia patients and advanced dementia patients. The association between spatial-temporal gait characteristics and cognitive stages was the most prominent: in the entire study population using gait speed, steps per meter (translation for mean step length), swing time variability, normalised gait speed (corrected for leg length) and normalised steps per meter at all five walking conditions; in the 50-to-70 years old participants applying step width at fast pace and steps per meter at usual pace; in the 70-to-80 years old persons using gait speed and normalised gait speed at usual pace, fast pace, animal walk and counting walk or steps per meter and normalised steps per meter at all five walking conditions; in over-80 years old participants using gait speed, normalised gait speed, steps per meter and normalised steps per meter at fast pace and animal dual-task walking. Multivariable logistic regression analysis adjusted for gender predicted in two compiled models the presence of dementia or cognitive impairment with acceptable accuracy in persons with memory complaints. Gait parameters in multiple walking conditions adjusted for age, gender and leg length showed a significant association with cognitive impairment. This study suggested that multifactorial gait analysis could be more informative than using gait analysis with only one test or one variable. Using this type of gait analysis in clinical practice could facilitate screening for cognitive impairment.

Background Breast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. We hypothesized that deafness , autosomal dominant 5 ( DFNA5 ) may be a valuable biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death. In this study, we aimed to analyze DFNA5 methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of DFNA5 as detection and/or prognostic marker in breast cancer. We analyzed Infinium HumanMethylation450k data, covering 22 different CpGs in the DFNA5 gene (668 breast adenocarcinomas and 85 normal breast samples) and DFNA5 expression (Agilent 244K Custom Gene Expression: 476 breast adenocarcinomas and 56 normal breast samples; RNA-sequencing: 666 breast adenocarcinomas and 71 normal breast samples). Results DFNA5 methylation and expression were significantly different between breast cancer and normal breast samples. Overall, breast cancer samples showed higher DFNA5 methylation in the putative gene promoter compared to normal breast samples, whereas in the gene body and upstream of the putative gene promoter, the opposite is true. Furthermore, DFNA5 methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5 , which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93). This model was externally validated in three independent datasets. Moreover, we showed that estrogen receptor state is associated with DFNA5 methylation and expression. Finally, we were able to find a significant effect of DFNA5 gene body methylation on a 5-year overall survival time. Conclusions We conclude that DFNA5 methylation shows strong potential as detection and prognostic biomarker for breast cancer.