Miracle-dz/UniFAR-FTUs huggingface dataset:
Label Free Glucose Electrochemical Biosensor Based on Poly(3,4-ethylenedioxy thiophene):Polystyrene Sulfonate/Titanium Carbide/Graphene Quantum Dots

The electrochemical biosensor devices based on enzymes for monitoring biochemical substances are still considered attractive. We investigated the immobilization of glucose oxidase (GOx) on a new composite nanomaterial poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT:PSS)/titanium carbide,(Ti3C2)/graphene quantum dots(GQD) modified screen-printed carbon electrode (SPCE) for glucose sensing. The characterization and electrochemical behavior of PEDOT:PSS/Ti3C2/GQD towards the electrocatalytic oxidation of GOx was analyzed by FTIR, XPS, SEM, cyclic voltammetry (CV), and differential pulse voltammetry (DPV). This composite nanomaterial was found to tend to increase the electrochemical behavior and led to a higher peak current of 100.17 µA compared to 82.01 µA and 95.04 µA for PEDOT:PSS and PEDOT:PSS/Ti3C2 alone. Moreover, the detection results demonstrated that the fabricated biosensor had a linear voltammetry response in the glucose concentration range 0–500 µM with a relatively sensitivity of 21.64 µAmM−1cm−2 and a detection limit of 65 µM (S/N = 3), with good stability and selectivity. This finding could be useful as applicable guidance for the modification screen printed carbon (SPCE) electrodes focused on composite PEDOT:PSS/Ti3C2/GQD for efficient detection using an enzyme-based biosensor.
Inside the Insulin Secretory Granule

The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.
Altered epigenetics at the center of NK-LGL leukemia.

In this issue of Blood , Olson et al describe (epi)genetic changes in 58 patients with chronic natural killer large granular lymphocyte (NK-LGL) leukemia, uncov-ering recurrent loss-of function mutations in the TET2 gene. They highlight the associations of these lesions with altered global patterns of DNA methylation, with distinct cytopenias, and with treatment responses. This signi ﬁ cantly adds to our understanding of the pathogenesis of and diagnostic approach to this rare disease. JAK/STAT signaling (eg, PTPRD and PTPRN ), strongly enriched in those patients with TET2 mutations. This suggests additional modes of JAK/STAT hyperactivation in NK-LGL leukemogenesis besides STAT3 gain-of-function mutations. TET2 mutations are a known genetic hallmark in several myeloid malignancies (eg, myelodysplastic syndrome [MDS] and acute myeloid leukemia)andhavelatelybeen identi ed as constituentsofa clonal hematopoiesisofindeterminate
Patient‐present teaching in the clinic: Effect on agency and professional behaviour

Although much has been written about the medical learning environment, the patient, who is the focus of care, is rarely the focus in this literature. The purpose of this study was to explore the role of the patient as an active participant with agency in the medical learning environment from the standpoint of the learner, the attending physician, and most importantly, the patient. We hoped to gain insights into the mechanisms that can reinforce professional values such as patient‐centred and respectful behaviours in a patient‐present learning environment.
Rheumatoid arthritis: Development after the emergence of a chemokine for neutrophils in the synovium

Rheumatoid arthritis (RA) may not be a multifactorial disease; it can be hypothesized that RA is developed through a series of events following a triggering event, which is the emergence of a chemokine for neutrophils in the synovium. IL‐17A, secreted by infiltrated neutrophils, stimulates synoviocytes to produce CCL20, which attracts various CCR6‐expressing cells, including Th17 cells. Monocytes (macrophages) appear after neutrophil infiltration according to the natural course of inflammation and secrete IL‐1β and TNFα. Then, IL‐17A, IL‐1β, and TNFα stimulate synoviocytes to produce CCL20, amplifying the inflammation. Varieties of chemokines secreted by infiltrating cells accumulate in the synovium and induce synoviocyte proliferation by binding to the corresponding G protein‐coupled receptors, thus expanding the synovial tissue. CCL20 in this tissue attracts circulating monocytes that express both CCR6 and receptor activator of NF‐κB (RANK), which differentiate into osteoclasts in the presence of RANKL. In this way, pannus is formed, and bone destruction begins.
Current insights into epigenetics, noncoding RNA interactome and clinical pharmacokinetics of dietary polyphenols in cancer chemoprevention

Abstract Several studies have reported the health-beneficial effects of dietary phytochemicals, namely polyphenols, to prevent various diseases, including cancer. Polyphenols, like (−)-epigallocatechin-3-gallate (EGCG) from green tea, curcumin from turmeric, and ellagic acid from pomegranate are known to act by modulating antioxidant, anti-inflammatory and apoptotic signal transduction pathways in the tumor milieu. The evolving literature underscores the role of epigenetic regulation of genes associated with cancer by these polyphenols, primarily via non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long noncoding RNA (lncRNA). However, there is little clarity on the exact role(s) played by these ncRNAs and their interactions with other ncRNAs, or with their protein targets, in response to modulation by these dietary polyphenols. Here, we review ncRNA interactions and functional networks of the complex ncRNA interactome with their targets in preclinical studies along with the role of epigenetics as well as key aspects of pharmacokinetics and phytochemistry of dietary polyphenols. We also summarize the current state of clinical trials with these dietary polyphenols. Taken together, this synthetic review provides insights into the molecular aspects underlying the anticancer chemopreventive effects of dietary polyphenols as well as summarizes data on novel biomarkers modulated by these polyphenols for preventive or therapeutic purposes in various types of cancer. Graphical Abstract
Chronic thromboembolic pulmonary hypertension anno 2021

Purpose of review In the past decades, the diagnostic and therapeutic management of chronic thromboembolic pulmonary hypertension (CTEPH) has been revolutionized. Recent findings Advances in epidemiological knowledge and follow-up studies of pulmonary embolism patients have provided more insight in the incidence and prevalence. Improved diagnostic imaging techniques allow accurate assessment of the location and extend of the thromboembolic burden in the pulmonary artery tree, which is important for the determination of the optimal treatment strategy. Next to the pulmonary endarterectomy, the newly introduced technique percutaneous pulmonary balloon angioplasty and/or P(A)H-targeted medical therapy has been shown to be beneficial in selected patients with CTEPH and might also be of importance in patients with chronic thromboembolic pulmonary vascular disease. Summary In this era of a comprehensive approach to CTEPH with different treatment modalities, a multidisciplinary approach guides management decisions leading to optimal treatment and follow-up of patients with CTEPH.
Deciphering Microbial Metal Toxicity Responses via Random Bar Code Transposon Site Sequencing and Activity-Based Metabolomics

Studying microbial interactions with their environment can lead to a deeper understanding of biological molecular mechanisms. In the manuscript, two global techniques, RB-TnSeq and activity metabolomics, were successfully used to probe the interactions between a metal-resistant microorganism, Pantoea sp. strain MT58, and metals contaminating a site where the organism can be located. ABSTRACT To uncover metal toxicity targets and defense mechanisms of the facultative anaerobe Pantoea sp. strain MT58 (MT58), we used a multiomic strategy combining two global techniques, random bar code transposon site sequencing (RB-TnSeq) and activity-based metabolomics. MT58 is a metal-tolerant Oak Ridge Reservation (ORR) environmental isolate that was enriched in the presence of metals at concentrations measured in contaminated groundwater at an ORR nuclear waste site. The effects of three chemically different metals found at elevated concentrations in the ORR contaminated environment were investigated: the cation Al3+, the oxyanion CrO42−, and the oxycation UO22+. Both global techniques were applied using all three metals under both aerobic and anaerobic conditions to elucidate metal interactions mediated through the activity of metabolites and key genes/proteins. These revealed that Al3+ binds intracellular arginine, CrO42− enters the cell through sulfate transporters and oxidizes intracellular reduced thiols, and membrane-bound lipopolysaccharides protect the cell from UO22+ toxicity. In addition, the Tol outer membrane system contributed to the protection of cellular integrity from the toxic effects of all three metals. Likewise, we found evidence of regulation of lipid content in membranes under metal stress. Individually, RB-TnSeq and metabolomics are powerful tools to explore the impact various stresses have on biological systems. Here, we show that together they can be used synergistically to identify the molecular actors and mechanisms of these pertubations to an organism, furthering our understanding of how living systems interact with their environment. IMPORTANCE Studying microbial interactions with their environment can lead to a deeper understanding of biological molecular mechanisms. In this study, two global techniques, RB-TnSeq and activity metabolomics, were successfully used to probe the interactions between a metal-resistant microorganism, Pantoea sp. strain MT58, and metals contaminating a site where the organism can be located. A number of novel metal-microbe interactions were uncovered, including Al3+ toxicity targeting arginine synthesis, which could lead to a deeper understanding of the impact Al3+ contamination has on microbial communities as well as its impact on higher-level organisms, including plants for whom Al3+ contamination is an issue. Using multiomic approaches like the one described here is a way to further our understanding of microbial interactions and their impacts on the environment overall.
Numeral order and the operationalization of the numerical system

Recent years have witnessed an increase in research on how numeral ordering skills relate to children’s and adults’ mathematics achievement both cross-sectionally and longitudinally. Nonetheless, it remains unknown which core competency numeral ordering tasks measure, which cognitive mechanisms underlie performance on these tasks, and why numeral ordering skills relate to arithmetic and math achievement. In the current study, we focused on the processes underlying decision-making in the numeral order judgement task with triplets to investigate these questions. A drift-diffusion model for two-choice decisions was fit to data from 97 undergraduates. Findings aligned with the hypothesis that numeral ordering skills reflected the operationalization of the numerical system, where small numbers provide more evidence of an ordered response than large numbers. Furthermore, the pattern of findings suggested that arithmetic achievement was associated with the accuracy of the ordinal representations of numbers.
Cytoskeletal Arrest: An Anoxia Tolerance Mechanism

Polymerization of actin filaments and microtubules constitutes a ubiquitous demand for cellular adenosine-5′-triphosphate (ATP) and guanosine-5′-triphosphate (GTP). In anoxia-tolerant animals, ATP consumption is minimized during overwintering conditions, but little is known about the role of cell structure in anoxia tolerance. Studies of overwintering mammals have revealed that microtubule stability in neurites is reduced at low temperature, resulting in withdrawal of neurites and reduced abundance of excitatory synapses. Literature for turtles is consistent with a similar downregulation of peripheral cytoskeletal activity in brain and liver during anoxic overwintering. Downregulation of actin dynamics, as well as modification to microtubule organization, may play vital roles in facilitating anoxia tolerance. Mitochondrial calcium release occurs during anoxia in turtle neurons, and subsequent activation of calcium-binding proteins likely regulates cytoskeletal stability. Production of reactive oxygen species (ROS) formation can lead to catastrophic cytoskeletal damage during overwintering and ROS production can be regulated by the dynamics of mitochondrial interconnectivity. Therefore, suppression of ROS formation is likely an important aspect of cytoskeletal arrest. Furthermore, gasotransmitters can regulate ROS levels, as well as cytoskeletal contractility and rearrangement. In this review we will explore the energetic costs of cytoskeletal activity, the cellular mechanisms regulating it, and the potential for cytoskeletal arrest being an important mechanism permitting long-term anoxia survival in anoxia-tolerant species, such as the western painted turtle and goldfish.
Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

Extramammary Paget’s disease (EMPD) is a rare neoplasm that usually develops in apocrine gland-bearing areas, such as the vulva, scrotum, and penis. EMPD may present with a focal, multifocal, or an ectopic lesion. Clinically, EMPD lesions often exhibit infiltrative erythema, which is sometimes similar to other skin disorders such as eczema. While primary EMPD arises as intraepithelial neoplasm of the epidermis, EMPD-like lesions may occur from epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm, known as secondary EMPD. Because treatment strategies differ for primary EMPD and secondary EMPD, accurate diagnosis based on detailed histopathological evaluation is required. In the early stages, EMPD usually shows indolent growth, and most cases are diagnosed as carcinoma in situ. However, invasive lesions may result in metastases, and deep invasion is associated with high incidence of metastases. Conventional chemotherapies have been used for EMPD treatment in patients with distant metastases, but the efficacy is not satisfactory, and the prognosis for such patients remains poor. Recent studies have provided various insights into the molecular pathogenesis of the development and advancement of EMPD, which may lead to novel treatment approaches for metastatic EMPD. This review addresses the diagnosis, pathogenesis, and treatment of EMPD with focus on recent progress in understanding this disease.
Stability Assessment of Four Chimeric Proteins for Human Chagas Disease Immunodiagnosis

The performance of an immunoassay relies on antigen-antibody interaction; hence, antigen chemical stability and structural integrity are paramount for an efficient assay. We conducted a functional, thermostability and long-term stability analysis of different chimeric antigens (IBMP), in order to assess effects of adverse conditions on four antigens employed in ELISA to diagnose Chagas disease. ELISA-based immunoassays have served as a model for biosensors development, as both assess molecular interactions. To evaluate thermostability, samples were heated and cooled to verify heat-induced denaturation reversibility. In relation to storage stability, the antigens were analyzed at 25 °C at different moments. Long-term stability tests were performed using eight sets of microplates sensitized. Antigens were structurally analyzed through circular dichroism (CD), dynamic light scattering, SDS-PAGE, and functionally evaluated by ELISA. Data suggest that IBMP antigens are stable, over adverse conditions and for over a year. Daily analysis revealed minor changes in the molecular structure. Functionally, IBMP-8.2 and IBMP-8.3 antigens showed reactivity towards anti-T. cruzi antibodies, even after 72 h at 25 °C. Long-term stability tests showed that all antigens were comparable to the control group and all antigens demonstrated stability for one year. Data suggest that the antigens maintained their function and structural characteristics even in adverse conditions, making them a sturdy and reliable candidate to be employed in future in vitro diagnostic tests applicable to different models of POC devices, such as modern biosensors in development.
The Impact of Photorespiratory Glycolate Oxidase Activity on Arabidopsis thaliana Leaf Soluble Amino Acid Pool Sizes during Acclimation to Low Atmospheric CO2 Concentrations

Photorespiration is a metabolic process that removes toxic 2-phosphoglycolate produced by the oxygenase activity of ribulose-1,5-bisphosphate carboxylase/oxygenase. It is essential for plant growth under ambient air, and it can play an important role under stress conditions that reduce CO2 entry into the leaf thus enhancing photorespiration. The aim of the study was to determine the impact of photorespiration on Arabidopsis thaliana leaf amino acid metabolism under low atmospheric CO2 concentrations. To achieve this, wild-type plants and photorespiratory glycolate oxidase (gox) mutants were given either short-term (4 h) or long-term (1 to 8 d) low atmospheric CO2 concentration treatments and leaf amino acid levels were measured and analyzed. Low CO2 treatments rapidly decreased net CO2 assimilation rate and triggered a broad reconfiguration of soluble amino acids. The most significant changes involved photorespiratory Gly and Ser, aromatic and branched-chain amino acids as well as Ala, Asp, Asn, Arg, GABA and homoSer. While the Gly/Ser ratio increased in all Arabidopsis lines between air and low CO2 conditions, low CO2 conditions led to a higher increase in both Gly and Ser contents in gox1 and gox2.2 mutants when compared to wild-type and gox2.1 plants. Results are discussed with respect to potential limiting enzymatic steps with a special emphasis on photorespiratory aminotransferase activities and the complexity of photorespiration.
Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation

The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals—pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recognized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.
Phylogenetic Signal, Congruence, and Uncertainty across Bacteria and Archaea

Abstract Reconstruction of the Tree of Life is a central goal in biology. Although numerous novel phyla of bacteria and archaea have recently been discovered, inconsistent phylogenetic relationships are routinely reported, and many inter-phylum and inter-domain evolutionary relationships remain unclear. Here, we benchmark different marker genes often used in constructing multidomain phylogenetic trees of bacteria and archaea and present a set of marker genes that perform best for multidomain trees constructed from concatenated alignments. We use recently-developed Tree Certainty metrics to assess the confidence of our results and to obviate the complications of traditional bootstrap-based metrics. Given the vastly disparate number of genomes available for different phyla of bacteria and archaea, we also assessed the impact of taxon sampling on multidomain tree construction. Our results demonstrate that biases between the representation of different taxonomic groups can dramatically impact the topology of resulting trees. Inspection of our highest-quality tree supports the division of most bacteria into Terrabacteria and Gracilicutes, with Thermatogota and Synergistota branching earlier from these superphyla. This tree also supports the inclusion of the Patescibacteria within the Terrabacteria as a sister group to the Chloroflexota instead of as a basal-branching lineage. For the Archaea, our tree supports three monophyletic lineages (DPANN, Euryarchaeota, and TACK/Asgard), although we note the basal placement of the DPANN may still represent an artifact caused by biased sequence composition. Our findings provide a robust and standardized framework for multidomain phylogenetic reconstruction that can be used to evaluate inter-phylum relationships and assess uncertainty in conflicting topologies of the Tree of Life.