Salt Substitute as a Population-level Intervention to Reduce the Risk of Cardiovascular Diseases

Both high sodium intake and low potassium intake are associated with high blood pressure and risk of cardiovascular diseases. Potassium-enriched sodium-reduced salt substitutes, in which a certain amount of sodium chloride is replaced by potassium chloride, can lower blood pressure. This is achieved both through reducing sodium intake and increasing potassium intake and may be a cost-effective, scalable, and sustainable approach to reducing blood pressure and cardiovascular diseases at the population level. This thesis develops the knowledge base required to inform the scale-up of salt substitutes as a population salt reduction strategy. The thesis comprises five interrelated but independent studies. First, a literature review summarised evidence about salt reduction and the potential of salt substitution. Second, a systematic review and meta-analysis assessed the effects of salt substitutes on blood pressure and clinical outcomes. Third, a secondary analysis quantified the use of a salt substitute among participants in a large trial. Forth, an environmental scan described the availability, formulation, labelling and price of salt substitutes globally. Lastly, a qualitative study identified facilitators and barriers associated with the scale-up of the salt substitute. The systematic review and meta-analysis found that salt substitutes lowered blood pressure across diverse population subgroups and geographies and had clear protective effects on total mortality, fatal and nonfatal cardiovascular events. The clinical outcome data were derived mostly from one large-scale pragmatic trial, the Salt substitute and Stroke Study (SSaSS), where the effects were achieved by replacing three-quarters of regular salt with reduced-sodium potassium-enriched salt. This level of replacement would be a plausible target for many other jurisdictions. But we found that salt substitutes were available in only 47 countries, of which 60% were high-income countries. The compositions and prices of identified salt substitutes varied substantially, with prices consistently above those of regular salt. Interviews with key informants showed that the taste and price of salt substitutes compared to regular salt, the awareness of the health benefits of salt substitutes, and safety concerns in individuals vulnerable to hyperkalaemia were important factors influencing how widely salt substitutes would be adopted. In conclusion, the thesis findings support the notion that salt substitutes could be scaled as an important population-level strategy to reduce dietary sodium intake, increase potassium intake, reduce blood pressure, and further prevent major cardiovascular and cerebrovascular events. However, the thesis findings highlight multiple potential challenges and the need to identify tailored implementation strategies that will address different barriers in various jurisdictions

Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus

We aimed to elucidate the cell types, tissues, and pathways influenced by common variants in systemic lupus erythematosus (SLE). We applied a nonparameter enrichment statistical approach, termed SNPsea, in 181 single nucleotide polymorphisms (SNPs) that have been identified to be associated with the risk of SLE through genome-wide association studies (GWAS) in Eastern Asian and Caucasian populations, to manipulate the critical cell types, tissues, and pathways. In the two most significant cells’ findings (B lymphocytes and CD14+ monocytes), we subjected the GWAS association evidence in the Han Chinese population to an enrichment test of expression quantitative trait locus (QTL) sites and DNase I hypersensitivity, respectively. In both Eastern Asian and Caucasian populations, we observed that the expression level of SLE GWAS implicated genes was significantly elevated in xeroderma pigentosum B cells (P ≤ 1.00 × 10−6), CD14+ monocytes (P ≤ 2.74 × 10−4) and CD19+ B cells (P ≤ 2.00 × 10−6), and plasmacytoid dendritic cells (pDCs) (P ≤ 9.00 × 10−6). We revealed that the SLE GWAS-associated variants were more likely to reside in expression QTL in B lymphocytes (q1/q0 = 2.15, P = 1.23 × 10−44) and DNase I hypersensitivity sites (DHSs) in CD14+ monocytes (q1/q0 = 1.41, P = 0.08). We observed the common variants affected the risk of SLE mostly through by regulating multiple immune system processes and immune response signaling. This study sheds light on several immune cells and responses, as well as the regulatory effect of common variants in the pathogenesis of SLE

Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo

Raw Single-Wall Carbon Nanotubes Induce Oxidative Stress and Activate MAPKs, AP-1, NF-κB, and Akt in Normal and Malignant Human Mesothelial Cells

Background Single-wall carbon nanotubes (SWCNTs), with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells. Objective Exposure to asbestos is the primary cause of malignant mesothelioma in 80–90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT. Methods In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1), stimulation of extracellular signal-regulated kinase (ERKs), Jun N-terminal kinases (JNKs), protein p38, and activation of activator protein-1 (AP-1), nuclear factor κB (NF-κB), and protein serine-threonine kinase (Akt). Results Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-κB, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure. Conclusions The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies

A dimeric Smac/ diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo

Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac

Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

Abstract Background Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status. Methods We utilized the genome-wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility. Results We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3. Conclusions This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis

Characterization of viral infections in children with influenza-like-illness during December 2018–January 2019

IntroductionRespiratory viral infection (RVI) is of very concern after the outbreak of COVID-19, especially in pediatric departments. Learning pathogen spectrum of RVI in children previous the epidemic of COVID-19 could provide another perspective for understanding RVI under current situation and help to prepare for the post COVID-19 infection control.MethodsA nucleic acid sequence-based amplification (NASBA) assay, with 19 pairs of primers targeting various respiratory viruses, was used for multi-pathogen screening of viral infections in children presenting influenza-like illness (ILI) symptoms. Children with ILI at the outpatient department of Beijing Tsinghua Changgung Hospital during the influenza epidemic from 12/2018 to 01/2019 were included. Throat swabs were obtained for both the influenza rapid diagnostic test (IRDT) based on the colloidal gold immunochromatographic assay and the NASBA assay, targeting various respiratory viruses with an integrated chip technology.Results and discussionOf 519 patients, 430 (82.9%) were positive in the NASBA assay. The predominant viral pathogens were influenza A H1N1 pdm1/2009 (pH1N1) (48.4%) and influenza A (H3N2) (18.1%), followed by human metapneumovirus (hMPV) (8.8%) and respiratory syncytial virus (RSV) (6.1%). Of the 320 cases identified with influenza A by NASBA, only 128 (40.0%) were positive in the IRDT. The IRDT missed pH1N1 significantly more frequently than A (H3N2) (P&lt;0.01). Influenza A pH1N1 and A (H3N2) were the major pathogens in &lt;6 years and 6-15 years old individuals respectively (P&lt;0.05). In summary, influenza viruses were the major pathogens in children with ILI during the 2018-2019 winter influenza epidemic, while hMPV and RSV were non-negligible. The coexistence of multiple pathogen leading to respiratory infections is the normalcy in winter ILI cases

Mapping the Distribution of Water Resource Security in the Beijing-Tianjin-Hebei Region at the County Level under a Changing Context

The Beijing-Tianjin-Hebei (Jingjinji) region is the most densely populated region in China and suffers from severe water resource shortage, with considerable water-related issues emerging under a changing context such as construction of water diversion projects (WDP), regional synergistic development, and climate change. To this end, this paper develops a framework to examine the water resource security for 200 counties in the Jingjinji region under these changes. Thus, county-level water resource security is assessed in terms of the long-term annual mean and selected typical years (i.e., dry, normal, and wet years), with and without the WDP, and under the current and projected future (i.e., regional synergistic development and climate change). The outcomes of such scenarios are assessed based on two water-crowding indicators, two use-to-availability indicators, and one composite indicator. Results indicate first that the water resources are distributed unevenly, relatively more abundant in the northeastern counties and extremely limited in the other counties. The water resources are very limited at the regional level, with the water availability per capita and per unit gross domestic product (GDP) being only 279/290 m3 and 46/18 m3 in the current and projected future scenarios, respectively, even when considering the WDP. Second, the population carrying capacity is currently the dominant influence, while economic development will be the controlling factor in the future for most middle and southern counties. This suggests that significant improvement in water-saving technologies, vigorous replacement of industries from high to low water consumption, as well as water from other supplies for large-scale applications are greatly needed. Third, the research identifies those counties most at risk to water scarcity and shows that most of them can be greatly relieved after supplementation by the planned WDP. Finally, more attention should be paid to the southern counties because their water resources are not only limited but also much more sensitive and vulnerable to climate change. This work should benefit water resource management and allocation decisions in the Jingjinji region, and the proposed assessment framework can be applied to other similar problems.This study is supported by the National Key Research and Development Program of China (2016YFC0401401) and the National Natural Science Foundation of China (51609256, 51609122, 51522907, 51739011, and 51569026). Partial support is also from the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (2017QNRC001