Single-arm clinical trials: design, ethics, principles.

Although randomised controlled trials are considered the gold standard in clinical research, they are not always feasible due to limitations in the study population, challenges in obtaining evidence, high costs and ethical considerations. As a result, single-arm trial designs have emerged as one of the methods to address these issues. Single-arm trials are commonly applied to study advanced-stage cancer, rare diseases, emerging infectious diseases, new treatment methods and medical devices. Single-arm trials have certain ethical advantages over randomised controlled trials, such as providing equitable treatment, respecting patient preferences, addressing rare diseases and timely management of adverse events. While single-arm trials do not adhere to the principles of randomisation and blinding in terms of scientific rigour, they still incorporate principles of control, balance and replication, making the design scientifically reasonable. Compared with randomised controlled trials, single-arm trials require fewer sample sizes and have shorter trial durations, which can help save costs. Compared with cohort studies, single-arm trials involve intervention measures and reduce external interference, resulting in higher levels of evidence. However, single-arm trials also have limitations. Without a parallel control group, there may be biases in interpreting the results. In addition, single-arm trials cannot meet the requirements of randomisation and blinding, thereby limiting their evidence capacity compared with randomised controlled trials. Therefore, researchers consider using single-arm trials as a trial design method only when randomised controlled trials are not feasible.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Effects of different restoration stages on soil microbial community composition and diversity in Naolihe Wetland, China.

Soil microorganisms can be used as one of the important indicators of wetland ecosystem restoration. To study the effects of different restoration stages on soil microbial community composition and diversity in Naolihe Wetland, we employed a "time and space parallel" method. Four restoration stages, namely corn field (Corn), short-term restoration wetland (2 years, ST), long-term restoration wetland (8 years, LT) and natural wetland (>25 years, NW), were selected to represent the restoration time and geographical location in Naolihe Nature Wetland. We investigated the composition and diversity of soil microbial communities in different restoration wetland (from corn fields to natural wetlands) by using 16S rRNA and ITS rRNA gene sequencing. We also performed chemical experiments to measure soil enzyme activity and physicochemical properties at each sampling site. The results showed that soil physicochemical properties and enzyme activities significantly differed with the extension of wetland restoration years (p < 0.05). Proteobacteria, Acidobacteria, and Actinobacteria are the most dominant phyla in bacterial. The alpha diversity of soil bacteria was the highest in the corn field (Corn), and ST-LT-NW first decreased and then increased with the extension of wetland restoration years. There are two most dominant phyla (Ascomycota and Mucoromycota) in fungal. However, the alpha diversity of soil fungi was the lowest in the Corn and LT stage, and ST-LT-NW first decreased and then increased with the extension of wetland restoration years. The research findings indicated that the changes in soil physicochemical properties with the extension of wetland restoration years play a significant role in shaping the structure and diversity changes of soil microbial communities. Through the analyses of bacterial and fungal functions using the FUNGuild and FAPROTAX databases, the results showed that the abundance of aerobic bacteria in the soil increased more than that of anaerobic bacteria as the wetland restoration years prolonged, while the abundance of saprotrophic, symbiotic, and pathogenic fungi in the soil significantly decreased with the prolonged wetland restoration years. This study will help us better understand the process of restoration after farmland abandonment, providing valuable reference information for the implementation of a series of wetland ecological restoration projects in the future.

Protocell Flow Reactors for Enzyme and Whole-Cell Mediated Biocatalysis.

The design and construction of continuous flow biochemical reactors comprising immobilized biocatalysts have generated great interest in the efficient synthesis of value-added chemicals. Living cells use compartmentalization and reaction-diffusion processes for spatiotemporal regulation of biocatalytic reactions, and implementing these strategies into continuous flow reactors can offer new opportunities in reactor design and application. Herein, the fabrication of protocell-based continuous flow reactors for enzyme and whole-cell mediated biocatalysis is demonstrated. Semipermeable membranized coacervate vesicles are employed as model protocells that spontaneously sequester enzymes or accumulate living bacteria to produce embodied microreactors capable of single- or multiple-step catalytic reactions. By packing millions of the enzyme/bacteria-containing coacervate vesicles in a glass column, a facile, cost-effective, and modular methodology capable of performing oxidoreductase, peroxidase and lipolytic reactions, enzyme-mediated L-DOPA synthesis, and whole-cell glycolysis under continuous flow conditions, is demonstrated. It is shown that the protocell-nested enzymes and bacterial cells exhibit enhanced activities and stability under deleterious operating conditions compared with their non-encapsulated counterparts. These results provide a step toward the engineering of continuous flow reactors based on cell-like microscale agents and offer opportunities in the development of green and sustainable industrial bioprocessing.

Break down the decentralization-security-privacy trilemma in management of distributed energy systems.

Distributed energy systems encompass a diverse range of generation and storage solutions on the user side, where decentralized management schemes to maximize the overall social welfare are preferred considering their dispersed ownership. However, either security or privacy problems occur in recently proposed schemes. Here we report a decentralized framework leveraging the strengths of blockchain and parallelizable mathematical algorithms to overcome these potential drawbacks. The system owners bid cost functions and operating constraints through masked but coupled management subproblems, which are redistributed by the blockchain to be verifiably solved by competent peers. Such processes are iteratively executed as decisions and shadow prices are exchanged among participants, until an equilibrium is reached. The interactive framework ensures decentralized, privacy-preserving, and secure management of multiple energy sources, and reduces the total cost by 3.0 ~ 7.5% in the test system. Our results benefit the energy prosumers and promote a more active and competitive power grid.

Quantum-centric high performance computing for quantum chemistry.

High performance computing (HPC) is renowned for its capacity to tackle complex problems. Meanwhile, quantum computing (QC) provides a potential way to accurately and efficiently solve quantum chemistry problems. The emerging field of quantum-centric high performance computing (QCHPC), which merges these two powerful technologies, is anticipated to enhance computational capabilities for solving challenging problems in quantum chemistry. The implementation of QCHPC for quantum chemistry requires interdisciplinary research and collaboration across multiple fields, including quantum chemistry, quantum physics, computer science and so on. This perspective provides an introduction to the quantum algorithms that are suitable for deployment in QCHPC, focusing on conceptual insights rather than technical details. Parallel strategies to implement these algorithms on quantum-centric supercomputers are discussed. We also summarize high performance quantum emulating simulators, which are considered a viable tool to explore QCHPC. We conclude with challenges and outlooks in this field.

Mental stress-induced myocardial ischemia detected by global longitudinal strain and quantitative myocardial contrast echocardiography in women with nonobstructive coronary artery disease.

BACKGROUND: The utility of radionuclide myocardial perfusion imaging including positron emission tomography (PET) for diagnosing mental stress-induced myocardial ischemia (MSIMI) is clinically restricted. This study aims to assess the diagnostic performance of novel echocardiographic techniques, including automated strain and quantitative myocardial contrast echocardiography (MCE) with dedicated software and deep neural network (DNN) model, for MSIMI detection. The secondary objective was to explore the correlation between changes in myocardial blood flow (MBF) and MSIMI. METHODS: 72 female patients aged 18 to 75 with angina and nonobstructive coronary artery disease (ANOCA), and 23 healthy controls were prospectively recruited. Both echocardiography with contrast agent and PET imaging were performed during structured mental stress testing. MSIMI was defined as a summed difference score ≥3 on PET. Echocardiographic parameters including left ventricular global longitudinal strain (LVGLS), ß and A×ß were obtained, and their trends during mental stress testing were observed. ΔGLS, ß reserve and A×ß reserve were respectively calculated. RESULTS: 32 ANOCA patients (44%) and 1 control (4%) were diagnosed with MSIMI (P<0.01). For ANOCA patients with MSIMI, LVGLS, ß and A×ß declined to varied extent during mental stress testing compared to those without MSIMI and the controls (P<0.05). Bland-Altman plots demonstrated good consistency between ß reserve and A×ß reserve output by the DNN model and iMCE software. Receiver operating characteristic (ROC) curve analyses showed that ΔGLS, ß reserve and A×ß reserve demonstrated favorable ability to predict MSIMI, especially the combination of A×ß reserve using iMCE analysis and ΔGLS (area under the curve [AUC] 0.94, sensitivity 83%, specificity 97%). CONCLUSIONS: Novel technologies in echocardiography exhibit the potential to be a clinical alternative to cardiac PET for effectively detecting MSIMI. Attenuated MBF response during structured mental stress testing was correlated with MSIMI, providing a reasonable explanation for the chest discomfort persisting in ANOCA women.

Perfluoroalkyl sulfonate induces cardiomyocyte apoptosis via endoplasmic reticulum stress activation and autophagy flux inhibition.

Perfluoroalkyl sulfonate (PFOS) is a commonly used chemical compound that often found in materials such as waterproofing agents, food packaging, and fire retardants. Known for its stability and persistence in the environment, PFOS can enter the human body through various pathways, including water and the food chain, raising concerns about its potential harm to human health. Previous studies have suggested a cardiac toxicity of PFOS, but the specific cellular mechanisms remained unclear. Here, by using AC16 cardiomyocyte as a model to investigate the molecular mechanisms potential the cardiac toxicity of PFOS. Our findings revealed that PFOS exposure reduced cell viability and induces apoptosis in human cardiomyocyte. Proteomic analysis and molecular biological techniques showed that the Endoplasmic Reticulum (ER) stress-related pathways were activated, while the cellular autophagy flux was inhibited in PFOS-exposed cells. Subsequently, we employed strategies such as autophagy activation and ER stress inhibition to alleviate the PFOS-induced apoptosis in AC16 cells. These results collectively suggest that PFOS-induced ER stress activation and autophagy flux inhibition contribute to cardiomyocyte apoptosis, providing new insights into the mechanisms of PFOS-induced cardiomyocyte toxicity.

Orchestrating neuronal activity-dependent translation via the integrated stress response protein GADD34.

In a recent study, Oliveira and colleagues revealed how growth arrest and DNA damage-inducible protein 34 (GADD34), an effector of the integrated stress response, initiates the translation of synaptic plasticity-related mRNAs following brain-derived neurotrophic factor (BDNF) stimulation. This work suggests that GADD34 may link transcriptional products with translation control upon neuronal activation, illuminating how protein synthesis is orchestrated in neuronal plasticity.

An immune cell map of human lung adenocarcinoma development reveals an anti-tumoral role of the Tfh-dependent tertiary lymphoid structure.

The immune responses during the initiation and invasion stages of human lung adenocarcinoma (LUAD) development are largely unknown. Here, we generated a single-cell RNA sequencing map to decipher the immune dynamics during human LUAD development. We found that T follicular helper (Tfh)-like cells, germinal center B cells, and dysfunctional CD8+ T cells increase during tumor initiation/invasion and form a tertiary lymphoid structure (TLS) inside the tumor. This TLS starts with an aggregation of CD4+ T cells and the generation of CXCL13-expressing Tfh-like cells, followed by an accumulation of B cells, and then forms a CD4+ T and B cell aggregate. TLS and its associated cells are correlated with better patient survival. Inhibiting TLS formation by Tfh or B cell depletion promotes tumor growth in mouse models. The anti-tumoral effect of the Tfh-dependent TLS is mediated through interleukin-21 (IL-21)-IL-21 receptor signaling. Our study establishes an anti-tumoral role of the Tfh-dependent TLS in the development of LUAD.

Effects of paternal deprivation on empathetic behavior and the involvement of oxytocin receptors in the anterior cingulate cortex.

Paternal deprivation (PD) impairs social cognition and sociality and increases levels of anxiety-like behavior. However, whether PD affects the levels of empathy in offspring and its underlying mechanisms remain unknown. The present study found that PD increased anxiety-like behavior in mandarin voles (Microtus mandarinus), impaired sociality, reduced the ability of emotional contagion, and the level of consolation behavior. Meanwhile, PD reduced OT neurons in the paraventricular nucleus (PVN) in both male and female mandarin voles. PD decreased the level of OT receptor (OTR) mRNA in the anterior cingulate cortex (ACC) of male and female mandarin voles. Besides, OTR overexpression in the ACC reversed the PD-induced changes in anxiety-like behavior, social preference, emotional contagion, and consolation behavior. Interference of OTR expression in the ACC increased levels of anxiety-like behaviors, while it reduced levels of sociality, emotional contagion, and consolation. These results revealed that the OTR in the ACC is involved in the effects of PD on empathetic behaviors, and provide mechanistic insight into how social experiences affect empathetic behaviors.

Construction of WS2/NC@C nanoflake composites as performance-enhanced anodes for sodium-ion batteries.

The development of layered metal sulfides with stable structure and accessible active sites is of great importance for sodium-ion batteries (SIBs). Herein, a simple liquid-mixing method is elaborately designed to immobilize WS2 nanoflakes on N-doped carbon (NC), then further coat carbon to produce WS2/NC@C. In the formation process of this composite, the presence of NC not only avoids the overlap and improves the dispersion of WS2 nanoflakes, but also creates a connection network for charge transfer, where the wrapped carbon provides a stable chemical and electrochemical reaction interface. Thus, the composite of WS2/NC@C exhibits the desired Na+ storage capacity as anticipated. The reversible capacity reaches the high value of 369.8 mA h g-1 at 0.2 A g-1 after 200 cycles, while excellent rate performances and cycle life are also acquired in that capacity values of 256.7 and 219.6 mA h g-1 at 1 and 5 A g-1 are preserved after 1000 cycles, respectively. In addition, the assembled sodium-ion hybrid capacitors (SIHCs, AC//WS2/NC@C) exhibit an energy/power density of 68 W h kg-1 at 64 W kg-1, and capacity retention of 82.9% at 1 A g-1 after 2000 cycles. The study provides insight into developing layered metal sulfides with eminent performance of Na+ storage.

A self-assembled 3D nanoflowers based nano-ELISA platform for the sensitive detection of pyridaben.

Biomimetic methods are invariably employed to synthesize hybrid organic-inorganic multilevel structure nanoflowers with self-assembly processes in aqueous solutions, which is an ideal way to meet the challenges of immobilizing antibodies or enzymes in nanomaterial based enzyme-linked immunosorbent assay (nano-ELISA). In this study, we developed protein-inorganic hybrid 3D nanoflowers composed of bovine serum albumin (BSA), horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG (IgG-HRP) and copper(Ⅱ) phosphate (BSA-(IgG-HRP)-Cu3(PO4)2) using a self-assembly biomimetic method. The preparation process avoided the use of any organic solvent and protein immobilization did not require covalent modifications. Additionally, the unique hierarchical structure enhances the thermal and storage stability of HRP. The BSA-(IgG-HRP)-Cu3(PO4)2 hybrid 3D nanoflower was then applied to a nano-ELISA platform for pyridaben detection, achieving a 50% inhibition concentration of 3.90 ng mL-1. The nano-ELISA achieved excellent accuracy for pyridaben detection. Such a novel BSA-(IgG-HRP)-Cu3(PO4)2 hybrid 3D nanoflower provide an excellent reagent for small molecule immunoassay.

Comprehensive widely targeted metabolomics to decipher the molecular mechanisms of Dioscorea opposita thunb. cv. Tiegun quality formation during harvest.

Dioscorea opposita Thumb. cv. Tiegun is commonly consumed as both food and traditional Chinese medicine, which has a history of more than two thousand years. Harvest time directly affects its quality, but few studies have focused on metabolic changes during the harvesting process. Here, a comprehensive metabolomics approach was performed to determine the metabolic profiles during six harvest stages. Thirty eight metabolites with significant differences were determined as crucial participants. Related metabolic pathways including phenylalanine, tyrosine and tryptophan biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, phenylpropanoid biosynthesis, flavonoid biosynthesis and tryptophan metabolism were the most active pathways during harvest. The results revealed that temperature has a significant impact on quality formation, which suggested that Dioscorea opposita thumb. cv. Tiegun harvested after frost had higher potential value of traditional Chinese medicine. This finding not only offered valuable guidance for yam production, but also provided essential information for assessing its quality.

Machine learning predicts atomistic structures of multielement solid surfaces for heterogeneous catalysts in variable environments.

Solid surfaces usually reach thermodynamic equilibrium through particle exchange with their environment under reactive conditions. A prerequisite for understanding their functionalities is detailed knowledge of the surface composition and atomistic geometry under working conditions. Owing to the large number of possible Miller indices and terminations involved in multielement solids, extensive sampling of the compositional and conformational space needed for reliable surface energy estimation is beyond the scope of ab initio calculations. Here, we demonstrate, using the case of iron carbides in environments with varied carbon chemical potentials, that the stable surface composition and geometry of multielement solids under reactive conditions, which involve large compositional and conformational spaces, can be predicted at ab initio accuracy using an approach that combines the bond valence model, Gaussian process regression, and ab initio thermodynamics. Determining the atomistic structure of surfaces under working conditions paves the way toward identifying the true active sites of multielement catalysts in heterogeneous catalysis.

Single-cell transcriptomics enable the characterization of local extension in retinoblastoma.

Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

Silencing lncRNA-DARS-AS1 suppresses nonsmall cell lung cancer progression by stimulating miR-302a-3p to inhibit ACAT1 expression.

Long noncoding RNAs (LncRNAs) have been gaining attention as potential therapeutic targets for lung cancer. In this study, we investigated the expression and biological behavior of lncRNA DARS-AS1, its predicted interacting partner miR-302a-3p, and ACAT1 in nonsmall cell lung cancer (NSCLC). The transcript level of DARS-AS1, miR-302a-3p, and ACAT1 was analyzed using qRT-PCR. Endogenous expression of ACAT1 and the expression of-and changes in-AKT/ERK pathway-related proteins were determined using western blotting. MTS, Transwell, and apoptosis experiments were used to investigate the behavior of cells. The subcellular localization of DARS-AS1 was verified using FISH, and its binding site was verified using dual-luciferase reporter experiments. The binding of DARS-AS1 to miR-302a-3p was verified using RNA co-immunoprecipitation. In vivo experiments were performed using a xenograft model to determine the effect of DARS-AS1 knockout on ACAT1 and NSCLC. lncRNA DARS-AS1 was upregulated in NSCLC cell lines and tissues and the expression of lncRNA DARS-AS1 was negatively correlated with survival of patients with NSCLC. Knockdown of DARS-AS1 inhibited the malignant behaviors of NSCLC via upregulating miR-302a-3p. miR-302a-3p induced suppression of malignancy through regulating oncogene ACAT1. This study demonstrates that the DARS-AS1-miR-302a-3p-ACAT1 pathway plays a key role in NSCLC.

Immunoglobulin A response to SARS-CoV-2 infection and immunity.

The novel coronavirus disease (COVID-19) and its infamous "Variants" of the etiological agent termed Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has proven to be a global health concern. The three antibodies, IgA, IgM, and IgG, perform their dedicated role as main workhorses of the host adaptive immune system in virus neutralization. Immunoglobulin-A (IgA), also known as "Mucosal Immunoglobulin", has been under keen interest throughout the viral infection cycle. Its importance lies because IgA is predominant mucosal antibody and SARS family viruses primarily infect the mucosal surfaces of human respiratory tract. Therefore, IgA can be considered a diagnostic and prognostic marker and an active infection biomarker for SARS CoV-2 infection. Along with molecular analyses, serological tests, including IgA detection tests, are gaining ground in application as an early detectable marker and as a minimally invasive detection strategy. In the current review, it was emphasized the role of IgA response in diagnosis, host defense strategies, treatment, and prevention of SARS-CoV-2 infection. The data analysis was performed through almost 100 published peer-reviewed research reports and comprehended the importance of IgA in antiviral immunity against SARS-CoV-2 and other related respiratory viruses. Taken together, it is concluded that secretory IgA- Abs can serve as a promising detection tool for respiratory viral diagnosis and treatment parallel to IgG-based therapeutics and diagnostics. Vaccine candidates that target and trigger mucosal immune response may also be employed in future dimensions of research against other respiratory viruses.

Bacterial Surface Appendages Modulate the Antimicrobial Activity Induced by Nanoflake Surfaces on Titanium.

Bioinspired nanotopography is a promising approach to generate antimicrobial surfaces to combat implant-associated infection. Despite efforts to develop bactericidal 1D structures, the antibacterial capacity of 2D structures and their mechanism of action remains uncertain. Here, hydrothermal synthesis is utilized to generate two 2D nanoflake surfaces on titanium (Ti) substrates and investigate the physiological effects of nanoflakes on bacteria. The nanoflakes impair the attachment and growth of Escherichia coli and trigger the accumulation of intracellular reactive oxygen species (ROS), potentially contributing to the killing of adherent bacteria. E. coli surface appendages type-1 fimbriae and flagella are not implicated in the nanoflake-mediated modulation of bacterial attachment but do influence the bactericidal effects of nanoflakes. An E. coli ΔfimA mutant lacking type-1 fimbriae is more susceptible to the bactericidal effects of nanoflakes than the parent strain, while E. coli cells lacking flagella (ΔfliC) are more resistant. The results suggest that type-1 fimbriae confer a cushioning effect that protects bacteria upon initial contact with the nanoflake surface, while flagella-mediated motility can lead to elevated membrane abrasion. This finding offers a better understanding of the antibacterial properties of nanoflake structures that can be applied to the design of antimicrobial surfaces for future medical applications.