Association of early life adversity with cardiovascular disease and its potential mechanisms: a narrative review

Strong epidemiological evidence has shown that early life adversity (ELA) has a profound negative impact on health in adulthood, including an increased risk of cardiovascular disease, the leading cause of death worldwide. Here, we review cohort studies on the effects of ELA on cardiovascular outcomes and the possible underlying mechanisms. In addition, we summarize relevant studies in rodent models of ELA. This review reveals that the prevalence of ELA varies between regions, time periods, and sexes. ELA increases cardiovascular health risk behaviors, susceptibility to mental illnesses, and neuroendocrine and immune system dysfunction in humans. Rodent models of ELA have been developed and show similar cardiovascular outcomes to those in humans but cannot fully replicate all ELA subtypes. Therefore, combining cohort and rodent studies to further investigate the mechanisms underlying the association between ELA and cardiovascular diseases may be a feasible future research strategy

High-Resolution 3D Heart Models of Cardiomyocyte Subpopulations in Cleared Murine Heart

Biological tissues are naturally three-dimensional (3D) opaque structures, which poses a major challenge for the deep imaging of spatial distribution and localization of specific cell types in organs in biomedical research. Here we present a 3D heart imaging reconstruction approach by combining an improved heart tissue-clearing technique with high-resolution light-sheet fluorescence microscopy (LSFM). We have conducted a three-dimensional and multi-scale volumetric imaging of the ultra-thin planes of murine hearts for up to 2,000 images per heart in x-, y-, and z three directions. High-resolution 3D volume heart models were constructed in real-time by the Zeiss Zen program. By using such an approach, we investigated detailed three-dimensional spatial distributions of two specific cardiomyocyte populations including HCN4 expressing pacemaker cells and Pnmt(+) cell-derived cardiomyocytes by using reporter mouse lines Hcn4(DreER/tdTomato) and Pnmt(Cre/ChR2−tdTomato). HCN4 is distributed throughout right atrial nodal regions (i.e., sinoatrial and atrioventricular nodes) and the superior-inferior vena cava axis, while Pnmt(+) cell-derived cardiomyocytes show distinct ventral, left heart, and dorsal side distribution pattern. Our further electrophysiological analysis indicates that Pnmt + cell-derived cardiomyocytes rich left ventricular (LV) base is more susceptible to ventricular arrhythmia under adrenergic stress than left ventricular apex or right ventricle regions. Thus, our 3D heart imaging reconstruction approach provides a new solution for studying the geometrical, topological, and physiological characteristics of specific cell types in organs

A clinical prediction model for hospitalized COPD exacerbations based on “treatable traits”

10.2147/COPD.S194922International Journal of COPD14719-72

Single-cell RNA sequencing of murine hearts for studying the development of the cardiac conduction system

The development of the cardiac conduction system (CCS) is essential for correct heart function. However, critical details on the cell types populating the CCS in the mammalian heart during the development remain to be resolved. Using single-cell RNA sequencing, we generated a large dataset of transcriptomes of ~0.5 million individual cells isolated from murine hearts at six successive developmental corresponding to the early, middle and late stages of heart development. The dataset provides a powerful library for studying the development of the heart's CCS and other cardiac components. Our initial analysis identified distinct cell types between 20 to 26 cell types across different stages, of which ten are involved in forming the CCS. Our dataset allows researchers to reuse the datasets for data mining and a wide range of analyses. Collectively, our data add valuable transcriptomic resources for further study of cardiac development, such as gene expression, transcriptional regulation and functional gene activity in developing hearts, particularly the CCS

Dbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart

The heterogeneity of functional cardiomyocytes arises during heart development, which is essential to the complex and highly coordinated cardiac physiological function. Yet the biological and physiological identities and the origin of the specialized cardiomyocyte populations have not been fully comprehended. Here we report a previously unrecognised population of cardiomyocytes expressing Dbhgene encoding dopamine beta-hydroxylase in murine heart. We determined how these myocytes are distributed across the heart by utilising advanced single-cell and spatial transcriptomic analyses, genetic fate mapping and molecular imaging with computational reconstruction. We demonstrated that they form the key functional components of the cardiac conduction system by using optogenetic electrophysiology and conditional cardiomyocyte Dbh gene deletion models. We revealed their close relationship with sympathetic innervation during cardiac conduction system formation. Our study thus provides new insights into the development and heterogeneity of the mammalian cardiac conduction system by revealing a new cardiomyocyte population with potential catecholaminergic endocrine function

Cell Membrane Is Impaired, Accompanied by Enhanced Type III Secretion System Expression in Yersinia pestis Deficient in RovA Regulator

BACKGROUND: In the enteropathogenic Yersinia species, RovA regulates the expression of invasin, which is important for enteropathogenic pathogenesis but is inactivated in Yersinia pestis. Investigation of the RovA regulon in Y. pestis at 26 °C has revealed that RovA is a global regulator that contributes to virulence in part by the direct regulation of psaEFABC. However, the regulatory roles of RovA in Y. pestis at 37 °C, which allows most virulence factors in mammalian hosts to be expressed, are still poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: The transcriptional profile of an in-frame rovA mutant of Y. pestis biovar Microtus strain 201 was analyzed under type III secretion system (T3SS) induction conditions using microarray techniques, and it was revealed that many cell-envelope and transport/binding proteins were differentially expressed in the ΔrovA mutant. Most noticeably, many of the T3SS genes, including operons encoding the translocon, needle and Yop (Yersinia outer protein) effectors, were significantly up-regulated. Analysis of Yop proteins confirmed that YopE and YopJ were also expressed in greater amounts in the mutant. However, electrophoresis mobility shift assay results demonstrated that the His-RovA protein could not bind to the promoter sequences of the T3SS genes, suggesting that an indirect regulatory mechanism is involved. Transmission electron microscopy analysis indicated that there are small loose electron dense particle-like structures that surround the outer membrane of the mutant cells. The bacterial membrane permeability to CFSE (carboxyfluorescein diacetate succinimidyl ester) was significantly decreased in the ΔrovA mutant compared to the wild-type strain. Taken together, these results revealed the improper construction and dysfunction of the membrane in the ΔrovA mutant. CONCLUSIONS/SIGNIFICANCE: We demonstrated that the RovA regulator plays critical roles in the construction and functioning of the bacterial membrane, which sheds considerable light on the regulatory functions of RovA in antibiotic resistance and environmental adaptation. The expression of T3SS was upregulated in the ΔrovA mutant through an indirect regulatory mechanism, which is possibly related to the altered membrane construction in the mutant

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Blockchain for RegTech: streamlining know your customer (KYC) pipelines

Financial institutions have to go through regulatory compliance processes when providing services to customers. Among these processes, Know Your Customer (KYC) and Customer Due Diligence (CDD) processes are essential for compliance of Anti-Money Laundering (AML) schemes in order to establish the legitimacy of a customer’s identity before conducting businesses with them. However, there are many problems that currently exist with traditional regulatory compliance systems including high costs to organisations, lengthy and repetitive processes that lead to bad customer experience, duplication of records that are stored, as well as the bundling problem that compromises the privacy of clients’ information. As technology continues to rapidly advance, the delivery of financial services have become increasingly digital. With the growing popularity of blockchain technology, different ecosystems such as Decentralised Finance and the Metaverse, which are built on this technology, have gained large traction. With Decentralised Finance being developed to replace traditional financial services and transactions of virtual land being conducted on the Metaverse, these ecosystems often involve large amounts of money and require regulatory compliance checks. This calls for a solution that can interoperate effectively with these emerging technologies. To overcome the above issues and keep up with the rise in the technology, we present a system using permissioned blockchain technology, which makes use of public and private smart contracts, to shorten these processes and give clients more authority over the data that they are required to present to different stakeholders during KYC and CDD processes.Bachelor of BusinessBachelor of Engineering (Computer Science

Empirical comparison of structural credit risk models for Bankruptcy Prediction of Financial Institutions in US.

In this paper, we compare and analyse the expected default probabilities (EDPs) derived from the six structural models: Merton model, Leland and Toft model, Longstaff and Schwartz model, Briys de Varenne model and the recent Ericsson and Reneby model. In our comparison, we cover the aspects of EDP ranking, average EDP differences, relationship of EDP with key financial ratios and relative predictive power of each model compared with the other models. We found that Merton model tends to overestimate the default probabilities of the 532 non-bankrupt financial institutions used in our study. Its average EDP is found to be at least 16.3% higher than the other models. Also, it is discovered that financial ratios do have a strong explanatory power for the EDPs calculated by the various models. Furthermore, our analysis cover

Discrimination in Singapore job advertisements.

Singapore is a culturally rich society. At first glance, diverse racial and nationality groups in this city state seem harmonious. On closer examination, we realise that job market discrimination exists. While there have been many comments and debates about discrimination in the job market, few studies have been done to probe deeper into whether there is an existence of discrimination in Singapore labour market. The aim of this paper is to look at employers’ hiring patterns in advertisements which could imply discrimination. The job-advertisement methodology was chosen because employers in Singapore are not strictly governed by anti-discrimination legislation, Instead, they are only required to adhere to the non-mandatory Tripartite Guidelines, whose basic purpose is to ensure non-discriminatory job advertisements. Thus, employers are not encouraged to specify for certain requirements like gender, race or age. Without such legislations, the Tripartite Guidelines allow employers to ask for certain things such as photographs, language proficiency or state preferences for Singaporean nationality. Given such freely usage of requirements in job advertisements, the adoption of the job-advertisement approach in this study will enable us to detect discrimination at the initial stage of the hiring process. Job advertisements from an online job portal were collected over a span of one week as our sample. In the first model, we assessed the association between specification for both Mandarin and photograph in job advertisements. The intuition behind the first model is that when employers ask for Mandarin, it may be due to business needs where employees are required to liaise with Chinese clientele, or it may simply be employers’ desire to recruit Chinese candidates. In the latter case, there should be evidence that employers are more likely to ask for photograph when they ask for Mandarin to filter out non-Chinese candidates. Our results prove that there is relationship between Mandarin and photograph specification in job advertisements even after taking into account confounders. In the second model, we looked at which job industries have less preference for Singaporeans. The rationale behind this model is to determine whether the non-specification for Singaporeans in the job advertisements is due to the shortage of local labour or lack of foreign talents, or simply because employers do not favour Singaporeans.Bachelor of Art