Discovery of HDL Subspecies and Investigation of Their Associations With Insulin Sensitivity and Early Carotid Atherosclerosis

Recent findings from genome-wide association studies and pharmaceutical trials of CETP inhibitors suggest that HDL cholesterol might not fully capture the anti-atherogenic functions of HDL. The protein component of HDL might be more informative in explaining HDL functions because proteins have characteristics that can modify the biological properties of HDL. In Chapter 1, I examined whether some proteins located in the HDL size or density range by proteomics studies were present in distinct apoA-I HDL subspecies that could be identified and quantified by a novel sandwich ELISA. Known HDL subspecies containing apoA-II, apoC-III and apoE comprised 70%, 6% and 10%, respectively, and found that novel HDL subspecies containing apoC-I, apoJ, alpha-1 antitrypsin, plasminogen, and apoC-II comprised 14%, 7%, 5%, 3% and 1%, respectively, of the total apoA-I in HDL. HDL that contains apoC-III has been associated with a higher prevalence of obesity and an elevated risk of CHD, opposite to what has been seen for HDL that does not contain apoC-III. To further our knowledge on apoC-III-based HDL subspecies, I investigated their associations with insulin sensitivity measured by oral glucose tolerance test (OGTT) in Chapter 2 and early stages of carotid atherosclerosis measured as carotid intima-media thickness (cIMT) in Chapter 3. Using the novel sandwich ELISA established in Chapter 1, I measured the concentrations of apoA-I in HDL with and without apoC-III in the European multi-center “Relationship between Insulin Sensitivity and Cardiovascular disease” (RISC) study. ApoA-I in HDL with and without apoC-III demonstrated significantly opposite associations with both 3-year change in insulin sensitivity and cIMT at baseline. ApoA-I with apoC-III was associated with a decrease in insulin sensitivity and higher cIMT, whereas the concentration of apoA-I without apoC-III was associated with an increase in insulin sensitivity and lower cIMT. The results for apoC-III itself in HDL was consistent with apoA-I with apoC-III. Total apoA-I was null in both cases. These findings suggest that the presence of apoC-III on HDL diminishes and impairs otherwise beneficial effects of HDL on glucose regulation and atheroprotection, and support the potential of HDL apoC-III as a promising target for diabetes and atherosclerosis prevention and treatment

In Vivo and In Vitro Studies Suggest a Possible Involvement of HPV Infection in the Early Stage of Breast Carcinogenesis via APOBEC3B Induction

High prevalence of infection with high-risk human papilloma virus (HPV) ranging from 25 to 100% (average 31%) was observed in breast cancer (BC) patients in Singapore using novel DNA chip technology. Early stage of BC demonstrated higher HPV positivity, and BC positive for estrogen receptor (ER) showed significantly higher HPV infection rate. This unique association of HPV with BC in vivo prompted us to investigate a possible involvement of HPV in early stages of breast carcinogenesis. Using normal breast epithelial cells stably transfected with HPV-18, we showed apparent upregulation of mRNA for the cytidine deaminase, APOBEC3B (A3B) which is reported to be a source of mutations in BC. HPV-induced A3B overexpression caused significant γH2AX focus formation, and DNA breaks which were cancelled by shRNA to HPV18 E6, E7 and A3B. These results strongly suggest an active involvement of HPV in the early stage of BC carcinogenesis via A3B induction

Terahertz emission from the intrinsic Josephson junctions of high-symmetry thermally-managed Bi2Sr2CaCu2O8+δ microstrip antennas

We show for high-symmetry disk, square, or equilateral triangular thin microstrip antennas of any composition respectively obeying C∞v, C4v, and C3v point group symmetries, that the transverse magnetic electromagnetic cavity mode wave functions are restricted in form to those that are one-dimensional representations of those point groups. Plots of the common nodal points of the ten lowest-energy non-radiating two-dimensional representations of each of these three symmetries are presented. For comparison with symmetry-broken disk intrinsic Josephson junction microstrip antennas constructed from the highly anisotropic layered superconductor Bi2 Sr2 CaCu2 O8+δ (BSCCO), we present plots of the ten lowest frequency orthonormal wave functions and of their emission power angular distributions. These results are compared with previous results for square and equilateral triangular thin microstrip antennas

Setting sodium targets for pre-packaged foods in China — an exploratory study

IntroductionSetting sodium targets for pre-packaged food has been a priority strategy for reducing population sodium intake. This study aims to explore the attitudes and considerations of researchers and key stakeholders toward implementing such policy in China.MethodsAn exploratory study comprising a survey and a focus group discussion was conducted among 27 purposively selected participants including 12 researchers, 5 consumers, 4 administrators, 3 industry association representatives and 3 food producers. The survey/discussion covered the key questions considered when developing/promoting sodium targets. Free-text responses were manually classified and summarized using thematic analysis.ResultsTwo-thirds of the participants supported target-setting policy. Researchers and administrators were most supportive, and food producers and associations were least supportive. Adapted WHO food categorization framework was well accepted to underpin target-setting to ensure international comparability and applicability for Chinese products. Maximum values were the most agreed target type. The WHO benchmarks were thought to be too ambitious to be feasible given the current food supply in China but can be regarded as long-term goals. Initially, a reduction of sodium content by 20% was mostly accepted to guide the development of maximum targets. Other recommendations included implementing a comprehensive strategy, strengthening research, engaging social resources, establishing a systematic monitoring/incentive system, maintaining a fair competitive environment, and developing a supportive information system. Target-setting policy was acceptable by most stakeholders and should be implemented alongside strategies to reduce discretionary salt use.DiscussionOur findings provide detailed guidance for the Chinese government when developing a target-setting strategy. The methods and results of this study also provide meaningful references for other countries to set sodium targets for pre-packaged foods and implement other salt reduction strategies simultaneously

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Does Genetic Predisposition Contribute to the Exacerbation of COVID-19 Symptoms in Individuals with Comorbidities and Explain the Huge Mortality Disparity between the East and the West?

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin–angiotensin–aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19

Validation of salivary cortisol and testosterone assays in chimpanzees by liquid chromatography-tandem mass spectrometry

Owing to its high temporal sensitivity, saliva has distinct advantages for measuring steroids, compared with other noninvasive samples such as urine and feces. Here, we report the validity of assaying salivary cortisol (C) and testosterone (T) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in captive male chimpanzees, Pan troglodytes. For both the C and T concentrations, we found positive relationships between saliva and plasma. The concentrations of C and T in saliva showed clear patterns of diurnal fluctuation, whereas those in urine and feces did not. These results suggest that the salivary steroid concentrations can be regarded as good indicators of circulating steroid levels. We also developed and validated an efficient method for collecting saliva samples from cotton rope. Although rope includes inherent steroid-like compounds and may affect the accuracy of steroid measurements, our rope-washing procedures effectively removed intrinsic steroidal materials. There was a significant association between the C and T concentrations measured from saliva collected from rope licked by the chimpanzees and those measured from saliva collected directly from the mouth. Salivary T values estimated by LC/MS-MS were similar to those measured by radioimmunoassay. The results indicate the usefulness of saliva as a noninvasive steroid measure and that steroids in the saliva of chimpanzees can be accurately measured by LC-MS/MS. Am. J. Primatol. 71:696–706, 2009

HDL Containing Apolipoprotein C-III is Associated with Insulin Sensitivity:a Multi-Center Cohort Study

CONTEXT: High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE: We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES: Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS: The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment

High density lipoprotein with apolipoprotein C-III is associated with carotid intima-media thickness among generally healthy individuals

Background and aims: About 6–7% of high density lipoprotein (HDL) has a protein called apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT). Methods: We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Results: HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend<0.01). Conclusions: HDL apoC-III is a promising target for atherosclerosis prevention and treatment

Correlation of A3B expression level and HPV infection in BC patients.

<p>Total RNA from BC patients were obtained from NUHS TR. Samples were subjected to quantitative RT-PCR (qRT-PCR). The data of A3B (a) and A3G (b) were shown after normalization by GAPDH mRNA level. The number at the bottom of graph indicates the number of patients. Patient 1–11 are HPV-negative, patient 12–23 are HPV-positive.</p