Cyclic Production Research Articles

Dynamics of Annual Сone Crops of Siberian Fir (Abies sibirica Ledeb.) in Conifer Forests of Pre-Ural Region (Russia) Based on 47 Years of Observations

Because seed reproduction is the sole means of reproduction available for coniferous tree species, it plays a crucial role in determining the species’ ecological adaptability and the competitiveness of species under specific biocoenosis conditions. Therefore, the primary goal of studying the periodicity and cyclical production of cones (seeds) is to forecast the peaks and recessions of natural renewal in various forest ecosystems. The crop dynamics of Siberian fir (Abies sibirica Ledeb.) cones in three mature natural conifer forests in the broad-leaf coniferous forest subzone of the pre-Ural region (Russia) was analysed based on long-term observations spanning 47 years. The conifer forests investigated had a considerable deficit of cones (seeds) for natural renewal under the forest canopy. High cone crops occur every 10 years or twice a decade under most favourable conditions. However, cone production has no distinct periodicity, and it is impossible to forecast a high crop of cones based only on long-term data. The levels of fir crop cones were clearly correlated with climate factors. Late winter climate in previous (weak and moderate positive correlation) and current years (weak and moderate negative correlation) affected the fir cone crop. High and even average fir cone crops occur spontaneously with no discernible pattern. In coniferous forests, cone crops are highest on slopes with high insolation levels and on sustainably wet soils.

Natural Cyclic Peptides: Synthetic Strategies and Biomedical Applications.

Natural cyclic peptides, a diverse class of bioactive compounds, have been isolated from various natural sources and are renowned for their extensive structural variability and broad spectrum of medicinal properties. Over 40 cyclic peptides or their derivatives are currently approved as medicines, underscoring their significant therapeutic potential. These compounds are employed in diverse roles, including antibiotics, antifungals, antiparasitics, immune modulators, and anti-inflammatory agents. Their unique ability to combine high specificity with desirable pharmacokinetic properties makes them valuable tools in addressing unmet medical needs, such as combating drug-resistant pathogens and targeting challenging biological pathways. Due to the typically low concentrations of cyclic peptides in nature, effective synthetic strategies are indispensable for their acquisition, characterization, and biological evaluation. Cyclization, a critical step in their synthesis, enhances metabolic stability, bioavailability, and receptor binding affinity. Advances in synthetic methodologies-such as solid-phase peptide synthesis (SPPS), chemoenzymatic approaches, and orthogonal protection strategies-have transformed cyclic peptide production, enabling greater structural complexity and precision. This review compiles recent progress in the total synthesis and biological evaluation of natural cyclic peptides from 2017 onward, categorized by cyclization strategies: head-to-tail; head-to-side-chain; tail-to-side-chain; and side-chain-to-side-chain strategies. Each account includes retrosynthetic analyses, synthetic advancements, and biological data to illustrate their therapeutic relevance and innovative methodologies. Looking ahead, the future of cyclic peptides in drug discovery is bright. Emerging trends, including integrating computational tools for rational design, novel cyclization techniques to improve pharmacokinetic profiles, and interdisciplinary collaboration among chemists, biologists, and computational scientists, promise to expand the scope of cyclic peptide-based therapeutics. These advancements can potentially address complex diseases and advance the broader field of biological drug development.

Key Elements in Integrity Management of Underground Gas Storage: A Framework for Energy Safety

Gas reservoir-type underground gas storage (UGS) plays a critical role in China’s natural gas reserves and peak shaving, serving as an essential component of the energy security system. Its unique cyclic injection and production operations not only stabilize the natural gas supply but also impose stringent requirements on the safety and integrity of geological structures, wellbores, and surface facilities. Weaknesses in current practices can cause accidents, directly threatening energy security. Therefore, continuously improving integrity management is the key to mitigating energy risks. Currently, the integrity management of gas storage faces challenges such as an abundance of standards and the complexity of management elements, which affect both operational safety and management efficiency. To address these issues, this study systematically analyzes domestic and international standards related to gas storage and establishes a technical system based on “three-in-one” integrity management (geological structure, wellbore, and surface facilities). Key elements of integrity management are identified and optimized, and recommended execution standards for critical factors are proposed to provide a theoretical basis and decision-making support for the safe operation of gas storage. This study not only offers a reference for optimizing and implementing integrity management standards but also has significant practical implications for enhancing energy security and reducing energy risks, ensuring the smooth execution of China’s natural gas reserve and peak shaving initiatives.

Valorization of Humins by Cyclic Levulinic Acid Production Using Polyoxometalates and Formic Acid.

At a time when increasing attention is paid to sustainability in chemistry, levulinic acid (LA) is one of the most important platform chemicals for the goal of overcoming our dependence on fossil raw materials. In this work, a new catalytic route for the effective utilization of these humin byproducts, enabling a cyclic synthesis of LA using formic acid (FA) as organocatalyst is proposed. Selective catalytic oxidation (SCO) of humins using the H5PV2Mo10O40 (HPA-2) polyoxometalate (POM) catalyst produces FA that can be isolated from the aqueous reaction mixture by using nanofiltration membranes accompanied by a complete catalyst recycling (>99%). After concentration of formic acid by distillation, the latter can be used as organocatalyst for levulinic acid production from sugars, whereby the formed humins can in turn be separated and used as substrates for further FA production via SCO to close the catalytic cycle. By using FA as a green and sustainable acidic organocatalyst, relatively high yields of LA (up to 42 mol%) could be achieved.

Effects of tryptophan-selective lipidated glucagon-like peptide 1 (GLP-1) peptides on the GLP-1 receptor.

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs, such as liraglutide and semaglutide, are acylated with fatty acids to delay their degradation by dipeptidyl peptidase-4, the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers). In this study, we evaluated their effects on the GLP-1 receptor in vitro and in vivo. Both novel peptides were shown to increase cyclic adenosine monophosphate production and insulin secretion similarly to that by GLP-1(7-37) and liraglutide in vitro. In addition, these novel peptides lowered blood glucose levels by increasing insulin levels after oral administration of glucose and they suppressed gastrointestinal motility as effectively as liraglutide. The effects of peptide A on activation of satiety-promoting neurons in the arcuate nucleus and the consequent suppression of food intake and body weight were also similar to those of liraglutide, while the effects of peptide B were less than those of liraglutide. Under high-fat diet feeding, both long-term administration of peptide A and peptide B improved glucose tolerance and insulin sensitivity similarly to liraglutide. Thus, tryptophan-selective lipidated GLP-1 peptides are as effective as conventional GLP-1 RAs in reducing plasma glucose levels and body weight and may represent a less demanding method of manufacture of GLP-1 RAs.

Iron and Zinc Metallates Supported on Ion Exchange Resins: Synergistic Catalysts for the Solvent‐Free Cyclic Carbonate Synthesis from Epoxides and CO2

AbstractDespite extensive research into developing efficient and environmentally friendly catalysts for converting CO2 over the last decade, the search for a robust and cost‐effective catalytic system is ongoing. This study describes developing and applying a new catalytic system using inexpensive ferrate and zincate anions immobilized on easily available commercial ion exchange resins (IER) to produce cyclic carbonates from CO2 with high efficiency and low cost. Two polystyrene‐based anion exchange resins, AmberlystTM A26‐Cl (A26‐Cl) and AmberliteTM IRA‐400‐Cl (IRA400‐Cl), were compared. The results demonstrated the catalysts’ remarkable activity under mild conditions and demonstrated the synergistic effect between the polystyrene support and the active ammonium metallates, presenting a scalable, eco‐friendly method for cyclic carbonate production using waste CO2. A Design of Experiment (DoE) approach was implemented to optimize the catalytic cycloaddition of CO2. The reaction scale‐up to produce a 5 g batch of propylene oxide and conducting recycling tests demonstrated that the catalyst retained its activity over four cycles. The research also explored the use of various epoxides and found that terminal epoxides produced very good yields. In summary, this study introduces a cost‐effective, scalable method for converting CO2 into valuable cyclic carbonates, leveraging the synergistic effects of polystyrene supports and active ammonium metallates.

Coupled hydro-mechanical model for underground hydrogen storage undergoing cyclic injection and production

ABSTRACT Excess renewable energy can be used to generate and store hydrogen underground, offering a secure and econimical solution to the intermittency challenges of renewable energy sources. The success of underground storage relies on understanding and controlling the geo-mechanical integrity of storage sites during cyclic loadings. While geological deformation during natural gas and carbon dioxide storage is well studied, few have investigated pore pressure and in-situ stress variations during cyclic loading, which is unique to underground hydrogen storage sites. This paper presents a predictive analytical model for the pore pressure and stress changes during cyclic loading. The model was derived based on continuous point source injection, a basic hydro-mechanical model while applying the superposition to consider the cyclic loading. The developed model was evaluated for hydrogen and natural gas subjected to cyclic injection and production. Comparing hydrogen and natural gas storage cases can offer valuable insights into the behavior of hydrogen since the deformation of natural gas storage is more studied. Finally, analytical solutions for both storage cases were validated by numerical models with discrepancies between the models amounting to less than 1%. Comparative analysis of the results from 3 to 99 cycles of injection and production for both hydrogen and methane demonstrates that rise in cycle numbers leads to a corresponding rise in stress accumulation in the system. Neglecting the stress accumulation during these cycles can lead to significant geomechanical issues, potentially compromising the storage system’s safety and integrity.

Synergistic catalysis of dual-sites promoted cycloaddition of CO2 with epoxides

This study explores the catalytic efficacy of fluorine-modified 1 wt% copper oxide on MCM-41 (F-1Cu/MCM-41) in carbon dioxide cycloaddition reactions. It delves into reaction mechanisms, active sites, and the practical applicability of the catalyst. Comprehensive examination through in situ diffuse reflectance infrared Fourier transform spectroscopy and other analytical methods substantiated the role of halogen-modified mono-dispersed copper species in carbon dioxide activation and silicon hydroxide sites in epoxide activation, while underscoring the role of Lewis bases and Brønsted acids. Kinetic studies and density functional theory calculations pinpointed carbon dioxide activation as the pivotal step. Furthermore, the catalyst exhibited robust stability and efficiency in continuous flow experiments, sustaining a 99% selectivity towards cyclic carbonate over 150 h. An eco-friendly evaluation confirmed the sustainability of the process, emphasizing its minimal environmental footprint and high efficiency. These results establish fluorine-modified 1 wt% copper oxide on MCM-41 as a formidable candidate for industrial-scale cyclic carbonate production, due to its promising performance and sustainability.

The Role of Vericiguat in Early Phases of Anterior Myocardial Infarction: A Potential Game-Changer?

Anterior myocardial infarction is a critical condition with significant implications for cardiac function and patient prognosis. Despite advancements in reperfusion therapies, optimizing recovery during the early phases of myocardial infarction remains challenging. Anterior myocardial infarction can lead to substantial long-term effects on a patient's health due to extensive damage to the heart muscle, particularly the left ventricle, impacting both quality of life and overall prognosis. Vericiguat, a soluble guanylate cyclase stimulator, has shown promise in heart failure, but its role in early anterior myocardial infarction has not yet been fully explored. By enhancing soluble guanylate cyclase activity, vericiguat may increase cyclic guanosine monophosphate production, leading to vasodilation, inhibition of platelet aggregation, and potential cardioprotective effects. Currently, treatment options for anterior myocardial infarction primarily focus on reperfusion strategies and managing complications. However, there is a critical need for adjunctive therapies that specifically target the pathophysiological changes occurring in the early phases of myocardial infarction. Vericiguat's mechanism of action offers a novel approach to improving vascular function and myocardial health, potentially contributing to innovative treatment strategies that could transform the care and prognosis of patients with anterior myocardial infarction.

Synergistic role of carbon quantum dots on biohydrogen production

Biohybrid system has their distinct ability to improve microbial fermentation. This study demonstrates the role of surface-doped carbon quantum dots (CQDs) on dark fermentative biohydrogen production using lactobacillus organic-hybrid biocatalyst. Herein, nitrogen-doped carbon quantum dots (N-CQDs) with < 5 nm (having a surface charge of +2.6 mV) and un-doped carbon quantum dots (CQDs) (having a surface charge of −4.5 mV) were synthesized via chemical assisted process. Subsequently, the biohybrid systems were constructed via augmentation of N-CQDs and CQDs with Lactobacillus delbreuckii and assessed for biohydrogen production. The results revealed that both the biohybrid systems (N-CQDs- Lactobacillus delbreuckii and CQDs- Lactobacillus delbreuckii) provided improved hydrogen production than that of the native bacterial strain. Interestingly, the obtained N-CQDs- Lactobacillus delbreuckii system provided the maximum hydrogen yield of 2.01 mol/mol hexose, followed by 1.86 mol/mol hexose from CQDs- Lactobacillus delbreuckii, which is about 33 % and 19 % higher than the bare bacterial strain. The electron transfer and metabolic alteration of microbes by carbon quantum dots were assessed using cyclic voltammetry (CV) and VFA production. It was concluded that the improved bio-hydrogen production from N-CQDs- Lactobacillus delbreuckii is attributed to enhanced electron transfer, which regulates the central metabolic pathway of acetate and butyrate synthesis with the least production of lactate and other reduced end product formation.

SARS-CoV-2 spike protein acts as a β-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac β-adrenergic receptor (β-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to β1- and β2-AR, but not to D1-dopamine receptor. These interactions were blocked by β1- and β2-AR blockers. Molecular docking and MST assay of β-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both β-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on β-ARs. Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric β-AR agonist, leading to cardiac β-AR hyperactivity, thus contributing to PASC-CVS.

Who Can Receive Clinical Benefit from Mid-Term Vericiguat Add-on Therapy Among Patients with Systolic Heart Failure Receiving Quadruple Medical Therapy?

Vericiguat, a soluble guanylate cyclase stimulator known for augmenting cyclic guanosine monophosphate production, has garnered substantial clinical attention in patients with systolic heart failure. Despite its proven efficacy, discerning the specific subset of individuals who can enjoy clinical advantages from vericiguat therapy in contemporary real-world clinical practice, particularly among the individuals undergoing "quadruple medical therapy" comprising administration of a beta-blocker, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2 inhibitor, remains an unresolved query. This study involved patients undergoing 3-month vericiguat therapy alongside complete quadruple medical therapy in a contemporary real-world clinical practice. Baseline characteristics associated with the primary outcome, defined as a reduction in serum NT pro-B-type natriuretic peptide (BNP) levels over the 3-month therapeutic duration, were scrutinized. A cohort of 24 patients (median age: 66 years; 20 males) were included. All participants diligently adhered to the 3-month vericiguat therapy in conjunction with the quadruple medical regimen. A higher baseline systolic blood pressure emerged as an independent factor linked to the primary outcome, yielding an adjusted odds ratio of 1.31 (95% confidence interval: 1.03-1.65, P = 0.026) at a threshold of 105 mmHg. This threshold notably stratified the trajectories of serum NT pro-BNP levels during the 3-month vericiguat therapy. In conclusion, preservation of baseline systolic blood pressure emerged as a pivotal determinant for reaping the clinical benefits from mid-term vericiguat therapy among patients with systolic heart failure receiving quadruple medical therapy.

Action research as a meta-methodology: insights from an operations development project

This research addresses action research (AR) as a meta-methodology and uses an operations development project as an illustration to provide some insights on AR as a meta-methodology. First, we report on a six-month action research (AR) project concerning analysing and improving production and inventory performance in an industrial firm in the food and beverage industry. The implementation of a new, basic period cyclic production approach resulted in higher production volumes and higher customer service levels while maintaining inventory levels. Second, we discuss the insights from the project concerning success factors related to novelty, rigour, relevance and usefulness, and applicability in other situations. The use of mixed methods, including case study research, conceptual modelling, mathematical modelling, and heuristic approaches, and the strong research interest of the management team at the company contributed to the success of the project. The novel cyclic production approach was subsequently transferred to other production lines. This AR project supports the perception of AR as serving as a meta-methodological framework, where different research methods can be used at various project stages where required and for triangulation purposes.

The impacts of geothermal gradients on compressed carbon dioxide energy storage in aquifers

Compressed CO2 energy storage in aquifers (CCESA) is new low-cost large scale energy storage technology. To further improve the energy efficiency of CCESA, we propose to combine the geothermal system with CCESA. In order to study the influence of geothermal energy on CCESA, aquifers with large vertical interval and different geothermal gradients from 0.026–0.07 °C/m are designed. The 3d wellbore-reservoir grid of underground part of CCESA was established. The simulation covering 100 days of intermittent initial gas fill and 50 days of cyclic injection and production was conducted. The hydrodynamic and thermodynamic behaviors and energy efficiency of the system were analyzed, comparatively. In the gas fill period, the higher the geothermal gradient, the farther the front of CO2 plume diffuses in the target aquifer, and thus the smaller the pressure accumulation. The temperature, pressure and energy efficiency of produced CO2 increases with the increase of geothermal gradient, while the density of released fluid decreases. The energy efficiency is greater than 1.0 under 6 geothermal gradients. The average energy efficiency of high- and low-pressure reservoirs can reach 1.282 and 1.061 under the geothermal gradient of 0.07 °C/m, which is 21.79 % and 5.5 % higher than that of 0.026 °C/m. The total energy efficiency of the joint system finally can reach 95.1 %. This research well confirms that the geothermal energy can dramatically improve the efficiency of CCESA and can enhance its application.

Advancing hydrogen generation: Kinetic insights and process refinement for sorption-enhanced steam gasification of biomass utilizing waste carbide slag

Sorption enhanced steam gasification of biomass (SESGB) presents a promising approach for producing high-purity H2 with potential for zero or negative carbon emissions. This study investigated the effects of gasification temperature, CaO to carbon in biomass molar ratio [CaO/C], and steam flow on the SESGB process, employing carbide slag (CS) and its modifications, CSSi2 (mass ratio of CS to SiO2 is 98:2) and CSCG5 (mass ratio of CS to coal gangue (CG) is 95:5), as CaO-based sorbents. The investigation included non-isothermal and isothermal gasification experiments and kinetic analyses using corn cob (CC) in a macro-weight thermogravimetric setup, alongside a fixed-bed pyrolysis-gasification system to assess operational parameter effects on gas product. The results suggested that CO2 capture by CaO reduced the mass loss during the main gasification as the [CaO/C] increased. The appropriate temperature for SESGB process should be selected between 550 and 700 °C at atmospheric pressure. The appropriate amount of sorbent or steam could facilitate the gasification reaction, but excessive addition led to adverse effects. Operational parameters influenced the apparent activation energy (Ea) by affecting various gasification reactions. For each test, Ea at the char gasification stage was significantly higher than that at the rapid pyrolysis stage. The addition of CS notably increased H2 concentration and yield, while sharply reducing CO2 levels. H2 concentration initially rose and then fell with greater steam flow, peaking at 76.11 vol% for a steam flow of 1.0 g/min. H2 yield peaked at 298 mL/g biomass with a steam flow of 1.5 g/min, a gasification temperature of 600 °C and a [CaO/C] of 1.0. Increasing gasification temperature remarkably boosted the H2 and CO2 yields. Optimal conditions for the SESGB using CS as a sorbent, determined via response surface methodology (RSM), include a gasification temperature of 666 °C, a [CaO/C] of 1.99, and a steam flow of 0.5 g/min, under which H2 and CO2 yields were 464 and 48 mL/g biomass, respectively. CSSi2 and CSCG5 demonstrated excellent cyclic H2 production stability, maintaining H2 yields around 440 mL/g biomass and low CO2 yields (∼60 mL/g biomass) across five cycles. The study results offer new insights for the high-value utilization of agroforestry biomass and the reduction and resource utilization of industrial waste.

Halloysite-kojic acid conjugate: A sustainable material for the photocatalytic CO2 reduction and fixation for cyclic carbonates production

This study introduces a straightforward synthesis method for producing a hybrid material composed of halloysite and kojic acid, which catalyzes carbon dioxide (CO2) conversion processes. Kojic acid, derived from malted rice fermentation, exhibits inherent chelating properties that facilitate the introduction of copper ions onto the material’s surface. Copper ions, an economically viable alternative to noble metals, catalyze CO2 conversion reactions effectively. The hybrid catalyst was evaluated for two distinct CO2 conversion pathways: photocatalytic methane production under simulated sunlight and CO2 fixation into cyclic carbonates via epoxide reactions. The hybrid material demonstrates remarkable catalytic activity under mild conditions, achieving high conversion efficiencies at 45 °C for methane production and 70 °C for carbonate fixation at atmospheric pressure. Conversion of 31 % and 89 % were achieved for the photocatalytic CO2 reduction and the carbonate fixation, respectively. FT-IR spectra confirmed the functionalization of the material. Additionally, its organic/inorganic hybrid nature is complemented by excellent thermal stability, as studied by TGA. It enables repeated utilization, maintaining a 25 % catalytic activity for methane production and 70 % for carbonate fixation after the fourth reuse. This research highlights the potential of using naturally derived materials for sustainable CO2 mitigation.

Impact of Cyclic Strain on Elastin Synthesis in a 3D Human Myometrial Culture Model.

The synthesis and assembly of mature, organized elastic fibers remains a limitation to the clinical use of many engineered tissue replacements. There is a critical need for a more in-depth understanding of elastogenesis regulation for the advancement of methods to induce and guide production of elastic matrix structures in engineered tissues that meet the structural and functional requirements of native tissue. The dramatic increase in elastic fibers through normal pregnancy has led us to explore the potential role of mechanical stretch in combination with pregnancy levels of the steroid hormones 17β-estradiol and progesterone on elastic fiber production by human uterine myometrial smooth muscle cells in a three-dimensional (3D) culture model. Opposed to a single strain regimen, we sought to better understand how the amplitude and frequency parameters of cyclic strain influence elastic fiber production in these myometrial tissue constructs (MTC). Mechanical stretch was applied to MTC at a range of strain amplitudes (5%, 10%, and 15% at 0.5 Hz frequency) and frequencies (0.1 Hz, 0.5 Hz, 1 Hz, and constant 0 Hz at 10% amplitude), with and without pregnancy-level hormones, for 6 days. MTC were assessed for cell proliferation, matrix elastin protein content, and expression of the main elastic fiber genes, tropoelastin (ELN) and fibrillin-1 (FBN1). Significant increases in elastin protein and ELN and FBN1 mRNA were produced from samples subjected to a 0.5 Hz, 10% strain regimen, as well as samples stretched at higher amplitude (15%, 0.5 Hz) and higher frequency (1 Hz, 10%); however, no significant effects because of third-trimester mimetic hormone treatment were determined. These results establish that a minimum level of strain is required to stimulate the synthesis of elastic fiber components in our culture model and show this response can be similarly enhanced by increasing either the amplitude or frequency parameter of applied strain. Further, our results demonstrate strain alone is sufficient to stimulate elastic fiber production and suggest hormones may not be a significant factor in regulating elastin synthesis. This 3D culture model will provide a useful tool to further investigate mechanisms underlying pregnancy-induced de novo elastic fiber synthesis and assembly by uterine smooth muscle cells.

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Protective Effects of Thymoquinone on Endothelial Cell Dysfunction in Hypercholesterolemia

Background: Increased reactive oxygen species (ROS) have been implicated as important mechanisms that contribute to endothelial dysfunction (ED). The administration of thymoquinone in animal models significantly inhibits ROS production. Purpose: The protective effects of thymoquinone on endothelial cell dysfunction were studied in cholesterol-fed rabbits. Thirty rabbits were randomly divided into five groups. Methods: The negative control group was fed a standard diet, the positive control group was fed the same diet with 2 % cholesterol, the Thymoquinone group was fed the same diet with 2 % cholesterol and Thymoquinone 100 mg/Kg BW/day, 200 mg/Kg BW/day or 400 mg/Kg BW/day. Results: The cholesterol-rich diet significantly increased Malondialdehyde (MDA) in the aortic blood vessels, as reflected by Thiobarbituric Acid-Reactive Substances (TBARS), inhibited endothelium-dependent vascular relaxations to acetylcholine and decrease cyclic GMP were compared with vessels from normal rabbits (negative control). In cholesterol-fed rabbits, Thymoquinone treatment decreased MDA in plasma production, improved endothelium-dependent relaxations to acetylcholine and increase cyclic GMP production. Conclusion: These results suggest that dietary treatment of rabbits with thymoquinone may prevent superoxide anion (O2-) induced inactivation of endothelium-dependent relaxing factor (EDRF), improve the endothelium-dependent relaxation to acetylcholine in the aortic blood vessels, and increase cyclic GMP content in aortic of cholesterol-fed rabbits.

Precision fabrication of polymer nanostructures on recyclable DNA template

AbstractThe fabrication of precisely patterned polymers at the nanoscale is of critical importance. We have previously succeeded in creating various nanopatterned polymers with nanoscale resolution through the use of in situ atom transfer radical polymerization (ATRP) techniques on deoxyribonucleic acid (DNA) origami. However, separating nanopatterned polymers from the origami template without damaging the origami presents a significant challenge, thereby increasing costs and limiting the development of applications involving nanopatterned polymers. Here, we achieved spatially and temporally controlled release of DNA origami templates through photo‐regulation by incorporating azobenzene‐modified DNA into the initiator. Under UV exposure, azobenzene isomerization rapidly induces the disassociation of patterned polymers from the origami template at ambient temperatures, without damaging the DNA origami. Additionally, the released origami template can be reused as a template for the cyclic production of nanopatterned polymers. This method provides a pathway for the large‐scale production of patterned polymers at reduced costs and facilitates dynamic control over the polymer‐DNA complex, with potential applications in both the biomedical and chemical fields.