Circulating Histones to Detect and Monitor the Progression of Cancer.

Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management. In this review, we provide an overview of circulating histones as a powerful liquid biopsy approach and methods for their detection. We highlight current knowledge on circulating histones in hematologic malignancies and solid cancer, with a focus on their role in cancer dissemination, monitoring, and tumorigenesis. Last, we describe recently developed strategies to identify cancer tissue-of-origin in blood plasma based on nucleosome positioning, inferred from nucleosomal DNA fragmentation footprint, which is independent of the genetic landscape.

Transcription Factor Zbtb20 as a Regulator of Malignancy and Its Practical Applications.

Zbtb20 (zinc finger and BTB domain-containing protein 20) is a transcription factor with a zinc finger DNA binding domain and a BTB domain responsible for protein-protein interaction. Recently, this TF has received attention because new data showed its pivotal involvement in normal neural development and its regulatory effects on proliferation and differentiation in different tissues. Zbtb20 was shown to increase proliferation and migration and confer resistance to apoptosis in the contexts of many malignant tumors like hepatocellular carcinoma, non-small-cell lung carcinoma, gastric adenocarcinoma, glioblastoma multiforme, breast cancer, and acute myeloid leukemia. The involvement of Zbtb20 in tumor biology is best studied in hepatocellular carcinoma, where it is a promising candidate as an immunohistochemical tumor marker or may be used in patient screening. Here we review the current data connecting Zbtb20 with malignant tumors.

Digital Interventions to Understand and Mitigate Stress Response: Protocol for Process and Content Evaluation of a Cohort Study.

BACKGROUND: Staffing and resource shortages, especially during the COVID-19 pandemic, have increased stress levels among health care workers. Many health care workers have reported feeling unable to maintain the quality of care expected within their profession, which, at times, may lead to moral distress and moral injury. Currently, interventions for moral distress and moral injury are limited. OBJECTIVE: This study has the following aims: (1) to characterize and reduce stress and moral distress related to decision-making in morally complex situations using a virtual reality (VR) scenario and a didactic intervention; (2) to identify features contributing to mental health outcomes using wearable, physiological, and self-reported questionnaire data; and (3) to create a personal digital phenotype profile that characterizes stress and moral distress at the individual level. METHODS: This will be a single cohort, pre- and posttest study of 100 nursing professionals in Ontario, Canada. Participants will undergo a VR simulation that requires them to make morally complex decisions related to patient care, which will be administered before and after an educational video on techniques to mitigate distress. During the VR session, participants will complete questionnaires measuring their distress and moral distress, and physiological data (electrocardiogram, electrodermal activity, plethysmography, and respiration) will be collected to assess their stress response. In a subsequent 12-week follow-up period, participants will complete regular assessments measuring clinical outcomes, including distress, moral distress, anxiety, depression, and loneliness. A wearable device will also be used to collect continuous data for 2 weeks before, throughout, and for 12 weeks after the VR session. A pre-post comparison will be conducted to analyze the effects of the VR intervention, and machine learning will be used to create a personal digital phenotype profile for each participant using the physiological, wearable, and self-reported data. Finally, thematic analysis of post-VR debriefing sessions and exit interviews will examine reoccurring codes and overarching themes expressed across participants' experiences. RESULTS: The study was funded in 2022 and received research ethics board approval in April 2023. The study is ongoing. CONCLUSIONS: It is expected that the VR scenario will elicit stress and moral distress. Additionally, the didactic intervention is anticipated to improve understanding of and decrease feelings of stress and moral distress. Models of digital phenotypes developed and integrated with wearables could allow for the prediction of risk and the assessment of treatment responses in individuals experiencing moral distress in real-time and naturalistic contexts. This paradigm could also be used in other populations prone to moral distress and injury, such as military and public safety personnel. TRIAL REGISTRATION: ClinicalTrials.gov NCT05923398; https://clinicaltrials.gov/study/NCT05923398. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54180.

Tracking 'transitional' diadectomorphs in the earliest Permian of equatorial Pangea.

Diadectomorpha was a clade of large-bodied stem-amniotes or possibly early-diverging synapsids that established a successful dynasty of late Carboniferous to late Permian high-fiber herbivores. Aside from their fairly rich record of body fossils, diadectomorphs are also well-known from widely distributed tracks and trackways referred to as Ichniotherium. Here, we provide detailed description of a diadectomorph trackway and a manus-pes couple originating from two different horizons in the Asselian (lowermost Permian) of the Boskovice Basin in the Czech Republic. The specimens represent two distinct ichnotaxa of Ichniotherium, I. cottae and I. sphaerodactylum. Intriguingly, the I. cottae trackway described herein illustrates a 'transitional' stage in the posture evolution of diadectomorphs, showing track morphologies possibly attributable to a Diadectes-like taxon combined with distances between the successive manus and pes imprints similar to those observable in earlier-diverging diadectomorphs, such as Orobates. In addition, this trackway is composed of 14 tracks, including six well-preserved manus-pes couples, and thus represents the most complete record of Ichniotherium cottae described to date from the Asselian strata. In turn, the manus-pes couple, attributed here to I. sphaerodactylum, represents only the second record of this ichnotaxon from the European part of Pangea. Our study adds to the diversity of the ichnological record of Permian tetrapods in the Boskovice Basin which had been essentially unexplored until very recently.

Liquid Liver Biopsy for Disease Diagnosis and Prognosis.

Liver diseases are a major burden worldwide, the scope of which is expected to further grow in the upcoming years. Clinically relevant liver dysfunction-related blood markers such as alanine aminotransferase and aspartate aminotransferase have limited accuracy. Nowadays, liver biopsy remains the gold standard for several liver-related pathologies, posing a risk of complication due to its invasive nature. Liquid biopsy is a minimally invasive approach, which has shown substantial potential in the diagnosis, prognosis, and monitoring of liver diseases by detecting disease-associated particles such as proteins and RNA molecules in biological fluids. Histones are the core components of the nucleosomes, regulating essential cellular processes, including gene expression and DNA repair. Following cell death or activation of immune cells, histones are released in the extracellular space and can be detected in circulation. Histones are stable in circulation, have a long half-life, and retain their post-translational modifications. Here, we provide an overview of the current research on histone-mediated liquid biopsy methods for liver diseases, with a focus on the most common detection methods.

Redescription of the soft-shell turtle Rafetus bohemicus (Testudines, Trionychidae) from the Early Miocene of Czechia.

The taxonomy of the soft-shell turtle Rafetus bohemicus (Liebus, 1930), family Trionychidae, subfamily Trionychinae, is revised based on new and previously mentioned material (including the type material) from the Early Miocene (Burdigalian, MN 3) sites of the Most Basin, Czechia. Given that the diagnosis was so far based only on plastral elements, here we focused on the cranial material and combined our study with previously published data on postcranial elements. 3D models of the skulls derived from CT scans allow us to provide the first complete skull description of R. bohemicus, including several new cranial diagnostic characters of the species. Our results not only enable the distinction of the trionychid genera Trionyx and Rafetus, both recorded from Central Europe during the Early Miocene, but further allow us to provide an emended diagnosis for R. bohemicus. We confirm the conclusions of a previous study according to which Trionyx pontanus, T. preschenensis, T. aspidiformis, and T. elongatus are nomina dubia. R. bohemicus from Brest'any (MN 3) represents the oldest record of this genus in Europe as well as the oldest occurrence of the genus.

Digital phenotyping for classification of anxiety severity during COVID-19.

COVID-19 has led to an increase in anxiety among Canadians. Canadian Perspectives Survey Series (CPSS) is a dataset created by Statistics Canada to monitor the effects of COVID-19 among Canadians. Survey data were collected to evaluate health and health-related behaviours. This work evaluates CPSS2 and CPSS4, which were collected in May and July of 2020, respectively. The survey data consist of up to 102 questions. This work proposes the use of the survey data characteristics to identify the level of anxiety within the Canadian population during the first- and second-phases of COVID-19 and is validated by using the General Anxiety Disorder (GAD)-7 questionnaire. Minimum redundancy maximum relevance (mRMR) is applied to select the top features to represent user anxiety, and support vector machine (SVM) is used to classify the separation of anxiety severity. We employ SVM for binary classification with 10-fold cross validation to separate the labels of Minimal and Severe anxiety to achieve an overall accuracy of 94.77 ± 0.13 % and 97.35 ± 0.11 % for CPSS2 and CPSS4, respectively. After analysis, we compared the results of the first and second phases of COVID-19 and determined a subset of the features that could be represented as pseudo passive (PP) data. The accurate classification provides a proxy on the potential onsets of anxiety to provide tailored interventions. Future works can augment the proposed PP data for carrying out a more detailed digital phenotyping.

Expression of Transcription Factor ZBTB20 in the Adult Primate Neurogenic Niche under Physiological Conditions or after Ischemia.

The Zbtb20 gene encodes for a transcription factor that plays an important role in mammalian cortical development. Recently, its expression was reported in the adult mouse subventricular zone (SVZ), a major neurogenic niche containing neural stem cells throughout life. Here, we analyzed its expression in the adult primate anterior SVZ (SVZa) and rostral migratory stream (RMS) using macaque monkeys (Macaca fuscata). We report that the majority of Ki67+ cells, 71.4% in the SVZa and 85.7% in the RMS, co-label for ZBTB20. Nearly all neuroblasts, identified by their Doublecortin expression, were positive for ZBTB20 in both regions. Nearly all GFAP+ neural stem cells/astrocytes were also positive for ZBTB20. Analysis of images derived from a public database of gene expression in control/ischemic monkey SVZa, showed evidence for ZBTB20 upregulation in postischemic monkey SVZa. Furthermore, the co-localization of ZBTB20 with Doublecortin and Ki67 was increased in the postischemic SVZa. Our results suggest that ZBTB20 expression is evolutionarily conserved in the mammalian neurogenic niche and is reactive to ischemia. This opens the possibility for further functional studies on the role of this transcription factor in neurogenesis in primates.

Early Miocene remains of Melissiodon from Mokrá-Quarry (Moravia, Czech Republic) shed light on the evolutionary history of the rare cricetid genus.

Background: Melissiodon is a rare cricetid genus endemic to Europe, known from the Early Oligoceneto the Early Miocene. It is usually a very rare find, and even in the few localities where Melissiodon remains are found, those are scarce and fragmentary. Only a few Central European localities have yielded rich remains of the genus. Currently, two species are known from the Early Miocene: Melissiodon schlosseri, which is based on two teeth from the MN2 German locality of Haslach and only found in two other sites of similar age (Ulm-Uniklinik and La Chaux, from Germany and Switzerland respectively); and Melissiodon dominans, found in MN3 and MN4 localities across Europe, even though the scarce and fragmentary remains make some of these attributions dubious. For that reason, Melissiodon dominans has become a catch-all species. However, Mokrá-Quarry represents one of the best documented findings of Melissiodon remains from MN4 localities of Europe. Methods: The Melissiodon assemblage from Mokrá-Quarry has been studied thoroughly, providing metrics and detailed descriptions of all teeth positions, as well as complete comparisons with other MN3 and MN4 localities bearing Melissiodon remains. Results: In this work, new remains of Melissiodon have been identified as a new morphotype that clearly differs from Melissiodon dominans by its unique m1 morphology but still shows some resemblance with Melissiodon schlosseri. Based on that, we here propose the hypothesis of an evolutionary lineage starting from Melissiodon schlosseri, diverging from the lineage leading towards Melissiodon dominans. With this finding, there are at least two different taxa of Melissiodon known during the Early Miocene, prior to the genus extinction. This study arises the certainty that the evolution history of the genus is more complex than previously thought and that more studies are necessary to elucidate it, including a complete revision of the type material of Melissiodon dominans and Melissiodon schlosseri in the light of current knowledge of the genus, which will help to elucidate the attribution of the populations from Mokrá-Quarry. For the time being, the assemblage presented here is referred as Melissiodon aff. schlosseri.

Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain.

Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in mammalian organs. A growing body of evidence suggests that this system participates in various signaling cascades that can regulate cell proliferation, blood pressure, fluid homeostasis, feeding behavior, and pituitary hormone release. Additional research has been done to elucidate the system's potential role in neurogenesis, the pathophysiology of Glioblastoma multiforme, and the protective effects of apelin peptides on some neurological and psychiatric disorders-ischemic stroke, epilepsy, Parkinson's, and Alzheimer's disease. This review discusses the current knowledge on the apelinergic system's involvement in brain physiology in health and disease.

Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.

Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.

Molecular Cloning, Structure and Phylogenetic Analysis of a Hemocyanin Subunit from the Black Sea Crustacean Eriphia verrucosa (Crustacea, Malacostraca).

Hemocyanins are copper-binding proteins that play a crucial role in the physiological processes in crustaceans. In this study, the cDNA encoding hemocyanin subunit 5 from the Black sea crab Eriphia verrucosa (EvHc5) was cloned using EST analysis, RT-PCR and rapid amplification of the cDNA ends (RACE) approach. The full-length cDNA of EvHc5 was 2254 bp, consisting of a 5' and 3' untranslated regions and an open reading frame of 2022 bp, encoding a protein consisting of 674 amino acid residues. The protein has an N-terminal signal peptide of 14 amino acids as is expected for proteins synthesized in hepatopancreas tubule cells and secreted into the hemolymph. The 3D model showed the presence of three functional domains and six conserved histidine residues that participate in the formation of the copper active site in Domain 2. The EvHc5 is O-glycosylated and the glycan is exposed on the surface of the subunit similar to Panulirus interruptus. The phylogenetic analysis has shown its close grouping with γ-type of hemocyanins of other crustacean species belonging to order Decapoda, infraorder Brachyura.

East Asian warm season temperature variations over the past two millennia.

East Asia has experienced strong warming since the 1960s accompanied by an increased frequency of heat waves and shrinking glaciers over the Tibetan Plateau and the Tien Shan. Here, we place the recent warmth in a long-term perspective by presenting a new spatially resolved warm-season (May-September) temperature reconstruction for the period 1-2000 CE using 59 multiproxy records from a wide range of East Asian regions. Our Bayesian Hierarchical Model (BHM) based reconstructions generally agree with earlier shorter regional temperature reconstructions but are more stable due to additional temperature sensitive proxies. We find a rather warm period during the first two centuries CE, followed by a multi-century long cooling period and again a warm interval covering the 900-1200 CE period (Medieval Climate Anomaly, MCA). The interval from 1450 to 1850 CE (Little Ice Age, LIA) was characterized by cooler conditions and the last 150 years are characterized by a continuous warming until recent times. Our results also suggest that the 1990s were likely the warmest decade in at least 1200 years. The comparison between an ensemble of climate model simulations and our summer reconstructions since 850 CE shows good agreement and an important role of internal variability and external forcing on multi-decadal time-scales.