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This article presents the findings of a study conducted in China that examined the effects of ISIS 449884, a medication for type 2 diabetes, on HbA1c levels in Chinese patients. The study found that ISIS 449884 significantly reduced HbA1c levels compared to a placebo after 16 weeks of treatment. The medication also increased fasting glucagon and total GLP-1 levels, and reduced fasting serum glucose. Adverse events were experienced by a majority of participants in both the ISIS 449884 and placebo groups, but there were no serious hypoglycemic events. The study concluded that ISIS 449884 improved HbA1c levels with an acceptable safety profile. [Extracted from the article]

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co‐organized and co‐sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross‐sector collaboration and partnerships as well as a forum for updating colleagues on research‐advancing tools and programs that are steadily moving the field forward. [ABSTRACT FROM AUTHOR]

Aims: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. Methods and results: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS‐HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine‐induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non‐significant after adjustment for age, sex, N‐terminal pro‐brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Conclusions: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions. [ABSTRACT FROM AUTHOR]

Dopamine (DA) plays an essential role in the central nervous, renal, hormonal and cardiovascular systems. Various modified carbon nanotubes (CNT)‐based dopamine sensors have been reported, but inexpensive, highly sensitive plain CNT‐based ones are seldom studied. In this work, a facile and inexpensive CNT‐based DA sensor is made by rich‐defect multi‐walled carbon nanotubes (RD‐CNT) via an ultrasound method. The defect and elemental states of the RD‐CNT are systematically studied by transmission electron microscopy (TEM), high‐resolution transmission electron microscopy (HR‐TEM), Raman spectroscopy, X‐ray powder diffraction (XRD) and X‐ray‐photoelectron spectroscopy (XPS). Results show that massive holes and cracks exist in RD‐CNT. The level of defects increases from the additional exposed edges. The electrochemical characterizations indicate that the electrochemical sensor has the highest sensitivity of 438.4 μA/(μM ⋅ cm2) among all carbon materials‐based DA sensors while well meeting the clinically required detection range and selectivity. The DA sensor was further used to detect live healthy human serum and live PC12 cells with satisfactory results, thus holding great promise for an inexpensive but sensitive DA sensor in practical applications of clinical diagnosis and biological research. [ABSTRACT FROM AUTHOR]

To simultaneously improve the hole extraction ability of the BiVO4 photoanode and accelerate the surface reaction kinetics, herein, a carbon nanolayer conformally coated Fe2O3 (C−Fe2O3) as oxygen evolution catalyst (OEC) is loaded on the H2 plasma treated nanoporous BiVO4 (BVO(H2)) surface by a hydrothermal reaction. It is found that the H2 plasma induced vacancies in BVO remarkably increases the conductivity, and the C−Fe2O3 enables hole extraction from the bulk to the surface as well as efficient hole injection to the electrolyte. As a result, the C−Fe2O3/BVO(H2) photoanode achieves a photocurrent density of 4.4 mA/cm2 at 1.23 V vs. reversible hydrogen electrode (RHE) and an ABPE value of 1.5 % at 0.68 V vs. RHE, which are 4.8‐fold and 13‐fold higher than that of BVO photoanode, respectively. [ABSTRACT FROM AUTHOR]

The conversion of biomass is a favorable alternative to the fossil energy route to solve the energy crisis and environmental pollution. As one of the most versatile platform compounds, 5‐hydroxymethylfural (HMF) can be transformed to various value‐added chemicals via electrolysis combining with renewable energy. Here, the recent advances in electrochemical oxidation of HMF, from reaction mechanism to reactor design are reviewed. First, the reaction mechanism and pathway are summarized systematically. Second, the parameters easy to be ignored are emphasized and discussed. Then, the electrocatalysts are reviewed comprehensively for different products and the reactors are introduced. Finally, future efforts on exploring reaction mechanism, electrocatalysts, and reactor are prospected. This review provides a deeper understanding of mechanism for electrochemical oxidation of HMF, the design of electrocatalyst and reactor, which is expected to promote the economical and efficient electrochemical conversion of biomass for industrial applications. [ABSTRACT FROM AUTHOR]

Various microorganisms play an important role in daily functions in the body and continue to flourish after death. Our prior investigation using frozen cadavers revealed that the appendix, rather than the transverse colon, was a superior sampling site for intestinal bacteria because the appendiceal flora had higher diversity than that in the transverse colon in the majority of experimental periods after death. We sought to explore out more about whether the appendicular flora is significantly related to postmortem interval (PMI) at natural temperatures following the host's death. In this work, we employed high‐throughput sequencing to evaluate the contents of rats' appendices within 2 weeks after death and then utilized the random forest algorithm to build a PMI prediction model after completing basic visual analyses on the sequencing data. The findings revealed that Firmicutes was the absolute dominant species of appendicular flora; alpha‐diversity of appendix flora first increased and then decreased, with the highest point appearing at 36 h after death; and the primary metabolic functions were carbohydrate metabolism, amino acid metabolism, as well as cofactors and vitamin metabolism. Finally, a random forest regression model for PMI prediction was built by the training data at the family level, with the mean absolute error of 10.27 h for prediction within 14 days postmortem, and the test set data subsequently proved the model's reliability. Changes in appendicular flora were strongly related to the PMI following rats' deaths, so we have reason to believe that the appendicular flora is valuable in predicting PMI. [ABSTRACT FROM AUTHOR]

Aim: Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS‐HFpEF cohort. Methods and results: Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high‐throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler‐based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n = 54; 30%) had higher body mass index (32 [28–40] vs. 27 [23–30] kg/m2; p < 0.001), lower N‐terminal pro‐B‐type natriuretic peptide (466 [193–1133] vs. 1120 [494–1990] pg/ml; p < 0.001), smaller indexed left ventricular (LV) end‐diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non‐indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00–1.04; p = 0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01–1.05; p = 0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR. Conclusion: Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated. [ABSTRACT FROM AUTHOR]

With rising CO2 emissions caused by the massive consumption of fossil fuels, it is highly desirable to develop strategies that adopt renewable energy to convert CO2 into value‐added chemical feedstocks. Over the past decades, photocatalytic reduction of CO2 using light energy has attracted considerable attention. However, the advanced photocatalysis techniques cannot exert their action where light is unavailable. Here, a method for CO2 reduction on basis of vibration‐driven piezoelectricity to yield a piezo‐electrocatalysis effect which requires mechanical vibration rather than light, is proposed. Under mild vibration and sacrificial agent‐free conditions, the piezoelectric BaTiO3 catalyst provides a suitable piezo‐potential to overcome the redox potential of CO2 and convert it into CO with a maximum yield of 63.3 µmol g−1, achieving a reactivity comparable to those of photocatalysts. The piezo‐electrocatalytic CO2 reduction reaction adds a new avenue in addition to the existing photocatalytic techniques by expanding the scope of energy utilization to promote carbon neutrality. [ABSTRACT FROM AUTHOR]

A robust and highly active homogeneous chiral nickel–phosphine complex for the asymmetric hydrogenation of aliphatic γ‐ and δ‐ketoacids has been discovered. The hydrogenation could proceed smoothly in the presence of 0.0133 mol% catalyst loading (S/C=7500). The coordination chemistry and catalytic behavior of Ni(OTf)2 with (S,S)‐Ph‐BPE were explored by 1H NMR and HRMS. The mechanistic studies revealed that a proton promoted the activation of the substrate C=O bond and controlled the stereoselectivity through hydrogen bonds. A series of chiral γ‐ and δ‐alkyl substituted lactones were obtained in high yields with excellent enantioselectivities (up to 98 % yield and 99 % ee). In addition, this catalytic system also demonstrated that levulinic acid produced from a biomass feedstock was converted into chiral γ‐valerolactone without loss of ee value. [ABSTRACT FROM AUTHOR]

Aims: Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex‐specific proteomic profiles associated with CMD in patients with HFpEF. Methods and results: Using the prospective multinational PROMIS‐HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high‐throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non‐overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy‐associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin‐like growth factor‐binding protein 1, phage shock protein D, CUB domain‐containing protein 1, prostasin, decorin, FMS‐like tyrosine kinase 3, ligand growth differentiation factor 15, spondin‐1, delta/notch‐like epidermal growth factor‐related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation‐mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13‐kinase and transforming growth factor‐beta signalling pathway among women with HFpEF. Conclusion: While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women. [ABSTRACT FROM AUTHOR]

A Rh2O3/BiVO4 composite photoanode exhibits enhanced surface reaction kinetics and charge transfer efficiency, enabling a photocurrent density of ca. 3.5 mA/cm2 at 1.23 V (vs. RHE), which is about 3.89 times higher than that of the pristine BiVO4, with a lower onset potential of 0.29 V (vs. RHE). [ABSTRACT FROM AUTHOR]

This is because of the differences in social spending, and the reduction in income inequality among elderly in China while income inequality among working-age families is stagnant. Keywords: D3; F6; J3; N3; O15; O33 EN D3 F6 J3 N3 O15 O33 42 44 3 01/13/23 20230101 NES 230101 I agree with Zhuang ([5]) in his summary assessments of the negative effects of income inequality. [Extracted from the article]

A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18‐/14‐membered sesterterpenoids including five new ones and two 14‐membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3‐ and 2.5‐fold, respectively, more sesterterpenoids than the wild‐type enzyme were engineered. Both 18‐ and 14‐membered ring sesterterpenoids displayed significant inhibitory activity on the IL‐2 and IFN‐γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well‐trodden territory of plant terpenoid biosynthesis. [ABSTRACT FROM AUTHOR]

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia‐induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague‐Dawley (SD) rats were exposed to hypoxia (10% O2) for 21 days to induce rat HPH model. PASMCs were treated with CoCl2 (200 µM) for 24 h to establish the HPH cell model. It was found that hypoxia up‐regulated the expression of Cx43 and phosphorylation of Cx43 at Ser 368 in rat pulmonary arteries and PASMCs, and stimulated the proliferation and migration of PASMCs. HIF‐1α inhibitor echinomycin attenuated the CoCl2‐induced Cx43 expression and phosphorylation of Cx43 at Ser 368 in PASMCs. The interaction between HIF‐1α and Cx43 promotor was also identified using chromatin immunoprecipitation assay. Moreover, Cx43 specific blocker (37,43Gap27) or knockdown of Cx43 efficiently alleviated the proliferation and migration of PASMCs under chemically induced hypoxia. Therefore, the results above suggest that HIF‐1α, as an upstream regulator, promotes the expression of Cx43, and the HIF‐1α/Cx43 axis regulates the proliferation and migration of PASMCs in HPH. [ABSTRACT FROM AUTHOR]

The COVID‐19 crisis that resulted in diminished close contact interaction and increased financial volatility could influence consumer's perception toward online automated financial robo‐advisor, in order to manage their financial planning. Based on the data collected (i.e., between February [9 reported cases] and March [36 reported cases] 2020) within the developed urban cities in Malaysia just before the nationwide lockdown, the present study examines the antecedents of financial robo‐advisor's adoption during the COVID‐19 crisis. A variance based analysis shows that consumers with higher financial knowledge and having a greater tendency to rely on robo‐advisor tend to adopt financial robo‐advisor in times of crisis. In line with the unified theory of acceptance and use of technology model, performance expectancy, social influence, and trust in robo‐advisor, in particular during the pandemic, drive consumer's intention to subscribe online financial robo‐advisor. The findings imply how consumers, robo‐advisory service providers, and regulators could respond to unprecedented crisis such as novel corona virus‐19. [ABSTRACT FROM AUTHOR]

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single‐blind, placebo‐controlled study, following once‐daily multiple ascending dosing to steady‐state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half‐life of ~ 60 hours. A dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady‐state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration‐dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

The increasingly stringent requirement in large‐scale energy storage necessitates the development of high‐performance sodium‐ion batteries (SIBs) that can operate under low‐temperature (LT) environment. Although SIBs can achieve good cycling stability and rate performance at room temperature, the sluggish electrochemical reaction kinetics at low temperature remains a great challenge for SIBs. Here, a superior LT SIB composed of 3D porous Na3V2(PO4)3/C (NVP/C‐F) and NaTi2(PO4)3/C foams (NTP/C‐F) is developed. First‐principles calculations reveal that the intrinsic Na+ diffusivity in NASICON‐type NVP and NTP is extremely high (maximum 3.84 × 10−5 for NVP and 2.94 × 10−9 cm2 s−1 for NTP) at –20 °C. In addition, the designed 3D interconnected porous foam structures demonstrate excellent electrolyte absorption ability and Na+ transport performance at low temperature. As a result, under −20 °C, the NVP/CF and NTP/CF electrodes (half‐cell configuration) can attain reversible capacities close to their theoretical values, and are able to be charged and discharged rapidly (20 C) for 1000 cycles. Based on these features, the designed NTP/CF||NVP/CF full cell also displays superb LT kinetics and cycling stability, making a great stride forward in the development of LT SIBs. [ABSTRACT FROM AUTHOR]

Small‐sized cages of Cn are possible intermediate species for the formation of fullerene molecules in the discharge or laser vaporization reaction of graphite, but the studies on them are scattered mainly owing to their high reactivity and unavailability. Here, the coordinates of small‐sized carbon cages of Cn (n = 4‐30) are generated by our developed codes, and their stability and structural connectivity are studied using density functional theory. The interesting findings include the following: (a) Cage‐shaped isomers of Cn are favored with increasing size; (b) the ground state of cage‐shaped C4, C8, C26, and C30 are open‐shelled, and cage‐shaped D3h‐C6 is a second saddle point; (c) small‐sized cages welcome strained square(s); and (d) the most favored cages of Cn from C16 to C30 are structurally related to direct C2 insertion without the rearrangement process. [ABSTRACT FROM AUTHOR]

Background: Tau post‐translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Proteolytic cleavage of tau by active caspases, including caspase‐6, represents an underexplored tau PTM implicated in tau pathology by generating tau species with an enhanced propensity for self‐aggregation and accumulation into neuronal cytoplasmic inclusions. Method: To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two neoepitope monoclonal antibodies (mAbs) against caspase‐6 tau proteolytic sites (D13 and D402) and cortical neurons (iNs) from induced pluripotent stem cells (iPSCs) with the frontotemporal dementia (FTD)‐causing V337M MAPT mutation (tauV337M). Result: FTLD tauV337M and AD postmortem brains showed positivity for both cleaved tau mAbs as well as active caspase‐6 (Fig. 1). Three month tauV337M iNs showed a three‐fold increase in caspase‐cleaved D402 and D13 tau protein levels and increased p‐tau and oligomeric tau species compared to controls (Fig. 2). Three month tauV337M iNs also showed a significantly higher rate of neuronal death than the tauWT counterpart. Treatment with staurosporine (STS), a stress inducer, led to a 5‐fold increase of cytotoxicity levels in STS‐treated tauV337M iNs compared to vehicle‐treated tauV337M iNs. Although STS‐induced cytotoxicity was anticipated, the increase was significantly higher in STS‐treated tauV337M iNs than in STS‐treated control iNs. Similarly, we observed a 4‐fold increase of caspase‐6 activity in STS‐treated tauV337M iNs compared to vehicle‐treated tauV337M iNs that was reversed following co‐treatment with the caspase‐6 inhibitor z‐VEID‐fmk (Fig. 2). Conclusion: We propose a model in which time‐dependent accumulation of caspase‐cleaved tau in V337M MAPT neurons promotes neurotoxicity that is reversed by caspase‐6 inhibition. Caspase‐cleaved tau may be a biomarker of tauopathy, and caspases could be viable targets for therapeutic intervention against tau pathogenesis in FTLD and other tauopathies. [ABSTRACT FROM AUTHOR]

Aims: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine‐induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine‐mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third‐degree atrioventricular block, prevents isoprenaline‐induced TS‐like akinesia in an experimental animal model. Methods and results: We used 142 female Sprague–Dawley rats in two separate protocols. The TS‐like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high‐resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS‐like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter‐quartile range (IQR) 0.0–18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0–0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS‐like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89–95) and IVAB2 groups (93%, IQR 87–96) than in the CONTROL group (78%, IQR 63–87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9–24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0–0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87–92) than in the CTRL group (51%, IQR 87–92, P < 0.05). Conclusions: Isoprenaline‐induced TS‐like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS. [ABSTRACT FROM AUTHOR]

Aims: In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. Methods and results: MPO, MPO‐related biomarkers, and echocardiography were assessed in 86 patients, 4–8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all‐cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e′ was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m2 (38;52). Controls were 60 (57;62) years old (vs. patients; P < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 μmol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e′ > 14, uric acid and SDMA were elevated (421 vs. 344 μM, P = 0.012; 0.54 vs. 0.47 μM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19–11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70–3.14; P = 0.304)] or the other biomarkers. Conclusions: In HFpEF, MPO‐dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target. [ABSTRACT FROM AUTHOR]

Using a new and representative data set of Chinese household finance, we document household usage and costs of finance, along with their correlates. As in many developing countries, informal credit is a crucial element of household finance, and interest‐free informal loans based on reciprocal personal relationships are highly prevalent in our sample. Not surprisingly, wealth tends to be associated with greater usage of both formal and informal finance. Political connections, extensive social networks and certain household demographic characteristics (such as size) are all positively associated with formal or informal credit usage (or both). Overall, our findings show signs that a dual credit market is emerging in China, with the poor, politically unconnected, and those with larger family sizes still heavily reliant on informal finance, most of which are interest‐free, while younger, wealthier households with better political connections and financial knowledge are increasingly using formal finance. [ABSTRACT FROM AUTHOR]

Background: Cyclic GMP‐AMP synthase (cGAS, Cgas), the major antiviral DNA sensor, binds double‐stranded DNA (dsDNA) and catalyzes cyclic GMP‐AMP (cGAMP) formation, which activates stimulator of interferon genes (STING). Activation of cGAS‐STING has been implicated in several neurodegenerative conditions. The role of cGAS in tauopathy remains unknown. Method: We investigated cGAS‐STING‐IFN activation in microglia of tauopathy mice and human AD brains. We crossed cGAS knockout mice with P301S tauopathy mice and performed behavioral, immunohistochemistry, electrophysiology and single‐nuclei (sn) RNA‐seq. Result: we demonstrated potent protective effects of Cgas genetic deletion against synaptic and cognitive deficits associated with induction of transcriptional network of MEF2C, a gene implicated in cognitive resilience against amyloid and tau pathology. SnRNA‐seq analyses of human AD brains revealed dysregulation of microglial IFN‐I genes and neuronal MEF2C transcriptional network. Conclusion: Our current study linked a hyperactive cGAS‐IFN antiviral response with diminished MEF2C‐associated cognitive resilience. In diseased conditions, cGAS hyperactivation promoted microglial IFN‐I response, reduced neuronal MEF2C transactivation, and rendered loss of cognitive resilience. cGAS ablation diminished microglial IFN‐I response and enhanced neuronal MEF2C transcription network and associated cognitive resilience against tau pathology. Pharmacological inhibition of cGAS with TDI‐6570 enhanced MEF2C target genes and restored synaptic integrity and memory, supporting the therapeutic potential of targeting cGAS‐MEF2C axis to improve resilience against AD and related neurological disorders. [ABSTRACT FROM AUTHOR]

This paper studies how the major economic events would have affected Chinese yuan's nominal exchange rate against US dollar from 1989 to 2013. The traditional average treatment effect estimation methods cannot be used to consistently estimate yuan's pegged exchange rate. We develop a new estimation strategy by combining a novel panel data method (proposed by Hisao, Ching and Wan) and the purchasing power parity theory. Based on this new estimation strategy, we find that during the period of pegging to US dollar, Chinese yuan were undervalued. Before the 1997 Asian Financial Crisis, the pegged exchange rate regime starting from January 1994 made the yuan undervalued by 2.62%. China's accession to WTO caused yuan undervalued by 36.60%. After the reform of Chinese exchange rate policy in July 2005, the undervaluation of the yuan was reduced to only 0.76%. Yuan was undervalued again by 20.43% because of 2008 China's economy stimulus package. The policy reform in June 2010 made yuan overvalued by 14.40%. We conclude that Chinese fixed exchange rate policy indeed undervalued the yuan, especially after its accession to WTO. The recent reforms of Chinese exchange rate policy made progresses in re‐evaluating the yuan. [ABSTRACT FROM AUTHOR]

A general and efficient synthetic methodology for the preparation of enantio‐ and diastereopure [6]‐, and [7]helicenes is developed. Commercially available chiral binaphthanols are utilized to generate the arylene‐vinylene precursors, which undergo helical folding via photocyclization to give enantio‐ and diastereopure [6]‐, and [7]helicenes. These optically pure helicenes could be easily obtained via silica gel column chromatography without the use of expensive HPLC or chiral resolution reagents. The configurations and structures of these helicenes are confirmed by CD spectra and X‐ray crystallographic analysis. This work provides a new method for preparation of enantiopure helicenes. [ABSTRACT FROM AUTHOR]

Aims: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation‐related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. Methods: In this randomized, single‐blind, placebo‐controlled, phase I, first‐in‐human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high‐calorie meal. Results: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half‐life of 38.2–50.0 hours. The area under the plasma concentration–time curve (AUC) increased proportionally with dose (AUC0–∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half‐life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) μmol L−1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. Conclusions: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half‐life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831. [ABSTRACT FROM AUTHOR]

Summary: Renal denervation (RDN) is a potential modality in the treatment of patients with resistant hypertension (RH) and has shown beneficial effect on a variety of cardiovascular surrogate markers. Coronary flow reserve, as assessed by transthoracic Doppler echocardiography (TDE‐CFR) is impaired in patients with hypertension and is an independent predictor of cardiac morbidity. However, data on the effect of RDN on TDE‐CFR are scarce. The main objective of this study was to assess the effect of RDN on TDE‐CFR. Twenty‐six consecutive patients with RH (9 female and 17 male; mean age 62 ± 8 years; mean number of antihypertensive drugs 4·2 ± 1·6) underwent bilateral RDN. CFR was assessed at baseline and 6 months after intervention. Mean flow velocity was measured in the left anterior descending artery by transthoracic Doppler echocardiography at baseline and during adenosine infusion (TDE‐CFR). Systolic office blood pressure was reduced at follow‐up (174 ± 24 versus 162 ± 27 mmHG; P = 0·01). Mean systolic ambulatory blood pressure decreased from 151 ± 21 to 147 ± 18 (P = 0·17). TDE‐CFR remained unchanged 6 months after intervention (2·7 ± 0·6 versus 2·7 ± 0·7; P = 0·67). In conclusion, renal denervation was not associated with any changes in regard to coronary flow reserve at 6‐month follow‐up. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post‐traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. Methods: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. Results: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. Discussion: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations. [ABSTRACT FROM AUTHOR]

Abstract: Excited by the recently experimental reports of monometallic cluster fullerenes, we examined the electronic and geometrical properties of monometallic cluster fullerenes YCN@Cn with size from C68 to C84 by density functional theory and statistical thermodynamic calculations. The calculations demonstrate that the thermodynamically favored isomers of YCN@Cn are in good agreement with available experimental results. Morphology analysis shows that the lowest‐energy YCN@Cn species are structurally connected by C2 insertion/extrusion and Stone–Wales rotation, which can be promoted under high temperature; enthalpy–entropy interplay can change the relative abundances of low‐energy isomers significantly at high temperature. All the results suggest that there is a structural evolution among these metallic cluster fullerenes in discharge condition, and thus, can rationalize their structural diversity in the soot and partly disclose their formation mechanism. The geometrical structures, electronic properties of these endohedral fullerene were discussed in detail. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5‐lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single‐blind, placebo‐controlled, first‐in‐human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4) production in whole blood and endogenous leukotriene E (LTE4) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half‐life of 10–12 h. Steady‐state levels were achieved after ∼3 days. After both SADs and MADs, a dose/concentration‐effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD). [ABSTRACT FROM AUTHOR]

This paper proposes and implements a mixture structure to model repayment behavior in group lending with unobserved group heterogeneity. We discuss the model properties and identification and estimate the model using a rich dataset from a group lending program in India. The estimation results support the existence of two different group types: “responsible” and “irresponsible” groups. We find that the effects of the factors driving repayment behavior differ across types. The model also shows a higher predictive performance than standard probabilistic models, particularly in the identification of potential defaulters. We provide evidence supporting the robustness of our estimations. (JEL O16, C35) [ABSTRACT FROM AUTHOR]

Abstract: Selective decomposition of hydrous hydrazine (N2H4⋅H2O) over metal catalysts provides a promising means for onboard or portable hydrogen source applications. Studies on N2H4⋅H2O decomposition catalysts mainly focus on the effects of bulk composition and structure on their performances, instead of the surface‐composition‐dependent properties. Herein, the synthesis of an Ir‐modified Ni/meso‐CeO2 catalyst is reported by using a combination of colloidal solution combustion synthesis and galvanic replacement methods. A combination of structural characterization, control experiments, and DFT calculations reveals that the Ni−Ir alloy resulting from calcination treatment exerts a profound effect on the catalytic properties. The resulting Ni@Ni−Ir/meso‐CeO2 catalyst shows excellent catalytic performance towards hydrogen generation from N2H4⋅H2O, which compares favorably with the Ni−Ir bimetallic catalysts reported to date. [ABSTRACT FROM AUTHOR]

Abstract: Background/Objective: To report our observations from a trial of the short‐term effectiveness and safety of topical carteolol hydrochloride drops to treat infantile hemangiomas (IHs). Methods: From October 2012 to September 2015, the study recruited 349 children with superficial IHs. Participants were randomized to two groups: treatment (n = 224 who received 2% carteolol hydrochloride drops administered to the lesion surface twice daily) and observation (n = 125 who did not receive treatment). Therapy duration was 6 months. Results: The mean age at the beginning of treatment was 3.2 months. Treatment responses were categorized as class 1 (total regression), class 2 (partial regression or controlled growth), or class 3 (no response). Of infants receiving carteolol treatment, 10.7% (24 patients) were categorized as class 1, 72.3% (162 patients) as class 2, and 17.0% (38 patients) as class 3. Of infants in the observation group, 5.6% (7 patients) were categorized as class 1, 25.6% (32 patients) as class 2, and 68.8% (86 patients) as class 3. No adverse effects were noted during treatment. Conclusion: Carteolol is an effective, safe topical treatment for superficial IHs. Carteolol may be used to treat proliferative superficial IHs, particularly in infants younger than 6 months. [ABSTRACT FROM AUTHOR]

To elucidate the structure of a compound is a necessary step for its practical applications. To study the structure and properties of metal sulfide fullerene Sc2S@C88 detected by mass spectrometry, 11 194 isomers of C88 and 33 isomers of Sc2S@C88 were systematically examined by density functional theory calculations. The calculations show that the two lowest-energy isomers are Sc2S@C88:81 738 (IPR-35) and Sc2S@C88:81 735 (IPR-32), followed by Sc2S@C88:81 729 (IPR-26), Sc2S@C88:81 712 (IPR-9), and Sc2S@C88:81 733 (IPR-30). Structural analysis shows that the first two energetically favored isomers are bridged by the third and fifth energetically favored isomers, which can transfer into each other via direct Stone-Wales rotation. The calculations of temperature effect show that the first two favored isomers become dominant forms of Sc2S@C88 with decreasing temperature and may coexist in the soot. This structural convertibility among favored isomers of Sc2S@C88 suggest a hidden rule that birds of a feather flock together in metal sulfide fullerenes. This rule may decrease the range of candidate cages for the structural identification of a metal sulfide fullerene. IR spectra are simulated for helping the future experimental identification of Sc2S@C88. [ABSTRACT FROM AUTHOR]

Two dimeric prenylindole alkaloids with a unique indole-benzoindolequinone skeleton, cimicifoetones A ( 1) and B ( 2), were isolated as black pigments from the rhizomes of Cimicifuga foetida. The structures were elucidated by spectroscopic methods including HRMS and 2D NMR, as well as single-crystal X-ray diffraction and computational chemical modeling techniques. Cimicifoetones A and B represented the first examples of dimeric indole alkaloids generated through [4+2] Diels-Alder cycloaddition between the prenyl side chain in one 3-prenylindole and the aromatic ring in another. The two compounds showed promising anti-proliferative activity on seven tumor cell lines with IC50 values in the range of 1.36-21.09 μ m. Flow cytometric and western blot analysis revealed that compound 2 induced cell apoptosis via death receptor-mediated extrinsic and mitochondrial-mediated intrinsic pathways. [ABSTRACT FROM AUTHOR]

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long-term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. [ABSTRACT FROM AUTHOR]

At the end of 1998, China launched a government-run mandatory insurance program, the urban employee basic medical insurance (UEBMI), to replace the previous medical insurance system. Using the UEBMI reform in China as a natural experiment, this study identifies variations in patient cost sharing that were imposed by the UEBMI reform and examines their effects on the demand for healthcare services. Using data from the 1991-2006 waves of the China Health and Nutrition Survey, we find that increased cost sharing is associated with decreased outpatient medical care utilization and expenditures but not with decreased inpatient care utilization and expenditures. Patients from low-income and middle-income households or with less severe medical conditions are more sensitive to prices. We observe little impact on patient's health, as measured by self-reported health status. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An increasing number of observations show that non-classical isomers may play an important role in the formation of fullerenes and their exo- and endo-derivatives. A quantum-mechanical study of all classical isomers of C58, C60, and C62, and all non-classical isomers with at most one square or heptagonal face, was carried out. Calculations at the B3LYP/6-31G* level show that the favored isomers of C58, C60, and C62 have closely related structures and suggest plausible inter-conversion and growth pathways among low-energy isomers. Similarity of the favored structures is reinforced by comparison of calculated ring currents induced on faces of these polyhedral cages by radial external magnetic fields, implying patterns of magnetic response similar to those of the stable, isolated-pentagon C60 molecule. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Four polycyclic norditerpenoids, cephalotanins A-D ( 1- 4) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis and structurally characterized by a combination of various methods. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Biosynthetic pathways for 1- 4 were proposed by involving diverse and very fascinating chemical events with the coexisting cephalotane troponoids as the precursors. Compound 1 exhibited good NF- κB inhibition with an IC50 value of 4.12±0.61 μΜ. [ABSTRACT FROM AUTHOR]

Recent experiments indicate that fullerene isomers outside the classical definition can also encapsulate metallic atoms or clusters to form endohedral metallofullerenes. Our systematic study using DFT calculations, suggests that many heptagon-including nonclassical trimetallic nitride template fullerenes are similar in stability to their classical counterparts, and that conversion between low-energy nonclassical and classical parent cages via Endo-Kroto insertion/extrusion of C2 units and Stone-Wales isomerization may facilitate the formation of endohedral trimetallic nitride fullerenes. Close structural connections are found between favored isomers of trimetallic nitride template fullerenes from C78 to C82. It appears that the lower symmetry and local deformations associated with introduction of a heptagonal ring favor encapsulation of intrinsically less symmetrical mixed metal nitride clusters. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Common marmosets are extensively used in immunological and pharmacological research, and the usage of methods such as flow cytometry gain increasing importance. Methods Using multicolor flow cytometry cross-reactivity of monoclonal antibodies with cells of common marmosets was analyzed. Furthermore, frequencies of immune cells and immunological parameters were assessed in healthy common marmosets. Results A total of 97 clones of monoclonal antibodies raised against CD markers, chemokine receptors, and miscellaneous markers were tested. Additionally, baseline frequencies of different innate and adaptive immune cells as well as certain parameters, such as activation and memory T-cell and B-cell distribution, are provided. Conclusion Our study gives an extended overview of cross-reactive antibodies for flow cytometric analysis of immune cells as well as baseline values for different immune parameters in healthy common marmosets. [ABSTRACT FROM AUTHOR]

The progress on sodium-ion battery technology faces many grand challenges, one of which is the considerably lower rate of sodium insertion/deinsertion in electrode materials due to the larger size of sodium (Na) ions and complicated redox reactions compared to the lithium-ion systems. Here, it is demonstrated that sodium ions can be reversibly stored in Zn-Sb intermetallic nanowires at speeds that can exceed 295 nm s−1. Remarkably, these values are one to three orders of magnitude higher than the sodiation rate of other nanowires electrochemically tested with in situ transmission electron micro­scopy. It is found that the nanowires display about 161% volume expansion after the first sodiation and then cycle with an 83% reversible volume expansion. Despite their massive expansion, the nanowires can be cycled without any cracking or facture during the ultrafast sodiation/desodiation process. In addition, most of the phases involved in the sodiation/desodiation process possess high electrical conductivity. More specifically, the NaZnSb exhibits a layered structure, which provides channels for fast Na+ diffusion. This observation indicates that Zn-Sb intermetallic nanomaterials offer great promise as high rate and good cycling stability anodic materials for the next generation of sodium-ion batteries. [ABSTRACT FROM AUTHOR]

A partial test for strategic behavior in bankruptcy filing may be formulated by testing whether consumers manipulate their debt and filing decision jointly, or not: that is, testing for endogeneity of financial benefit and the bankruptcy filing decision. Using joint maximum likelihood estimation of an extended discrete choice model, test results are consistent with nonstrategic filing: financial benefit is exogenous to the filing decision. This result is confirmed in two different datasets ( Panel Study of Income Dynamics and Survey of Consumer Finances). This result is consistent with an ex ante low net gain from a bankruptcy filing; a type of 'rational inattention' to rare events such as bankruptcy. ( JEL D12, D14) [ABSTRACT FROM AUTHOR]

ABSTRACT Two pairs of new neolignan enantiomers, (±)-torreyayunan A ( 1a/ 1b) and (±)-torreyayunan B ( 2a/ 2b), featuring a rare C-8 − C-9′ linked skeleton, were isolated from leaves and twigs of Torreya yunnanensis. Their absolute configuration involving two chiral centers was determined by combined spectral and Density Functional Theory (DFT) calculation. This is the first report of the absolute configuration of this group of neolignans. Chirality 26:825-828, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]