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The interaction between genipin and a model protein bovine serum albumin (BSA), with and without the addition of acetic acid, has been studied experimentally and by modelling. The number of amino groups available to react was determined to be 5.6 % of the total number of amino acid building blocks on BSA. Fluorescence intensity was used to record the progress of the reaction over the 24 h, while the modelling study focused on capturing the kinetic profiles of the reaction. The experiments revealed a slow start to the BSA and genipin interaction, that subsequently accelerated in an S-shaped curve which the modelling study linked with the existence of the feedback cycle for both reactive amino groups and genipin. At BSA concentrations ≥30 mg/mL the reaction was accelerated in the presence of acid, while below 30 mg/mL the acidified conditions delayed the onset of the reaction. Contrary to the reaction mechanisms previously proposed, a degree of breakdown of the fluorescent links in the products formed was denoted both experimentally and in a modelling study. This indicated the reversibility of the processes forming fluorescent product/s and suggested feasibility of the successful release of the protein following prospective encapsulation within the genipin-crosslinked hydrogel structure.

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It is well-known that aqueous dispersions of phospholipids spontaneously assemble into bilayer structures. These structures have numerous applications across chemistry and materials science and form the fundamental structural unit of the biological membrane. The particular environment of the lipid bilayer, with a water-poor low dielectric core surrounded by a more polar and better hydrated interfacial region, gives the membrane particular biophysical and physicochemical properties and presents a unique environment for chemical reactions to occur. Many different types of molecule spanning a range of sizes, from dissolved gases through small organics to proteins, are able to interact with membranes and promote chemical changes to lipids that subsequently affect the physicochemical properties of the bilayer. This Review describes the chemical reactivity exhibited by lipids in their membrane form, with an emphasis on conditions where the lipids are well hydrated in the form of bilayers. Key topics include the following: lytic reactions of glyceryl esters, including hydrolysis, aminolysis, and transesterification; oxidation reactions of alkenes in unsaturated fatty acids and sterols, including autoxidation and oxidation by singlet oxygen; reactivity of headgroups, particularly with reactive carbonyl species; and E/Z isomerization of alkenes. The consequences of reactivity for biological activity and biophysical properties are also discussed.

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PURPOSE: The diagnosis of obstructive sleep apnea (OSA) relies on time-consuming and complicated procedures which are not always readily available and may delay diagnosis. With the widespread use of artificial intelligence, we presumed that the combination of simple clinical information and imaging recognition based on facial photos may be a useful tool to screen for OSA. METHODS: We recruited consecutive subjects suspected of OSA who had received sleep examination and photographing. Sixty-eight points from 2-dimensional facial photos were labelled by automated identification. An optimized model with facial features and basic clinical information was established and tenfold cross-validation was performed. Area under the receiver operating characteristic curve (AUC) indicated the model's performance using sleep monitoring as the reference standard. RESULTS: A total of 653 subjects (77.2% males, 55.3% OSA) were analyzed. CATBOOST was the most suitable algorithm for OSA classification with a sensitivity, specificity, accuracy, and AUC of 0.75, 0.66, 0.71, and 0.76 respectively (P < 0.05), which was better than STOP-Bang questionnaire, NoSAS scores, and Epworth scale. Witnessed apnea by sleep partner was the most powerful variable, followed by body mass index, neck circumference, facial parameters, and hypertension. The model's performance became more robust with a sensitivity of 0.94, for patients with frequent supine sleep apnea. CONCLUSION: The findings suggest that craniofacial features extracted from 2-dimensional frontal photos, especially in the mandibular segment, have the potential to become predictors of OSA in the Chinese population. Machine learning-derived automatic recognition may facilitate the self-help screening for OSA in a quick, radiation-free, and repeatable manner.

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BACKGROUND: SARS-CoV-2 invades human cells and leads to COVID-19 by direct associating with angiotensin converting enzyme 2 (ACE2) receptors, the level of which may be increased by treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). This meta-analysis aimed to explore the impact of ACEI/ARB treatment on the clinical outcomes of patients with COVID-19 infections among population in the East-Asia region. METHODS: We collected clinical data published from January 2000 to May 2022 in the English databases including PubMed, Embase, and the Cochrane Library. Two reviewers independently screened and identified studies that met the prespecified criteria. Review Manager 5.3 software was used to perform the meta-analysis. RESULTS: A total of 28 articles were included in this analysis. The results showed that patients who were prescribed with ACEI/ARB had a shorter duration of hospital stay [MD = -2.37, 95%CI (-3.59, -1.14), P = 0.000 2] and a lower mortality rate [OR = 0.61, 95% CI (0.52, 0.70), P<0.000 01] than patients who were not on ACEI/ARB. Furthermore, there was no statistically significant difference in disease severity [OR = 0.99, 95% CI (0.83, 1.17), P = 0.90] between individuals receiving ACEI/ARB or not. CONCLUSIONS: This meta-analysis suggested that the use of ACEI/ARB was not associated with adverse clinical outcomes in East-Asian Covid-19 patients and a reduced mortality and shorter duration of hospital stay among East-Asian population (especially for female subjects) was found. Thus, ACEI/ARB should be continued in patients infected by Covid-19.

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Amyloid formation continues to be a widely studied area because of its association with numerous diseases, such as Alzheimer's and Parkinson's diseases. Despite a large body of work on protein aggregation and fibril formation, there are still significant gaps in our understanding of the factors that differentiate toxic amyloid formation in vivo from alternative misfolding pathways. In addition to proteins, amyloid fibrils are often associated in their cellular context with several types of molecule, including carbohydrates, polyanions, and lipids. This review focuses in particular on evidence for the presence of lipids in amyloid fibrils and the routes by which those lipids may become incorporated. Chemical analyses of fibril composition, combined with studies to probe the lipid distribution around fibrils, provide evidence that in some cases, lipids have a strong association with fibrils. In addition, amyloid fibrils formed in the presence of lipids have distinct morphologies and material properties. It is argued that lipids are an integral part of many amyloid deposits in vivo, where their presence has the potential to influence the nucleation, morphology, and mechanical properties of fibrils. The role of lipids in these structures is therefore worthy of further study.

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The protein α-synuclein, a key player in Parkinson's disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible "prion-like" propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a "prion-like" aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and "prion-like" aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.

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BACKGROUND: Early detection of left ventricular (LV) subclinical dysfunction is clinically relevant before developing irreversible impairment in obstructive sleep apnea (OSA) patients. Mitral annulus plane systolic excursion (MAPSE) is a fast tool for OSA due to high prevalent obesity; another quick but more comprehensive tool is LV global longitudinal stain (GLS) based on automated function imaging (AFI). We therefore aimed to compare the feasibility and reproducibility of AFI to MAPSE in OSA patients, as a good model in whom obesity is common. METHODS: A comprehensive echocardiographic examination was done in 186 consecutive patients having polysomnography for suspected OSA. MAPSE was measured by using M-mode to calculate excursion of mitral annulus. GLS was derived by offline analysis of three long-axis views that semi-automatically detects LV endocardial boundary, which is adjusted manually as necessary with AFI measurement. Variability of AFI and MAPSE were compared among the different subgroups. RESULTS: Despite a relatively high obesity rate (42.9%), the feasibility of AFI was 94% (175/186) and that of 100% in MAPSE. AFI showed excellent correlation (r = .882) superior to MAPSE (r = .819) between the Expert and Beginner. Intra- and inter- observer variability of AFI and MAPSE in Bland-Altman analysis were 5.5% and 6.5%; 6.2% and 8.8%, respectively. In repeated measurements, AFI showed higher intra-class correlation (ICC = .95) than MAPSE (ICC = .87) (p < 0.05). Furthermore, analysis showed that AFI was feasible even in more obese patients (BMI≥28 kg/m2 ). CONCLUSIONS: Even in obese patients with OSA, AFI-GLS is feasible and more reliable for less expert operators than MAPSE in detecting LV longitudinal dysfunction.

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Background: Obstructive sleep apnoea (OSA) is highly prevalent and significantly associated with major adverse cardiovascular events (MACEs). Continuous positive airway pressure (CPAP) treatment has a protective effect on cardiovascular events in OSA patients. However, whether CPAP therapy significant reduces the risk of recurrent cardiovascular (CV) events in OSA patients with established cardiovascular or cerebrovascular diseases remains disputed. We aim to evaluate the effect of CPAP on recurrent cardiovascular outcomes in moderate to severe OSA patients with previous cardiovascular or cerebrovascular diseases. Methods: We searched the electronic databases (PubMed, EMBASE, and Cochrane library) from their inception to August, 2021. Only randomized controlled trials (RCTs) that described the association of CPAP treatment in patients with cardiovascular or cerebrovascular disease and OSA were included in our analysis. The primary outcome of interest was major adverse cardiac or cerebral events (MACCEs), a composite endpoint of myocardial infraction (MI), non-fatal stroke, CV mortality; secondary outcomes included all-caused death, cardiac mortality, myocardial infraction, atrial fibrillation, heart failure, repeat revascularization, angina, stroke, and transient ischemic attack. In addition, subgroup analyses based on CPAP adherence were performed. Result: Six RCTs of 4493 participants were included in the analysis. Compared with usual care, CPAP therapy did not significantly reduce the risk of recurrent MACCEs odds ratio (OR) 0.94, 95% confidence interval (CI) 0.79-1.12, p = 0.5, CV mortality (OR 0.83, 95% CI [0.54-1.26], p = 0.37), myocardial infarction (OR 1.09, 95% CI [0.8-1.47], p = 0.6), heart failure (OR 0.94, 95% CI [0.66-1.33], p = 0.71), stroke (OR 0.9, 95% CI [0.67-1.23], p = 0.52), or all-cause death (OR 0.86, 95% CI [0.63-1.16], p = 0.32). However, the subgroup analyses revealed that CPAP can decrease the risk of CV mortality (OR 0.25, 95% CI [0.08-0.77], p = 0.02) and stoke (OR 0.39, 95% CI [0.15-0.97], p = 0.04) in patients who used it more than 4 hours. Conclusions: CPAP therapy was not associated with reduce the risk of MACCEs in OSA patients with a history of chronic cardiovascular disease who utilize CPAP < 4 hours/night, although CPAP appeared to have a positive effect on CV mortality and stroke among those who used CPAP > 4 hours. The correlation between CPAP and the prognosis of OSA patients warrants further study.

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Acyl transfer from lipids to membrane-associated peptides is a well-documented process, leading to the generation of a lipidated peptide and a lysolipid. In this article, we demonstrate that acyl transfer from lysophosphatidylcholines (lysoPCs) to the peptide melittin also occurs, both in micelles of pure lysolipid and in lipid/lysolipid mixtures. In the case of bilayers containing lysolipids, acyl transfer from the lysolipid is marginally favoured over transfer from the lipid. In pure bilayers of saturated lipids, the introduction of even small amounts of lysolipid appears to significantly increase the reactivity towards lipidation.

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BACKGROUND: Limited evidence is available regarding the association between OSA and coronary plaque assessed by using quantitative coronary CT angiography. RESEARCH QUESTION: Are there any associations between OSA severity-related indexes and the presence and burden of coronary plaque? STUDY DESIGN AND METHODS: Cross-sectional data from 692 patients who underwent sleep monitoring and coronary CT angiography were used for this study. Of these patients, 120 (17.3%) underwent polysomnography, and 572 (82.7%) underwent respiratory polygraphy. Multivariable logistic and linear regression analyses were used to investigate the associations of OSA severity-related indexes with the presence, volume, and composition of plaque. RESULTS: In multivariable analyses, patients with moderate to severe OSA were more likely to have coronary plaques (P = .037), and plaques were more likely to contain a noncalcified plaque (NCP) component (P = .032) and a low-density NCP (LD NCP) component (P = .030). Furthermore, the apnea-hypopnea index and oxygen desaturation index as continuous variables were both associated with the presence of plaque, NCP, and LD NCP (all, P < .05). Multivariable linear regression models showed that moderate to severe OSA was associated with NCP volume (ß = 50.328; P = .042) and LD NCP volume (ß = 15.707; P = .011). Moreover, the apnea-hypopnea index (P = .015), oxygen desaturation index (P = .005), and percentage of nighttime with oxygen saturation < 90% (P = .017) were all significant predictors of LD NCP volume. Compared with those with no or mild OSA, patients with severe OSA had a significantly higher total plaque volume (P = .036), NCP volume (P = .036), and LD NCP volume (P = .013). INTERPRETATION: OSA was independently associated with the presence and burden of coronary plaque, which suggests an increased risk of coronary events. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry; No. ChiCTR-ROC-17011027; http://chictr.org.cn.

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BACKGROUND: Early detection of left ventricular (LV) dysfunction is crucial in obstructive sleep apnea (OSA) due to its close relationship with cardiovascular diseases. Global longitudinal strain (GLS) derived from automated function imaging (AFI) can precisely assess global longitudinal function. The aim of this study was to determine if LV GLS was reduced in patients with OSA and a normal LV ejection fraction (LVEF) and to assess any associated determinants. METHODS: Polysomnography (PSG) and echocardiography were done in consecutive patients with suspected OSA and normal LVEF in this prospective study. Patients were divided into two groups according to apnea-hypopnea index (AHI) (Group 1, normal or mild OSA: AHI < 15/h; Group 2, moderate-to-severe OSA: AHI ≥ 15/h). Clinical, PSG, and echocardiographic parameters were compared between the two groups and the associated factors were investigated. RESULTS: Of 425 consecutive patients, 244 were analyzed after exclusions. Patients in Group 2 had significantly worse GLS than those in Group 1 (p < 0.001). The prevalence of GLS reduction (defined as < - 19.7%) was 25% and 76%, respectively (χ2 = 34.19, p < 0.001). Nocturnal lowest pulse oxygen saturation (SpO2), AHI, body mass index (BMI), and gender were associated with GLS reduction (all p < 0.05). Further multivariate analysis showed that the lowest SpO2 (OR: 2.15), gender (OR: 2.45), and BMI (OR: 2.66) remained independent (all p < 0.05), and the lowest SpO2 was the most powerful determinant (χ2 = 33.0, p < 0.001) in forward regression analysis. The intra- and inter-operator variability for AFI and coefficient of repeatability was low even in those with relatively poor images. CONCLUSIONS: In patients with normal LVEF, more severe OSA was associated with a worse GLS. The major determinants were lowest nocturnal SpO2, gender, and obesity, but not AHI. GLS can be rapidly and reliably assessed using AFI.

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α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called "cisternae." In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.

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Secondary prevention therapy reduces death and reinfarction after acute myocardial infarction (AMI), but it is underutilized in clinical practice. Mechanisms for this therapeutic gap are not well established. In this study, we have explored and evaluated the impact of passive continuation compared to active initiation of secondary prevention therapy for AMI during the index hospitalization. For this purpose, we have analyzed 1083 consecutive patients with AMI to a tertiary referral hospital in Hong Kong and assessed discharge prescription rates of secondary prevention therapies (aspirin, beta-blockers, statins, and ACEI/ARBs). Multivariate analysis was used to identify independent predictors of discharge medication, and Kaplan-Meier survival curve was used to evaluate 12-month survival. Overall, prescription rates of aspirin, beta-blocker, statin, and ACEI/ARBs on discharge were 94.8%, 64.5%, 83.5%, and 61.4%, respectively. Multivariate analysis showed that prior use of each therapy was an independent predictor of prescription of the same therapy on discharge: aspirin (odds ratio (OR) = 4.8, 95% CI = 1.9-12.3, P < 0.01), beta-blocker (OR = 2.5, 95% CI = 1.8-3.4, P < 0.01); statin (OR = 8.3, 95% CI = 0.4-15.7, P < 0.01), and ACEI/ARBs (OR = 2.9, 95% CI = 2.0-4.3, P < 0.01). Passive continuation of prior medication was associated with higher 1-year mortality rates than active initiation in treatment-naïve patients (aspirin (13.7% vs. 5.7%), beta-blockers (12.9% vs. 5.6%), and statins (11.0% vs. 4.6%); all P < 0.01). Overall, the use of secondary prevention medication for AMI was suboptimal. Our findings suggested that the practice of passive continuation of prior medication was prevalent and associated with adverse clinical outcomes compared to active initiation of secondary preventive therapies for acute myocardial infarction during the index hospitalization.

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Obstructive sleep apnoea (OSA) is recognised to be a potent risk factor for hypertension, coronary heart disease, strokes and heart failure with a reduced ejection fraction. However, the association between OSA and heart failure with a preserved ejection fraction (HFpEF) is less well recognised. Both conditions are very common globally.It appears that there are many similarities between the pathological effects of OSA and other known aetiologies of HFpEF and its postulated pathophysiology. Intermittent hypoxia induced by OSA leads to widespread stimulation of the sympathetic nervous system, renin-angiotensin-aldosterone system and more importantly a systemic inflammatory state associated with oxidative stress. This is similar to the consequences of hypertension, diabetes, obesity and ageing that are the common precursors to HFpEF. The final common pathway is probably via the development of myocardial fibrosis and structural changes in collagen and myocardial titin that cause myocardial stiffening. Thus, considering the pathophysiology of OSA and HFpEF, OSA is likely to be a significant risk factor for HFpEF and further trials of preventive treatment should be considered.

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