Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

Investigating Anisotropic Magnetoresistance in Epitaxially Strained CoFe Thin Films on a Flexible Mica.

This study investigates the crystal structure, epitaxial relation, and magnetic properties in CoFe thin films deposited on a flexible mica substrate. The epitaxial growth of CoFe thin films was successfully achieved by DC magnetron sputtering, forming three CoFe(002) domains exhibiting four-fold symmetry on the mica substrate. A notable achievement of this work was the attainment of the highest anisotropic magnetoresistance (AMR) value reported to date on a flexible substrate. Additionally, it was observed that the magnetic characteristics of the CoFe films on the flexible mica substrate display reversibility upon strain release. More importantly, the AMR effect of epitaxial CoFe films on flexible mica shows lesser dependence on the crystalline orientation and remains the same under different bending states. These findings demonstrate the potential of utilizing CoFe films on flexible substrates to develop wearable magnetoresistance sensors with diverse applications.

A Comprehensive Study of CsSnI3-Based Perovskite Solar Cells with Different Hole Transporting Layers and Back Contacts.

By an abrupt rise in the power conservation efficiency (PCE) of perovskite solar cells (PSCs) within a short span of time, the instability and toxicity of lead were raised as major hurdles in the path toward their commercialization. The usage of an inorganic lead-free CsSnI3-based halide perovskite offers the advantages of enhancing the stability and degradation resistance of devices, reducing the cost of devices, and minimizing the recombination of generated carriers. The simulated standard device using a 1D simulator like solar cell capacitance simulator (SCAPS) with Spiro-OMeTAD hole transporting layer (HTL) at perovskite thickness of 330 nm is in good agreement with the previous experimental result (12.96%). By changing the perovskite thickness and work operating temperature, the maximum efficiency of 18.15% is calculated for standard devices at a perovskite thickness of 800 nm. Then, the effects of replacement of Spiro-OMeTAD with other HTLs including Cu2O, CuI, CuSCN, CuSbS2, Cu2ZnSnSe4, CBTS, CuO, MoS2, MoOx, MoO3, PTAA, P3HT, and PEDOT:PSS on photovoltaic characteristics were calculated. The device with Cu2ZnSnSe4 hole transport in the same condition shows the highest efficiency of 21.63%. The back contact also changed by considering different metals such as Ag, Cu, Fe, C, Au, W, Ni, Pd, Pt, and Se. The outcomes provide valuable insights into the efficiency improvement of CsSnI3-based PSCs by Spiro-OMeTAD substitution with other HTLs, and back-contact modification upon the comprehensive analysis of 120 devices with different configurations.

Phase/Interfacial-Engineered Two-Dimensional-Layered WSe2 Films by a Plasma-Assisted Selenization Process: Modulation of Oxygen Vacancies in Resistive Random-Access Memory.

Here, we propose phase and interfacial engineering by inserting a functional WO3 layer and selenized it to achieve a 2D-layered WSe2/WO3 heterolayer structure by a plasma-assisted selenization process. The 2D-layered WSe2/WO3 heterolayer was coupled with an Al2O3 film as a resistive switching (RS) layer to form a hybrid structure, with which Pt and W films were used as the top and bottom electrodes, respectively. The device with good uniformity in SET/RESET voltage and high low-/high-resistance window can be obtained by controlling a conversion ratio from a WO3 film to a 2D-layered WSe2 thin film. The Pt/Al2O3/(2D-layered WSe2/WO3)/W structure shows remarkable improvement to the pristine Pt/Al2O3/W and Pt/Al2O3/2D-layered WO3/W in terms of low SET/RESET voltage variability (-20/20)%, multilevel characteristics (uniform LRS/HRS distribution), high on/off ratio (104-105), and retention (∼105 s). The thickness of the obtained WSe2 was tuned at different gas ratios to optimize different 2D-layered WSe2/WO3 (%) ratios, showing a distinctive trend of reduced and uniform SET/RESET voltage variability as 2D-layered WSe2/WO3 (%) changes from 90/10 (%) to 45/55 (%), respectively. The electrical measurements confirm the superior ability of the metallic 1T phase of the 2D-layered WSe2 over the semiconducting 2H phase. Through systemic studies of RS behaviors on the effect of 1T/2H phases and 2D-layered WSe2/WO3 ratios, the low-temperature plasma-assisted selenization offers compatibility with the temperature-limited 3D integration process and also provides much better thickness control over a large area.

Gamma-Ray Irradiation Induced Ultrahigh Room-Temperature Ferromagnetism in MoS2 Sputtered Few-Layered Thin Films.

Defect engineering is of great interest to the two-dimensional (2D) materials community. If nonmagnetic transition-metal dichalcogenides can possess room-temperature ferromagnetism (RTFM) induced by defects, then they will be ideal for application as spintronic materials and also for studying the relation between electronic and magnetic properties of quantum-confined structures. Thus, in this work, we aimed to study gamma-ray irradiation effects on MoS2, which is diamagnetic in nature. We found that gamma-ray exposure up to 9 kGy on few-layered (3.5 nm) MoS2 films induces an ultrahigh saturation magnetization of around 610 emu/cm3 at RT, whereas no significant changes were observed in the structure and magnetism of bulk MoS2 (40 nm) films even after gamma-ray irradiation. The RTFM in a few-layered gamma-ray irradiated sample is most likely due to the bound magnetic polaron created by the spin interaction of Mo 4d ions with trapped electrons present at sulfur vacancies. In addition, density functional theory (DFT) calculations suggest that the defect containing one Mo and two S vacancies is the dominant defect inducing the RTFM in MoS2. These DFT results are consistent with Raman, X-ray photoelectron spectroscopy, and ESR spectroscopy results, and they confirm the breakage of Mo and S bonds and the existence of vacancies after gamma-ray irradiation. Overall, this study suggests that the occurrence of magnetism in gamma-ray irradiated MoS2 few-layered films could be attributed to the synergistic effects of magnetic moments arising from the existence of both Mo and S vacancies as well as lattice distortion of the MoS2 structure.

Enhancing the Areal Capacity and Stability of Cu2ZnSnS4 Anode Materials by Carbon Coating: Mechanistic and Structural Studies During Lithiation and Delithiation.

The widespread use of energy storage technologies has created a high demand for the development of novel anode materials in Li-ion batteries (LIBs) with high areal capacity and faster electron-transfer kinetics. In this work, carbon-coated Cu2ZnSnS4 with a hierarchical 3D structure (CZTS@C) is used as an anode material for LIBs. The CZTS@C microstructures with enhanced electrical conductivity and improved Li-ion diffusivity exhibit high areal and gravimetric capacities of 2.45 mA h/cm2 and 1366 mA h/g, respectively. The areal capacity achieved in the present study is higher than that of previously reported CZTS-based materials. Moreover, in situ X-ray diffraction results show that lithium ions are stored in CZTS through the insertion reaction, followed by the alloying and conversion reactions at ∼1 V. The structural evolution of Li2S and Cu-Sn/Cu-Zn alloy phases occurs during the conversion and alloying reactions. The present work provides a cost-effective and simple method to prepare bulk CZTS and highlights the conformal carbon coating over CZTS, which can enhance the electrical and ionic conductivities of CZTS materials and increase the mass loading (1-2.3 mg/cm2). The improved stability and rate capability of CZTS@C anode materials can therefore be achieved.

Exerkines in health, resilience and disease.

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.

Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor.

Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD.

Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway.

Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.

Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

Mitophagy and mitochondrial integrated stress response (ISR) are 2 primary protective mechanisms to maintain functional mitochondria. Whether these 2 processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 overexpression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD-fed mice. RNA-Seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis, and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I-stimulated genes through activating transcription factor 5 (Atf5), which inhibits the transactivation activity of interferon regulatory factor 3 (Irf3) known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 overexpression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD-fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.

Changes in metabolomics profiles over ten years and subsequent risk of developing type 2 diabetes: Results from the Nurses' Health Study.

BACKGROUND: Metabolomics profiles were consistently associated with type 2 diabetes (T2D) risk, but evidence on long-term metabolite changes and T2D incidence is lacking. We examined the associations of 10-year plasma metabolite changes with subsequent T2D risk. METHODS: We conducted a nested T2D case-control study (n=244 cases, n=244 matched controls) within the Nurses' Health Study. Repeated metabolomics profiling (170 targeted metabolites) was conducted in participant blood specimens from 1989/1990 and 2000/2001, and T2D occurred between 2002 and 2008. We related 10-year metabolite changes (Δ-values) to subsequent T2D risk using conditional logistic models, adjusting for baseline metabolite levels and baseline levels and concurrent changes of BMI, diet quality, physical activity, and smoking status. FINDINGS: The 10-year changes of thirty-one metabolites were associated with subsequent T2D risk (false discovery rate-adjusted p-values [FDR]<0.05). The top three high T2D risk-associated 10-year changes were (odds ratio [OR] per standard deviation [SD], 95%CI): Δisoleucine (2.72, 1.97-3.79), Δleucine (2.53, 1.86-3.47), and Δvaline (1.93, 1.52-2.44); other high-risk-associated metabolite changes included alanine, tri-/diacylglycerol-fragments, short-chain acylcarnitines, phosphatidylethanolamines, some vitamins, and bile acids (ORs per SD between 1.31and 1.82). The top three low T2D risk-associated 10-year metabolite changes were (OR per SD, 95% CI): ΔN-acetylaspartic acid (0.54, 0.42-0.70), ΔC20:0 lysophosphatidylethanolamine (0.68, 0.56-0.82), and ΔC16:1 sphingomyelin (0.68, 0.56-0.83); 10-year changes of other sphingomyelins, plasmalogens, glutamine, and glycine were also associated with lower subsequent T2D risk (ORs per SD between 0.66 and 0.78). INTERPRETATION: Repeated metabolomics profiles reflecting the long-term deterioration of amino acid and lipid metabolism are associated with subsequent risk of T2D.

Tricarboxylic acid cycle related-metabolites and risk of atrial fibrillation and heart failure.

BACKGROUND: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. METHODS: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. RESULTS: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. CONCLUSION: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent.

INTRODUCTION: We investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults. RESEARCH DESIGN AND METHODS: We used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40-75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates. RESULTS: Six metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS. CONCLUSIONS: Among Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.

Glycolysis Metabolites and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Trial.

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case-control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR for 1 SD increase: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies.

A Bi-Anti-Ambipolar Field Effect Transistor.

Multistate logic is recognized as a promising approach to increase the device density of microelectronics, but current approaches are offset by limited performance and large circuit complexity. We here demonstrate a route toward increased integration density that is enabled by a mechanically tunable device concept. Bi-anti-ambipolar transistors (bi-AATs) exhibit two distinct peaks in their transconductance and can be realized by a single 2D-material heterojunction-based solid-state device. Dynamic deformation of the device reveals the co-occurrence of two conduction pathways to be the origin of this previously unobserved behavior. Initially, carrier conduction proceeds through the junction edge, but illumination and application of strain can increase the recombination rate in the junction sufficiently to support an alternative carrier conduction path through the junction area. Optical characterization reveals a tunable emission pattern and increased optoelectronic responsivity that corroborates our model. Strain control permits the optimization of the conduction efficiency through both pathways and can be employed in quaternary inverters for future multilogic applications.

Correction: Consequences of gamma-ray irradiation on structural and electronic properties of PEDOT:PSS polymer in air and vacuum environments.

[This corrects the article DOI: 10.1039/D1RA03463D.].

Consequences of gamma-ray irradiation on structural and electronic properties of PEDOT:PSS polymer in air and vacuum environments.

In this work, the effects of gamma-ray irradiation (up to 3 kGy) on the structural and electronic properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), irradiated in air and vacuum environments are systematically investigated. Raman spectroscopy indicates that there is no significant change in structural conformation of PEDOT:PSS film after gamma-ray irradiation. However, the conductivity of the film decreases as a function of dose in both air and vacuum environments, which can be deduced as a result of defects created in the structure. Hall effect measurements showed higher carrier concentration when the samples are irradiated under vacuum in comparison to the air environment, whereas mobility decreases as a function of dose irrespective of the environment. Furthermore, the electron spin resonance spectra provided evidence of the evolution of polaron population after gamma-ray exposure of 3 kGy, due to the decrease in charge delocalization and molecular ordering of the molecules. This decrease in conductivity and mobility of the PEDOT:PSS films irradiated in air and vacuum environments can be mainly ascribed to the defects and radical formation after gamma-ray exposure, favoring chain scission or cross-linking of the polymers.