Miracle-dz/UniFAR-FTUs huggingface dataset:
Comprehensive NGS Panel Validation for the Identification of Actionable Alterations in Adult Solid Tumors

The increasing identification of driver oncogenic alterations and progress of targeted therapies addresses the need of comprehensive alternatives to standard molecular methods. The translation into clinical practice of next-generation sequencing (NGS) panels is actually challenged by the compliance of high quality standards for clinical accreditation. Herein, we present the analytical and clinical feasibility study of a hybridization capture-based NGS panel (Action OncoKitDx) for the analysis of somatic mutations, copy number variants (CNVs), fusions, pharmacogenetic SNPs and Microsatellite Instability (MSI) determination in formalin-fixed paraffin-embedded (FFPE) tumor samples. A total of 64 samples were submitted to extensive analytical validation for the identification of previously known variants. An additional set of 166 tumor and patient-matched normal samples were sequenced to assess the clinical utility of the assay across different tumor types. The panel demonstrated good specificity, sensitivity, reproducibility, and repeatability for the identification of all biomarkers analyzed and the 5% limit of detection set was validated. Among the clinical cohorts, the assay revealed pathogenic genomic alterations in 97% of patient cases, and in 82.7%, at least one clinically relevant variant was detected. The validation of accuracy and robustness of this assay supports the Action OncoKitDx’s utility in adult solid tumors.
Progressive Cellular Architecture in Microscale Gas Chromatography for Broad Chemical Analyses

Gas chromatography is widely used to identify and quantify volatile organic compounds for applications ranging from environmental monitoring to homeland security. We investigate a new architecture for microfabricated gas chromatography systems that can significantly improve the range, speed, and efficiency of such systems. By using a cellular approach, it performs a partial separation of analytes even as the sampling is being performed. The subsequent separation step is then rapidly performed within each cell. The cells, each of which contains a preconcentrator and separation column, are arranged in progression of retentiveness. While accommodating a wide range of analytes, this progressive cellular architecture (PCA) also provides a pathway to improving energy efficiency and lifetime by reducing the need for heating the separation columns. As a proof of concept, a three-cell subsystem (PCA3mv) has been built; it incorporates a number of microfabricated components, including preconcentrators, separation columns, valves, connectors, and a carrier gas filter. The preconcentrator and separation column of each cell are monolithically implemented as a single chip that has a footprint of 1.8 × 5.2 cm2. This subsystem also incorporates two manifold arrays of microfabricated valves, each of which has a footprint of 1.3 × 1.4 cm2. Operated together with a commercial flame ionization detector, the subsystem has been tested against polar and nonpolar analytes (including alkanes, alcohols, aromatics, and phosphonate esters) over a molecular weight range of 32–212 g/mol and a vapor pressure range of 0.005–231 mmHg. The separations require an average column temperature of 63–68 °C within a duration of 12 min, and provide separation resolutions >2 for any two homologues that differ by one methyl group.
Damage Localization and Severity Assessment of a Cable-Stayed Bridge Using a Message Passing Neural Network

Cable-stayed bridges are damaged by multiple factors such as natural disasters, weather, and vehicle load. In particular, if the stayed cable, which is an essential and weak component of the cable-stayed bridge, is damaged, it may adversely affect the adjacent cables and worsen the bridge structure condition. Therefore, we must accurately determine the condition of the cable with a technology-based evaluation strategy. In this paper, we propose a deep learning model that allows us to locate the damaged cable and estimate its cross-sectional area. To obtain the data required for the deep learning training, we use the tension data of the reduced area cable, which are simulated in the Practical Advanced Analysis Program (PAAP), a robust structural analysis program. We represent the sensor data of the damaged cable-stayed bridge as a graph composed of vertices and edges using tension and spatial information of the sensors. We apply the sensor geometry by mapping the tension data to the graph vertices and the connection relationship between sensors to the graph edges. We employ a Graph Neural Network (GNN) to use the graph representation of the sensor data directly. GNN, which has been actively studied recently, can treat graph-structured data with the most advanced performance. We train the GNN framework, the Message Passing Neural Network (MPNN), to perform two tasks to identify damaged cables and estimate the cable areas. We adopt a multi-task learning method for more efficient optimization. We show that the proposed technique achieves high performance with the cable-stayed bridge data generated from PAAP.
Foodborne TiO2 Nanoparticles Induced More Severe Hepatotoxicity in Fructose-Induced Metabolic Syndrome Mice via Exacerbating Oxidative Stress-Mediated Intestinal Barrier Damage

The hazard of titanium dioxide nanoparticles (TiO2 NPs) in diseased population should be given focus due to the huge number of these NPs in foods and medicine. This study aimed to evaluate the stronger biological adverse effect of oral exposure to TiO2 NPs in a fructose-induced metabolic syndrome mouse model. Compared to the normal mice, low-dose (2 mg/kg) TiO2 NPs did not cause severe hepatotoxicity. However, high-dose (20 mg/kg) TiO2 NPs induced aggravated hepatic inflammation, fibrosis, and apoptosis, with substantial alteration of related biochemical parameters in the mouse model. Moreover, significantly increased Ti and lipopolysaccharide burden were observed in metabolic syndrome murine liver and serum, which possibly worsened the portend intestinal leakage. The expression of tight junction-related protein showed that TiO2 NPs induced further increase in serious intestinal permeability. The intestinal inflammatory and oxidative stress response in the model were also assessed. Results showed that TiO2 NPs caused more severe intestinal inflammatory injury by intensifying the oxidative stress in metabolic syndrome mice and then induced further liver injury. This work provides information on the insights into the toxic effect of TiO2 NPs in sub-healthy population.
Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Simple Summary The Sos Ras-GEFs are known to participate in a wide range of skin-related diseases including cutaneous cancers, cardio-facio-cutaneous syndromes, or hirsutism. However, the specific functional roles played by the Sos1 and/or Sos2 family members in specific skin compartments remain largely unknown. This report aimed at precisely characterizing the specific functions played by Sos1 and/or Sos2 in keratinocytes, an essential cellular component of the skin. Our data show that Sos1 and Sos2 make overlapping contributions to both keratinocyte proliferation and survival. However, Sos1 seems to have a preferential involvement in regulating the ERK axis, whereas Sos2 seems to control the signaling output from the PI3K axis. We also uncovered an essential role of Sos2 in the control of the population of epidermal stem cells. Abstract Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.
The role of H2A-H2B dimers in the mechanical stability of nucleosomes

Eukaryotic genomes are densely compacted into chromatin, so that they can be contained in the nucleus. Despite the tight packaging genes need to be accessible for normal metabolic activities to occur, such as transcription, repair and replication. These processes are regulated by a vast number of proteins but also by the level of compaction of chromatin. The translocation of motor proteins along DNA produces torsional stress which in turn alters chromatin compaction both upstream and downstream. Few singlemolecule studies have investigated the behaviour of nucleosomes when subjected to torsion. The inability to measure the applied torque though represented a major limitation to those reports. The implementation of the rotor bead assay, which allows to directly measure the torque applied in magnetic tweezers experiments, has been hindered by a difficult sample preparation procedure. In order to overcome this limitation an efficient protocol for the insertion of chemical or structural modifications in long DNA substrates was developed. This was then further expanded to allow the introduction of labels in multiple loci and/or both strands and has been used successfully in a number of studies. Furthermore this is the first report of tensile experiments performed on nucleosomes with a histone variant. H2AvD nucleosomes were studied due to the interest in the biological role of H2A.Z-family proteins. Interestingly, the variant nucleosomes appear to bind less DNA and to be evicted from the DNA at lower forces than those observed for canonical nucleosomes. These findings show an important role for the H2A-H2B dimers in the mechanical stability of nucleosomes. Furthermore these results are in agreement with recently proposed models of a dynamic nucleosome, in contrast to the long-standing view of nucleosomes as static structures.
Green Propolis Compounds (Baccharin and p-Coumaric Acid) Show Beneficial Effects in Mice for Melanoma Induced by B16f10

Abstract: Background: Cutaneous melanoma is the most aggressive form of skin cancer, with the worst prognosis, and it affects a younger population than most cancers. The high metastatic index, in more advanced stages, and the high aggressiveness decrease the effectiveness of currently used therapies, such as surgical removal, radiotherapy, cryotherapy, and chemotherapy, used alone or in combination. Based on these disadvantages, research focused on alternative medicine offers great potential for therapeutic innovation. Medicinal plants represent a remarkable source of compounds for the treatment of various diseases. Methods: In this study, we investigated the tumoral behavior of melanoma under treatment with the compounds baccharin and p-coumaric acid, extracted from green propolis, in mice inoculated with B16F10 cells for 26 days. Results: A significant modulation in the number of inflammatory cells recruited to the tumor region and blood in the groups treated with the compounds was observed. In addition, a significant reduction in the amount of blood vessels and mitosis in the neoplastic area was noticed. Conclusions: Through our research, we confirmed that baccharin and coumaric acid, isolated substances from Brazilian green propolis, have a promising anticarcinogenic potential to be explored for the development of new antitumor agents, adhering to the trend of drugs with greater tolerance and biological effectiveness.
Is complement the culprit behind COVID-19 vaccine-related adverse reactions?

Undeniably, a global and coordinated COVID-19 vaccination effort is a prerequisite for taming the spread of emerging SARS-CoV-2 variants and achieving population-wide immunity that can thwart future viral surges. However, rare vaccine-related adverse events were recently reported in individuals that received the adenoviral-encoded ChAdOx1 nCov-19 and Ad26.COV2. S vaccines. Here, we discuss the the potential contribution of complement activation to vaccine-related pathology.
Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CLR) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CLRpost-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CLR was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CLint,OAT1,3,invivo) and its ontogeny. CLint,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CLR predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months–15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CLint,OAT1,3,invivo that yields accurate CLR predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.
A Comprehensive Review on Energy Harvesting Integration in IoT Systems from MAC Layer Perspective: Challenges and Opportunities

The Internet of Things (IoT) is revolutionizing technology in a wide variety of areas, from smart healthcare to smart transportation. Due to the increasing trend in the number of IoT devices and their different levels of energy requirements, one of the significant concerns in IoT implementations is powering up the IoT devices with conventional limited lifetime batteries. One efficient solution to prolong the lifespan of these implementations is to integrate energy harvesting technologies into IoT systems. However, due to the characteristics of the energy harvesting technologies and the different energy requirements of the IoT systems, this integration is a challenging issue. Since Medium Access Control (MAC) layer operations are the most energy-consuming processes in wireless communications, they have undergone different modifications and enhancements in the literature to address this issue. Despite the essential role of the MAC layer to efficiently optimize the energy consumption in IoT systems, there is a gap in the literature to systematically understand the possible MAC layer improvements allowing energy harvesting integration. In this survey paper, we provide a unified framework for different wireless technologies to measure their energy consumption from a MAC operation-based perspective, returning the essential information to select the suitable energy harvesters for different communication technologies within IoT systems. Our analyses show that only 23% of the presented protocols in the literature fulfill Energy Neutral Operation (ENO) condition. Moreover, 48% of them are based on the hybrid approaches, which shows its capability to be adapted to energy harvesting. We expect this survey paper to lead researchers in academia and industry to understand the current state-of-the-art of energy harvesting MAC protocols for IoT and improve the early adoption of these protocols in IoT systems.
A systematic evaluation of learning rate policies in training CNNs for brain tumor segmentation

Convolutional neural networks (CNNs) have recently emerged as a powerful approach for automatic segmentation of brain tumor subregions on 3D multi-parametric MRI scans. Learning rate is a crucial hyperparameter in the training of CNNs, impacting the performance of the learned model. Different learning rate policies trace unique trajectories in the optimization landscape that converge to local minima with varying generalization properties. In this work, we empirically evaluated nine learning rate policy-optimizer pairs with two state-of-the-art architectures, namely 2D slice-based U-Net and 3D DeepMedicRes, on an augmented brain tumor dataset of 534 subjects. Segmentation performance was quantified in terms of Dice similarity coefficient and Hausdorff distance metrics. The policies were ranked based on the final ranking score (FRS) employed by the BraTS challenge, with the statistical significance of the rankings evaluated by random permutation test. For 2D slice-based U-Net architecture, an overall ranking of learning rate policies showed that the polynomial decay policy with Adam optimizer significantly outperformed other policies for the task of individual and hierarchical segmentation of tumor subregions (p < 10−4). For 3D segment-based DeepMedicRes architecture, polynomial decay policy with Adam optimizer performed significantly better than all other policies, with the exception of polynomial decay with SGD optimizer for the same task (p < 10−4). Based on the FRS, polynomial decay policy with Adam and SGD optimizer occupied the top two positions respectively, but the difference was not statistically significant (p > 0.3). These findings were also validated on the BraTS 2019 Validation dataset which comprised of an additional 125 subjects.
Validation of a Gas Chromatography-Mass Spectrometry Method for the Measurement of the Redox State Metabolic Ratios Lactate/Pyruvate and β-Hydroxybutyrate/Acetoacetate in Biological Samples

The metabolic ratios lactate/pyruvate and β-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1. The calibration curves presented acceptable linearity, with a limit of quantification of 0.001 mM for pyruvate, β-hydroxybutyrate and acetoacetate and of 0.01 mM for lactate. The intra-day and inter-day accuracy and precision were within the European Medicines Agency’s Guideline specifications. No significant differences were observed in the slope coefficient of three-point standard metabolite-spiked curves in plasma or liver and water, and acceptable recoveries were obtained in the metabolite-spiked samples. Applicability of the method was tested in precision-cut liver rat slices and also in HepG2 cells incubated under different experimental conditions challenging the redox state. In conclusion, the validated method presented good sensitivity, specificity and reproducibility in the quantification of lactate/pyruvate and β-hydroxybutyrate/acetate metabolites and may be useful in the evaluation of in vivo redox states.
Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944–45: The Dutch famine Birth Cohort

ABSTRACT This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944–45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.
Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models

Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.