Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

Phenotype-Specific Outcome and Treatment Response in Heart Failure with Preserved Ejection Fraction with Comorbid Hypertension and Diabetes: A 12-Month Multicentered Prospective Cohort Study.

Despite evidence of SGLT2 inhibitors in improving cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF), the heterogenous mechanism and characteristic multimorbidity of HFpEF require a phenotypic approach. Metabolic phenotype, one common HFpEF phenotype, has various presentations and prognoses worldwide. We aimed to identify different phenotypes of hypertensive-diabetic HFpEF, their phenotype-related outcomes, and treatment responses. The primary endpoint was time to the first event of all-cause mortality or hospitalization for heart failure (HHF). Among 233 recruited patients, 24.9% experienced primary outcomes within 12 months. A total of 3.9% was lost to follow-up. Three phenotypes were identified. Phenotype 1 (n = 126) consisted of lean, elderly females with chronic kidney disease, anemia, and concentric hypertrophy. Phenotype 2 (n = 62) included younger males with coronary artery disease. Phenotype 3 (n = 45) comprised of obese elderly with atrial fibrillation. Phenotype 1 and 2 reported higher primary outcomes than phenotype 3 (p = 0.002). Regarding treatment responses, SGLT2 inhibitor was associated with fewer primary endpoints in phenotype 1 (p = 0.003) and 2 (p = 0.001). RAAS inhibitor was associated with fewer all-cause mortality in phenotype 1 (p = 0.003). Beta blocker was associated with fewer all-cause mortality in phenotype 1 (p = 0.024) and fewer HHF in phenotype 2 (p = 0.011). Our pioneering study supports the personalized approach to optimize HFpEF management in hypertensive-diabetic patients.

An Approach to Semantic-Aware Heterogeneous Network Embedding for Recommender Systems.

Recent studies on heterogeneous information network (HIN) embedding-based recommendations have encountered challenges. These challenges are related to the data heterogeneity of the associated unstructured attribute or content (e.g., text-based summary/description) of users and items in the context of HIN. In order to address these challenges, in this article, we propose a novel approach of semantic-aware HIN embedding-based recommendation, called SemHE4Rec. In our proposed SemHE4Rec model, we define two embedding techniques for efficiently learning the representations of both users and items in the context of HIN. These rich-structural user and item representations are then used to facilitate the matrix factorization (MF) process. The first embedding technique is a traditional co-occurrence representation learning (CoRL) approach which aims to learn the co-occurrence of structural features of users and items. These structural features are represented for their interconnections in terms of meta-paths. In order to do that, we adopt the well-known meta-path-based random walk strategy and heterogeneous Skip-gram architecture. The second embedding approach is a semantic-aware representation learning (SRL) method. The SRL embedding technique is designed to focus on capturing the unstructured semantic relations between users and item content for the recommendation task. Finally, all the learned representations of users and items are then jointly combined and optimized while integrating with the extended MF for the recommendation task. Extensive experiments on real-world datasets demonstrate the effectiveness of the proposed SemHE4Rec in comparison with the recent state-of-the-art HIN embedding-based recommendation techniques, and reveal that the joint text-based and co-occurrence-based representation learning can help to improve the recommendation performance.

Fake news detection: A survey of graph neural network methods.

The emergence of various social networks has generated vast volumes of data. Efficient methods for capturing, distinguishing, and filtering real and fake news are becoming increasingly important, especially after the outbreak of the COVID-19 pandemic. This study conducts a multiaspect and systematic review of the current state and challenges of graph neural networks (GNNs) for fake news detection systems and outlines a comprehensive approach to implementing fake news detection systems using GNNs. Furthermore, advanced GNN-based techniques for implementing pragmatic fake news detection systems are discussed from multiple perspectives. First, we introduce the background and overview related to fake news, fake news detection, and GNNs. Second, we provide a GNN taxonomy-based fake news detection taxonomy and review and highlight models in categories. Subsequently, we compare critical ideas, advantages, and disadvantages of the methods in categories. Next, we discuss the possible challenges of fake news detection and GNNs. Finally, we present several open issues in this area and discuss potential directions for future research. We believe that this review can be utilized by systems practitioners and newcomers in surmounting current impediments and navigating future situations by deploying a fake news detection system using GNNs.

Impact of Novel Guidelines on Multifactorial Control and Its Association with Mortality in Adult Patients with Hypertension and Newly Diagnosed Type 2 Diabetes: A 4-Year Prospective Multicenter Study.

METHODS: This prospective, observational study involved adult hypertensive patients with newly diagnosed type 2 diabetes mellitus at two university hospitals in Vietnam. The median time of follow-up was 4 years (August 2016-August 2020). The primary outcome was time to all-cause mortality. RESULTS: 246 patients were included with a mean age of 64.5 ± 10.4. 58.5% were females. 64.2% were categorized as high risk. At baseline, ischemic heart disease, dyslipidemia, and chronic kidney disease (CKD) were present in 54.9%, 67.1%, and 41.1% of patients. Renin-angiotensin-aldosterone inhibitor, metformin, and statin were prescribed in 89.8%, 66.3%, and 67.1%. Among three risk factors, LDL-c control was the hardest to achieve, increasing from 5.7% to 8.5%. In contrast, blood pressure control decreased from 56.1% in 2016 to 30.2% in 2020, when the second wave of COVID-19 hit our nation. While contemporary targets resulted in persistently low simultaneous control at 1.2%, significant improvement was observed with conventional criteria (blood pressure < 140/90 mmHg, HbA1c < 7%, LDL-c < 70 mg/dl), increasing from 14.6% to 33.7%. During follow-up, the mortality rate was 24.4 events per 1000 patient-years, exclusively in patients with early newly diagnosed diabetes. Improving control overtime, not at baseline, was associated with less mortality. Conversely, age >75 years (HR = 2.6) and CKD (HR = 4.9) were associated with increased mortality. CONCLUSION: These findings demonstrated real-world difficulties in managing hypertension and newly diagnosed diabetes, especially with stringent criteria from novel guidelines. High-risk profile, high mortality, and poor simultaneous control warrant more aggressive cardiorenal protection, focusing more on aging CKD patients with early newly diagnosed diabetes.

Clinical Phenotypes and Age-Related Differences in Presentation, Treatment, and Outcome of Heart Failure with Preserved Ejection Fraction: A Vietnamese Multicenter Research.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a rising health problem with heterogeneous presentation and no evidence-based treatment. While Southeast Asia reported the highest mortality and morbidity among Asian population, little is known about the Vietnamese population, including patient characteristics, prescribing pattern and mortality rate. METHODS: We conducted an observational study on 477 patients diagnosed with HFpEF from seven hospitals in Southern Vietnam from January 2019 to December 2019. RESULTS: Mean age was 67.6 (40.9% < 65 years). 62.3% were female. 82.4% were diagnosed within 5 years. Dyspnea, congestion, and hypoperfusion on admission were noted in 63.9%, 48.8%, and 4.6% of the patients, respectively. Median ejection fraction was 63%. Valvular heart disease (VHD) was the leading cause of heart failure (35.9%). 78.6% had at least two comorbidities, mostly hypertension (68.6%). 30.6% of the patients were hospitalized, with a median stay of 7.0 (4.0-10.0) days and inhospital mortality of 4.8%. Older patients (≥65 years) were more likely to be females (OR = 1.52); had multimorbid conditions (OR = 3.14), including hypertension (OR = 4.28), diabetes (OR = 1.73), coronary artery disease (CAD) (OR = 2.50), dyslipidemia (OR = 1.94), and chronic kidney disease (OR = 2.44); and were more frequently prescribed statin (OR = 3.15). Younger individuals (<65 years) were associated with higher mineralocorticoid antagonist uptake (OR = 0.52) and VHD (OR = 0,40). Prescription rate for renin-angiotensin-aldosterone system inhibitor, beta blocker, mineralocorticoid antagonist, and loop diuretic was 72.5%, 59.1%, 43.0%, and 60.6%, respectively. Four phenotypes were identified, including the lean/elderly/multimorbid; congestive/metabolic; CAD-induced; and younger/atrial fibrillation (AF)/VHD. The novel phenotype "younger/AF/VHD" exhibited high symptom burden and poor functional capacity despite being the youngest and least multimorbid. The "lean/elderly/multimorbid" phenotype demonstrated the highest symptom severity and inhospital mortality. CONCLUSIONS: Our research highlights a younger, predominantly female population with high disease burden. The four novelly identified phenotypes provide contemporary and pragmatic insights into a phenotype-guided approach, exclusively targeting the Vietnamese population.

Mono-PEGylates of exenatide in branched and dimeric structures can improve in vivo stability and hypoglycemic bioactivity.

Exenatide, a synthetic version of exendin-4, is a glucagon-like peptide-1 receptor agonist (GLP-1RA) used for treating diabetes, but its relatively short half-life is a major disadvantage. In this study, we attempted residue-specific mono-PEGylation to the middle of the amino acid backbone to extend its in vivo half-life. Exenatide was point-mutated from Lys to Cys at the 12th residue to yield a variant (K12C), and PEG-maleimide of varying molecular weights (MW) (5, 10, 20, 40 kD) was site-specifically conjugated to yield a mono-PEGylate with branched T-shape molecular structure. In another approach, we conjugated a bis-maleimide PEG (10 kD) to the middle of two K12Cs to yield an H-shape homodimer PEGylate In vitro bioactivity assays indicated that: (1) PEGylates conjugated with higher MW PEG lead to stronger receptor binding, (2) the branched form was superior to the linear configuration in the binding, and (3) both T-shape and H-shape mono-PEGylates demonstrated better potency than the native exenatide, evidenced by lower EC50. Db/db mouse experiments to evaluate in vivo hypoglycemic activity indicated that: (1) all mono-PEGylates resulted in improved glucose tolerance compared to the native exenatide, (2) the homodimer PEGylate demonstrated much stronger hypoglycemic activity, especially during the initial period, and (3) the H-shape and T-shape mono-PEGylates (40 kD) maintained hypoglycemia for up to ca. 168 and 140 h, representing approximately 12- and 14-fold increase, respectively, compared with the native exenatide. Our findings suggest that the exenatide mono-PEGylates in unclassical molecular structures can improve in vivo pharmacokinetics properties.

In-vivo half-life and hypoglycemic bioactivity of a fusion protein of exenatide and elastin-based polypeptide from recombinant Saccharomyces cerevisiae.

Exenatide (Ex) is a 39-amino acid peptide of glucagon-like peptide-1 (GLP-1) receptor agonist that was approved by the FDA in 2005 as a Type II diabetes treatment. It shows a 53% homology with GLP-1 but has an extended half-life (ca. 2.4 h) relative to GLP-1 (ca. 2-3 min). In this study, to further extend its in vivo half-life, we constructed a fusion protein (Ex-(EBP)10-6xHis) using a biocompatible and inert elastin-based polypeptide (EBP) as a fusion partner. Valine was inserted into the guest position of the pentapeptide (VPGXG), no linker sequence was inserted in between the EBPs, and (EBP)10-6xHis tag was attached to the C-terminus of exenatide. By using a recombinant Saccharomyces cerevisiae expression system, the fusion protein was expressed and secreted to the broth and purified by Ni-NTA affinity chromatography. Compared with the native exenatide, the physical half-life of the fusion protein was ca. 3.7-fold extended while approximately 72% of the in-vitro insulin secreting activity was maintained. However, the biological half-life measured by a glucose tolerance test (GTT) and the hypoglycemic test in mice was not significantly different from that of the native form. The effects of EBPylation on bioactivity and half-life of the fusion protein are similar to those of PEGylation. The result suggests that the bioactivity and half-life should be carefully balanced to obtain optimal fusion proteins. We expect that EBPylation using an optimal repeat number of EBP can be an alternative to chemical modification for therapeutic biobetters with extended half-life.

Shielding effect of a PEG molecule of a mono-PEGylated peptide varies with PEG chain length.

'Shielding' effect of a conjugated PEG molecule could cause a change in the electrostatic interaction characteristics of a PEGylate. We investigated how PEG chain length (or molecular weight) alters the electrostatic interaction potential of exenatide variants using their mono-PEGylates in a branched and linear form as model PEGylates. First, we performed the experiments to demonstrate the elution time changes of the mono-PEGylates conjugated with various MW PEGs (5, 10, 20, and 40 kD) using cation exchange chromatography (HiTrap® SP) at various pHs (2.5, 3.0, 3.5, and 4.0). Then, we calculated the net surface charge of each mono-PEGylate to propose the PEG molecule's shielding range in terms of the number of amino acids adjacent to the conjugation residue, assuming that a PEG molecule in solution sweeps out a spherical space and an exenatide molecule have a secondary structure. The net charge calculation result was well-correlated with the experimental elution time data, where 5, 10, 20, and 40 kD PEG hindered the electrostatic potential of 5, 8, 12, and 17 amino acid residues in maximum, respectively, on each side of the conjugation point.

Impact of heat-moisture and annealing treatments on physicochemical properties and digestibility of starches from different colored sweet potato varieties.

The objective of this study is to investigate the change in physicochemical properties and digestibility of starches isolated from colored sweet potato varieties under heat-moisture treatment (HMT) or annealing treatment (ANN). The results showed that morphology and X-ray diffraction patterns of the sweet potato starches remained unchanged after the HMT or ANN. The HMT significantly reduced peak viscosity, breakdown and setback and significantly increased pasting temperature, trough and final viscosities of the sweet potato starches. The swelling powers and solubility of the heat-moisture treated starches were significantly lower than those of the native or annealed starches. The decreased rapid digestible starch and the increased slowly digestible and resistant starch contents of the sweet potato starches after HMT or ANN as compared to those of the native starches were observed. The resistant starch (RS) contents of the heat-moisture treated sweet potato starches were in a range of 30.6-39.3%, significantly higher than those of the annealed starches (28.8-32.0%). The strong impact of the HMT on physicochemical properties and RS formation of the sweet potato starches compared to the ANN might be due to the high stability of the occurred interactions between starch molecules and amylopectin chains during treatment.

Physicochemical characteristics and in vitro digestibility of potato and cassava starches under organic acid and heat-moisture treatments.

A combination of acid (citric acid or lactic acid) and heat-moisture treatment was used to modify cassava and potato starches in this study. Changes in physicochemical properties and in vitro digestibility of the treated starches were investigated. The cassava starch contained 17.0% amylose and possessed A-type crystallinity, whereas the potato starch had 27.4% amylose and possessed B-type crystallinity. After acid and heat-moisture treatment, the crystalline structure of the cassava starch remained unchanged (A type), while the crystalline structure of the potato starch changed from B type to the C (B+A) type. The acid and heat-moisture treatment increased gelatinization temperature, peak and final viscosities of cassava starch but reduced peak and breakdown viscosities of the potato starch. After acid and heat-moisture treatment, rapid digestible starch contents of the treated cassava and potato starches were significantly reduced. However, resistant starch (RS) contents of the treated starches significantly increased as compared to the native starches. Citric acid was found to have high impact on formation of RS in starches. The RS contents of cassava and potato starches obtained under the citric acid and heat-moisture treatment were 40.2% and 39.0%, respectively, two times higher than those of the native starches.

Separation of mono- and di-PEGylate of exenatide and resolution of positional isomers of mono-PEGylates by preparative ion exchange chromatography.

Exenatide is a synthetic version of the 39-mer peptide of Exendin-4, which is an FDA-approved therapeutic against Type II diabetes mellitus. However, exenatide has a very short in-serum half-life and PEGylation have been performed to improve its in-serum stability. PEGylation often yields multivalent binding to non-specific residues, and the desired species should be carefully separated by chromatographies. In this study, we first devised an aqueous-phase, two-step PEGylation process. This consists of thiolation of Lys 12 and 27 residues followed by attachment of PEG-maleimide (10kD) to thiol groups. This process yields various species: mono-PEGylates with positional isomers, di-PEGylate, and other higher MW substances. A prep-grade cationic exchange chromatography (HiTrap SP) at pH 3.0 partially separated mono- and di-PEGylates based on the molar ratio of conjugated PEG and peptide and thus molecular weight of the conjugates. To further investigate the chromatographic separation of positional isomers of mono-PEGylates, we prepared two kinds of exenatide analogs by point mutation; K12C and K27C. Each analog was mono-PEGylated with very high yield (>95%). When a mixture of the two positional isomers of mono-PEGylates was applied to HiTrap SP chromatography, K12C-PEGylate and K27C-PEGylate eluted separately at 0.22M and 0.33M NaCl, respectively. When the proportions of acid and its conjugate base of the amino acid residues adjacent to the PEGylation site at pH 3.0 were analyzed, K27C-PEGylate shows stronger positive charge than K12C-PEGylate, and we propose the residence time difference between the two mono-PEGylates could be due to the charge difference. ELISA result shows that the immuno-binding activity of both analogs and their mono-PEGylates are well maintained. Furthermore, both mono-PEGylates of the analogs show higher than 50-fold improved anti-trypsin stability. We expect that mono-PEGylates of the exenatide analogs are alternatives to the conventional C40-PEG.

Crystal structure of (2E)-1-(4-hy-droxy-1-methyl-2-oxo-1,2-di-hydro-quinolin-3-yl)-3-(4-hy-droxy-3-meth-oxy-phen-yl)prop-2-en-1-one.

In the title compound, C20H17NO5, the dihedral angle between the mean plane of the di-hydro-quinoline ring system (r.m.s. deviation = 0.003 Å) and the benzene ring is 1.83 (11)°. The almost planar conformation is a consequence of an intra-molecular O-H⋯O hydrogen bond and the E configuration about the central C=C bond. In the crystal structure, O-H⋯O hydrogen bonds generate chains of mol-ecules along the [10-1] direction. These chains are linked via π-π inter-actions [inter-centroid distances are in the range 3.6410 (16)-3.8663 (17) Å].

Comparative effects of fumonisins on sphingolipid metabolism and toxicity in ducks and turkeys.

Fumonisins (FBs) are mycotoxins that are found worldwide in maize and maize products. Their main toxic effects have been well characterized in poultry, but differences between species have been demonstrated. Ducks appeared very sensitive to toxicity, whereas turkeys are more resistant. At the same time, alterations of sphingolipid metabolism, with an increase of the concentration of the free sphinganine (Sa) in serum and liver, have been demonstrated in the two species, but the link between the toxicity of FBs and Sa accumulation remains difficult to interpret. The aim of the present work was to compare the effects of FBs (10 mg FB1 + FB2/kg body weight) on sphingolipid metabolism in ducks and turkeys. Growth, feed consumption, and serum biochemistry were also investigated to evaluate toxicity. The main results showed that FBs increased Sa concentrations in liver and serum in ducks and turkeys, but these accumulations were not directly correlated with toxicity. Sa accumulation was higher in the livers of turkeys than in ducks, whereas Sa levels were higher in the sera of ducks than in turkeys. Hepatic toxicity was more pronounced in ducks than in turkeys and accompanied a decrease of body weight and an increase of serum biochemistry in ducks but not in turkeys. So, although FBs increase Sa concentration in the livers of both species, this effect is not directly proportional to toxicity. The mechanisms of FB toxicity and/or the mechanisms of protection of ducks and turkeys to the Sa accumulation within the liver remain to be established.