Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation

AbstractIntroductionNeutrophils can be induced to release DNA combined with histones. The resulting neutrophil extracellular trap (NET) provides a scaffold for growing hemostatic plug. Therefore, the NET formation may be inevitable in clinical conditions that are characterized by formation of vascular thrombi. Thus far, there have been no reports on the clinical significance of NET in disseminated intravascular coagulation (DIC). Therefore, we investigated circulating levels of NET in DIC and analyzed their potential values to assess coagulation severity and predict clinical outcome.MethodsThe plasma levels of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers of NET, were measured in 199 patients suspected of having DIC and 20 healthy controls.ResultThe circulating levels of DNA-histone complexes and dsDNA were significantly elevated in overt-DIC. The increased levels of these two markers correlated with the severity of coagulopathy including DIC score and D-dimer. Multivariable Cox regression analysis, adjusted for the conventional DIC markers, revealed that elevated DNA-histone complexes and dsDNA are poor independent prognostic markers.ConclusionThe circulating levels of NET release reflect the coagulation activation and adverse clinical outcomes in patients with DIC, thereby providing potential clinical relevance for mortality prediction in DIC

Azeroth: Auditable Zero-knowledge Transactions in Smart Contracts

With the rapid growth of the blockchain market, privacy and security issues for digital assets are becoming more important. In the most widely used public blockchains such as Bitcoin and Ethereum, all activities on user accounts are publicly disclosed, which violates privacy regulations such as EU GDPR. Encryption of accounts and transactions may protect privacy, but it also raises issues of validity and transparency: encrypted information alone cannot verify the validity of a transaction and makes it difficult to meet anti-money laundering regulations, i.e. auditability. In this paper, we propose $\textsf{Azeroth}$, an auditable zero-knowledge transfer framework. $\textsf{Azeroth}$ connects a zero-knowledge proof to an encrypted transaction, enabling it to check its validation while protecting its privacy. $\textsf{Azeroth}$ also allows authorized auditors to audit transactions. $\textsf{Azeroth}$ is designed as a smart contract for flexible deployment on existing blockchains. %According to the result of our experiment, the proof generation time is about $0.9s$, and the asset transferring time is only $4.4s$, which is practically usable. We implement the $\textsf{Azeroth}$ smart contract, execute it on various platforms including an Ethereum testnet blockchain, and measure the time to show the practicality of our proposal. The end-to-end latency of a privacy-preserving transfer takes about $4.4s$. In particular, the client\u27s transaction generation time with a proof only takes about $0.9s$. The security of $\textsf{Azeroth}$ is proven under the cryptographic assumptions

Re-intermediation in the Fashion Industry: A Qualitative Study on Brokers in the Dongdae-mun Fashion District

Traditionally, middlemen had a large role in physical markets, serving as intermediaries by evaluating and distributing products. However, the rise of online markets and intermediaries have diminished their roles. This study investigates the change of intermediaries' roles in the presence of infomediaries, and the conditions that necessitate the re-introduction of the middlemen as ``re-intermediaries''. We observed a group of brokers who work in the Dongdae-mun (DDM) fashion district in Seoul, Korea through multiple qualitative research methods including observations, contextual inquiries, and in-depth interviews. Our findings show that the reliability and depth of information relayed by human sources, along with the subjective nature of fashion have contributed to the brokers playing a major role again, despite infomediaries. The DDM fashion district relies heavily on the brokers' evaluations on trends, fashion, and product popularity, in addition to their traditional role of distributing goods in a quick manner

Case report: Successful treatment of malignant pericardial effusion with pericardiocentesis, concurrent anti-inflammatory therapy and cancer therapy

Despite significant advancements in systemic anticancer therapies, cardiac tamponade remains a serious and potentially life-threatening complication in metastatic breast cancer (MBC). However, there is a paucity of comprehensive research investigating alternative management approaches, such as pericardiocentesis and anti-inflammatory therapy (AIT), to effectively address cardiac tamponade and mitigate the risk of heart failure arising from constrictive physiology (CP) in patients with MBC when traditional systemic anticancer drugs fail to yield favorable outcomes. Herein, we describe two cases of MBC with cardiac tamponade that occurred despite the administration of effective systemic anticancer drugs. In each case, pericardial effusion was detected in a patient who was undergoing palliative anticancer therapy for human epidermal growth factor receptor 2 (HER2)-positive MBC. The patients in these cases were successfully treated with pericardiocentesis and AIT (prednisolone and colchicine) for subsequent CP without substitution with their systemic anticancer drugs. Cardiac tamponade and CP are regarded as signs of advanced cancer and are associated with a worse clinical outcome in general; however, they can still be treated with an effective anticancer drug, pericardiocentesis, and management of CP by cardiooncology specialists

Microsatellite-Based Genetic Diversity Among Three Duck Populations in Sumatera Island

This study aimed to determine the genetic diversity among three duck populations (Bayang, Pegagan, and Pitalah) reared in Sumatera island, Indonesia, using microsatellite markers. Genetic diversity among populations (n = 90) was determined using 22 microsatellite markers, based on several indices: number of alleles (Na), observed heterozygosity (Ho), expected heterozygosity (He), polymorphism information content (PIC), and Wright’s F-statistics ( ). The total number of alleles detected across loci was 121. The Na per locus ranged from 2 (APH24, CAUD128, and CAUD009) to 18 (CAUD048 and CAUD040). The mean Ho (0.429) dan He (0.509) indicated that the level of genetic diversity among populations was moderate, while the mean PIC (0.46) suggested that the tested loci were informative for assessing genetic diversity. The mean F-statistics ( ) were 0.148, 0.198, and 0.060, respectively. The  value indicated that the level of genetic differentiation among populations was moderate. The results confirms a moderate genetic diversity among populations, which could be beneficial for designing conservation and utilization of the local ducks in Sumatera island

ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

Background: Delta Np63 alpha is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-damage induced p53 phosphorylation is confined to Delta Np63 alpha-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylation of the p53 tumour suppressor is positively regulated by Delta Np63 alpha in immortalised human keratinocytes. Delta Np63 alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of Delta Np63 alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct Delta Np63 alpha transcriptional target and that the Delta Np63 alpha response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the Delta Np63-specific TA2 transactivation domain mediates ATM transcription in coordination with the DNA binding and SAM domains. Conclusions: Germline p63 point mutations are associated with a range of ectodermal developmental disorders, and targeted p63 deletion in the skin causes premature ageing. The Delta Np63 alpha-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes

Human Papillomavirus E6 Triggers Upregulation of the Antiviral and Cancer Genomic DNA Deaminase APOBEC3B

ABSTRACT Several recent studies have converged upon the innate immune DNA cytosine deaminase APOBEC3B (A3B) as a significant source of genomic uracil lesions and mutagenesis in multiple human cancers, including those of the breast, head/neck, cervix, bladder, lung, ovary, and other tissues. A3B is upregulated in these tumor types relative to normal tissues, but the mechanism is unclear. Because A3B also has antiviral activity in multiple systems and is a member of the broader innate immune response, we tested the hypothesis that human papillomavirus (HPV) infection causes A3B upregulation. We found that A3B mRNA expression and enzymatic activity were upregulated following transfection of a high-risk HPV genome and that this effect was abrogated by inactivation of E6. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins. Knockdown experiments in HPV-positive cell lines showed that endogenous E6 is required for A3B upregulation. Analyses of publicly available head/neck cancer data further support this relationship, as A3B levels are higher in HPV-positive cancers than in HPV-negative cancers. Taken together with the established role for high-risk E6 in functional inactivation of TP53 and published positive correlations in breast cancer between A3B upregulation and genetic inactivation of TP53, our studies suggest a model in which high-risk HPV E6, possibly through functional inactivation of TP53, causes derepression of A3B gene transcription. This would lead to a mutator phenotype that explains the observed cytosine mutation biases in HPV-positive head/neck and cervical cancers

Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth

BackgroundMicroenvironmental factors, including microbe-induced inflammation and immune-checkpoint proteins that modulate immune cells have been associated with both cervical insufficiency and preterm delivery. These factors are incompletely understood. This study aimed to explore and compare interactions among microbiome and inflammatory factors, such as cytokines and immune-checkpoint proteins, in patients with cervical insufficiency and preterm birth. In particular, factors related to predicting preterm birth were identified and the performance of the combination of these factors was evaluated.MethodsA total of 220 swab samples from 110 pregnant women, prospectively recruited at the High-Risk Maternal Neonatal Intensive Care Center, were collected between February 2020 and March 2021. This study included 63 patients with cervical insufficiency receiving cerclage and 47 control participants. Endo- and exocervical swabs and fluids were collected simultaneously. Shotgun metagenomic sequencing for the microbiome and the measurement of 34 immune-checkpoint proteins and inflammatory cytokines were performed.ResultsFirst, we demonstrated that immune-checkpoint proteins, the key immune-regulatory molecules, could be measured in endocervical and exocervical samples. Secondly, we identified significantly different microenvironments in cervical insufficiency and preterm birth, with precise cervical locations, to provide information about practically useful cervical locations in clinical settings. Finally, the presence of Moraxella osloensis (odds ratio = 14.785; P = 0.037) and chemokine CC motif ligand 2 levels higher than 73 pg/mL (odds ratio = 40.049; P = 0.005) in endocervical samples were associated with preterm birth. Combining M. osloensis and chemokine CC motif ligand 2 yielded excellent performance for predicting preterm birth (area under the receiver operating characteristic curve = 0.846, 95% confidence interval = 0.733-0.925).ConclusionMultiple relationships between microbiomes, immune-checkpoint proteins, and inflammatory cytokines in the cervical microenvironment were identified. We focus on these factors to aid in the comprehensive understanding and therapeutic modulation of local microbial and immunologic compositions for the management of cervical insufficiency and preterm birth

Circadian clock control of the cellular response to DNA damage

Mammalian cells possess a cell-autonomous molecular clock which controls the timing of many biochemical reactions and hence the cellular response to environmental stimuli including genotoxic stress. The clock consists of an autoregulatory transcription-translation feedback loop made up of four genes/proteins, BMal1, Clock, Cryptochrome, and Period. The circadian clock has an intrinsic period of about 24 hours, and it dictates the rates of many biochemical reactions as a function of the time of the day. Recently, it has become apparent that the circadian clock plays an important role in determining the strengths of cellular responses to DNA damage including repair, checkpoints, and apoptosis. These new insights are expected to guide development of novel mechanism-based chemotherapeutic regimens