Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a multifaceted intracellular protein belonging to the evolutionarily conserved pleckstrin homology-related domain family. Its murine homologue, T-cell death-associated 51 (TDAG51) gene, was initially discovered for its role in activation-induced apoptosis in T-cell hybridomas. In recent years, PHLDA1 has received increased attention due to its association with obesity, fatty liver disease, diabetes, atherosclerosis, and cancer. Accumulating evidence also supports its role in endoplasmic reticulum stress signaling pathways as a crucial mediator of apoptosis, autophagy, and cell proliferation. In this review, the current knowledge of PHLDA1 gene and protein regulation, localization, and function is summarized. This review highlights the pro- and anti-apoptotic roles of PHLDA1 that contribute to vast array of metabolic diseases.
Due to its constant pumping and contraction, the heart requires a substantial amount of energy, with fatty acids (FAs) providing a major part of its adenosine triphosphate (ATP). However, the heart is incapable of making this substrate and attains its FAs from multiple sources, including the action of lipoprotein lipase (LPL). LPL is produced in cardiomyocytes and subsequently secreted to its heparan sulfate proteoglycan (HSPG) binding sites on the plasma membrane. To then move LPL to the endothelial cell (EC) lumen, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) attaches to interstitial LPL and transfers it to the vascular lumen, where the LPL is ready to perform its function of breaking down circulating triglycerides (TG) into FAs. The endo-β-glucuronidase heparanase (Hpa) is unique in that it is the only known mammalian enzyme to cleave heparan sulfate (HS), thereby promoting the abovementioned release of LPL from the cardiomyocyte HSPG. In diabetes, it has been suggested that changes in how the heart generates energy are responsible for the development of diabetic cardiomyopathy (DCM). Following moderate diabetes, with the reduction in glucose utilization, the heart increases its LPL activity at the vascular lumen due to an increase in Hpa action. Although this adaptation might be beneficial to compensate for the underutilization of glucose by the heart, it is toxic over the long term, as harmful lipid metabolite accumulation, along with augmented FA oxidation and thus oxidative stress, leads to cell death. This coincides with the loss of a cardioprotective growth factor—namely, vascular endothelial growth factor B (VEGFB). This review discusses interconnections between Hpa, LPL, and VEGFB and their potential implications in DCM. Given that mechanism-based therapeutic care for DCM is unavailable, understanding the pathology of this cardiomyopathy, along with the contribution of LPL, will help us advance its clinical management.
The aim of this study was to explore the associations of moderate-to-vigorous-intensity physical activity (MVPA) time and sedentary (SED) time with a history of cardiovascular disease (CVD) and multifactorial (i.e., blood pressure (BP), body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), and glycated hemoglobin A1c (HbA1c)) control status among type 2 diabetes mellitus (T2DM) patients in China. A cross-sectional analysis of 9152 people with type 2 diabetes from the Multifactorial Intervention on Type 2 Diabetes (MIDiab) study was performed. Patients were grouped according to their self-reported MVPA time (low, < 150 min·week−1; moderate, 150 to < 450 min·week−1; high, ≥ 450 min·week−1) and SED time (low, < 4 h·d–1; moderate, 4 to < 8 h·d–1; high, ≥ 8 h·d–1). Participants who self-reported a history of CVD were identified as having a CVD risk. Odds ratios (ORs) and 95% confidence intervals (95% CI) of CVD risk and multifactorial control status associated with MVPA time and SED time were estimated using mixed-effect logistic regression models, adjusting for China's geographical region characteristics. The participants had a mean ± standard deviation (SD) age of (60.87 ± 8.44) years; 44.5% were women, and 25.1% had CVD. After adjustment for potential confounding factors, an inverse association between high MVPA time and CVD risk that was independent of SED time was found, whereas this association was not observed in the moderate-MVPA group. A higher MVPA time was more likely to have a positive effect on the control of BMI. Compared with the reference group (i.e., those with MVPA time ≥ 450 min·week−1 and SED time < 4 h·d–1), CVD risk was higher in the low-MVPA group: The OR associated with an SED time < 4 h·d–1 was 1.270 (95% CI, 1.040–1.553) and that associated with an SED time ≥ 8 h·d–1 was 1.499 (95% CI, 1.149–1.955). We found that a high MVPA time (i.e., ≥ 450 min·week−1) was associated with lower odds of CVD risk regardless of SED time among patients with T2DM.
Hydrogen sulfide (H2S) is endogenously produced in adipocytes and fat tissues and stimulates adipogenesis. The integrated pathogenic effects of H2S on the development of obesity and the underlying mechanisms, however, have been unclear. Here, we find that a decreased endogenous H2S level lowered lipid accumulation in mouse adipocytes. Exogenous H2S treatment significantly increased the adipogenesis of primary mouse preadipocytes after six days of adipogenic induction. In the early phase of adipogenesis, H2S increased cell proliferation and prepared cells to go through hyperplasia. After H2S treatment for ten days, preadipocytes exhibited significantly greater cell surface area and diameter, indicating cell hypertrophy. Although it stimulated lipid accumulation and adipogenesis, H2S had no effect on lipolysis. With nutrition overload and high glucose/insulin incubation, H2S further stimulated glucose consumption and deteriorated adipocyte hypertrophy. H2S upregulated hyperplasia genes (CCAAT/enhancer-binding protein (C/EBPβ), cell division cycle 25 (Cdc25), minichromosome maintenance 3 (Mcm3), and cell division cycle (Cdc45)) and cyclin-dependent kinase 2 protein (Cdk2), which regulates cell proliferation. H2S also upregulated the insulin receptor β (Irβ)-activated mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) pathways, leading to adipogenesis. In conclusion, H2S increases adipocyte differentiation, hypertrophy, and hyperplasia, implying that it plays a pathogenic role in obesity disorder.
Myocardial infarction (MI), the most serious of the ischemic heart diseases, is accompanied by myocardial metabolic disorders and the loss of cardiomyocytes. Increasing evidence has shown that long noncoding RNAs (lncRNAs) are involved in various pathological conditions such as cancer and cardiovascular diseases (CVDs), and are emerging as a novel biomarker for these disorders. This study aims to investigate the regulatory role and mechanisms of lncRNAs in myocardial remodeling in the setting of MI. We find that post-infarcted hearts exhibit a reduction of adenosine triphosphate (ATP) and an alteration of the glucose and lipid metabolism genes cluster of differentiation 36 (CD36), hexokinase 1 (HK1), and glucose transporter 4 (GLUT4), accompanied by cardiomyocyte pyroptosis. We then identify a previously unknown conserved lncRNA, AK009126 (cardiomyocyte pyroptosis-associated lncRNA, CPAL), which is remarkably upregulated in the myocardial border zone of MI mice. Importantly, the adeno-associated virus 9 (AAV9)-mediated silencing of endogenous CPAL by its short hairpin RNA (shRNA) partially abrogates myocardial metabolic alterations and cardiomyocyte pyroptosis during MI in mice. Mechanistically, CPAL is shown to bind directly to nuclear factor kappa B (NFκB) and to act as an activator of NFκB to induce NFκB phosphorylation in cardiomyocytes. We also find that CPAL upregulates caspase-1 expression at the transcriptional level and consequently promotes the release of interleukin (IL)-18 and IL-1b from cardiomyocytes. Collectively, our findings reveal the conserved lncRNA CPAL as a new regulator of cardiac metabolic abnormalities and cardiomyocyte pyroptosis in the setting of MI and suggest CPAL as a new therapeutic target to protect cardiomyocytes against ischemic injury in infarcted hearts.
Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 154 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.
Although the relationship between anesthesia and consciousness has been investigated for decades, our understanding of the underlying neural mechanisms of anesthesia and consciousness remains rudimentary, which limits the development of systems for anesthesia monitoring and consciousness evaluation. Moreover, the current practices for anesthesia monitoring are mainly based on methods that do not provide adequate information and may present obstacles to the precise application of anesthesia. Most recently, there has been a growing trend to utilize brain network analysis to reveal the mechanisms of anesthesia, with the aim of providing novel insights to promote practical application. This review summarizes recent research on brain network studies of anesthesia, and compares the underlying neural mechanisms of consciousness and anesthesia along with the neural signs and measures of the distinct aspects of neural activity. Using the theory of cortical fragmentation as a starting point, we introduce important methods and research involving connectivity and network analysis. We demonstrate that whole-brain multimodal network data can provide important supplementary clinical information. More importantly, this review posits that brain network methods, if simplified, will likely play an important role in improving the current clinical anesthesia monitoring systems.
Next-generation sequencing technology has transformed our ability to assess the taxonomic composition functions of host-associated microbiota and microbiomes. More human microbiome research projects—particularly those that explore genomic mutations within the microbiome—will be launched in the next decade. This review focuses on the coevolution of microbes within a microbiome, which shapes strain-level diversity both within and between host species. We also explore the correlation between microbial genomic mutations and common metabolic diseases, and the adaptive evolution of pathogens and probiotics during invasion and colonization. Finally, we discuss advances in methods and algorithms for annotating and analyzing microbial genomic mutations.
A synergistic pathway is regarded as a critical measure for tackling the intertwined challenges of climate change and air pollution in China. However, there is as yet no indicator that can comprehensively reflect such synergistic effects; hence, existing studies lack a consistent framework for comparison. Here, we introduce a new synergistic indicator defined as the pollutant generation per gross domestic product (GDP) and adopt an integrated analysis framework by linking the logarithmic mean Divisia index (LMDI) method, response surface model (RSM), and global exposure mortality model (GEMM) to evaluate the synergistic effects of carbon mitigation on both air pollutant reduction and public health in China. The results show that synergistic effects played an increasingly important role in the emissions mitigation of SO2, NOx, and primary particulate matter with an aerodynamic diameter no greater than 2.5 μm (PM2.5), and the synergistic mitigation of pollutants respectively increase from 3.1, 1.4, and 0.3 Mt during the 11th Five-Year Plan (FYP) (2006–2010) to 5.6, 3.7, and 1.9 Mt during the 12th FYP (2011–2015). Against the non-control scenario, synergistic effects alone contributed to a 15% reduction in annual mean PM2.5 concentration, resulting in the prevention of 0.29 million (95% CI: 0.28–0.30) PM2.5-attributable excess deaths in 2015. Synergistic benefits to air quality improvement and public health were remarkable in the developed and population-dense eastern provinces and municipalities. With the processes of urbanization and carbon neutrality in the future, synergistic effects are expected to continue to increase. Realizing climate targets in advance in developed regions would concurrently bring strong synergistic effects to air quality and public health.
Surface acoustic wave (SAW) technology has been extensively explored for wireless communication, sensors, microfluidics, photonics, and quantum information processing. However, due to fabrication issues, the frequencies of SAW devices are typically limited to within a few gigahertz, which severely restricts their applications in 5G communication, precision sensing, photonics, and quantum control. To solve this critical problem, we propose a hybrid strategy that integrates a nanomanufacturing process (i.e., nanolithography) with a LiNbO3/SiO2/SiC heterostructure and successfully achieve a record-breaking frequency of about 44 GHz for SAW devices, in addition to large electromechanical coupling coefficients of up to 15.7%. We perform a theoretical analysis and identify the guided higher order wave modes generated on these slow-on-fast SAW platforms. To demonstrate the superior sensing performance of the proposed ultra-high-frequency SAW platforms, we perform micro-mass sensing and obtain an extremely high sensitivity of approximately 33151.9 MHz·mm2·μg−1, which is about 1011 times higher than that of a conventional quartz crystal microbalance (QCM) and about 4000 times higher than that of a conventional SAW device with a frequency of 978 MHz.
The reusable launch vehicle (RLV) presents a new avenue for reducing cost of space transportation. The landing mechanism, which provides landing support and impact absorption, is a vital component of the RLV at final stage of recovery. This study proposes a novel legged deployable landing mechanism (LDLM) for RLV. The Watt-II six-bar mechanism is adopted to obtain the preferred configuration via the application of the linkage variation approach. To endow the proposed LDLM with advantages of large landing support region, lightweight, and reasonable linkage internal forces, a multi-objective optimization paradigm is developed. Furthermore, the optimal scale parameters for guiding the LDLM prototype design is obtained numerically using the non-dominated sorting genetic algorithm-II (NSGA-II) evolutionary algorithm. A fully-functional scaled RLV prototype is developed by integrating the gravity-governed deploying scheme to facilitate unfolding action to avoid full-range actuation, a dual-backup locking mechanism to enhance reliability of structure stiffening as fully deployed, and a shock absorber (SA) with multistage honeycomb to offer reliable shock absorbing performance. The experimental results demonstrate that the proposed LDLM is capable of providing rapid and smooth deployment (duration less than 1.5 s) with mild posture disturbance to the cabin (yaw and pitch fluctuations less than 6°). In addition, it provides satisfactory impact attenuation (acceleration peak less than 10g) in the 0.2 m freefall test, which makes the proposed LDLM a potential alternative for developing future RLV archetype.
Sodium nitrate passivation has been developed as a new insulation technology for the production of FeSiAl soft magnetic composites (SMCs). In this work, the evolution of coating layers grown at different pH values is investigated involving analyses on their composition and microstructure. An insulation coating obtained using an acidic NaNO3 solution is found to contain Fe2O3, SiO2, Al2O3, and AlO(OH). The Fe2O3 transforms into Fe3O4 with weakened oxidizability of the NO3– at an elevated pH, whereas an alkaline NaNO3 solution leads to the production of Al2O3, AlO(OH), and SiO2. Such growth is explained from both thermodynamic and kinetic perspectives and is correlated to the soft magnetic properties of the FeSiAl SMCs. Under tuned passivation conditions, optimal performance with an effective permeability of 97.2 and a core loss of 296.4 mW∙cm−3 is achieved at 50 kHz and 100 mT.
Metamaterials have attracted increasing attention in recent years due to their powerful abilities in manipulating electromagnetic (EM) waves. However, most previously reported metamaterials are unable to actively control full-band EM waves. In this paper, we propose a thermo-tunable broadband metamaterial (T-TBM) using paraffin-based composites (PD-Cs) with different phase transition temperatures. Active control of the T-TBM reflection loss peaks from low to high frequency is realized by manipulating the solid–liquid state of the PD-Cs at different phase transition temperatures. The absorption peak bandwidth (where the reflection loss value is less than −30 dB) can be changed, while the broad bandwidth absorption (where the reflection loss value is less than −10 dB) is satisfied by adjusting the temperature of the T-TBM. It is shown that the stagnation of the phase transition temperature of the PD-Cs in the T-TBM provides a time window for actively controlling the EM wave absorption response under different thermal conditions. The device has a broad application prospect in the fields of EM absorption, intelligent metamaterials, multifunctional structural devices, and more.
Highly hydrophilic materials enable rapid water delivery and salt redissolution in solar-driven seawater desalination. However, the lack of independent floatability inhibits heat localization at the air/water interface. In nature, seaweeds with internal gas microvesicles can float near the sea surface to ensure photosynthesis. Here, we have developed a seaweed-inspired, independently floatable, but superhydrophilic
(SIFS) solar evaporator. It needs no extra floatation support and can simultaneously achieve continuous water pumping and heat concentration. The evaporator resists salt accumulation, oil pollution, microbial corrosion, and protein adsorption. Densely packed hollow glass microbeads promote intrinsic floatability and heat insulation. Superhydrophilic zwitterionic sulfobetaine hydrogel provides a continuous water supply, redissolves the deposited salt, and endows the SIFS evaporator with excellent anti-fouling properties. With its unprecedented anti-contamination ability, this SIFS evaporator is expected to open a new avenue for designing floatable superhydrophilic materials and solving realworld
issues of solar steam generation in complex environmental conditions.
Alkali-activated slag concrete (AASC) is a new green building material. The amount of CO2 produced by AASC is 1/5th of that produced by ordinary Portland cement concrete (OPCC). In addition, AASC promotes the reuse of slag and other wastes and saves resources. Furthermore, the scope of use of slag has been expanded. The progress of the research on the hydration characteristics, microstructure, interfacial transition zone, and pore structure of AASC based on the relevant literatures was analyzed and summarized in this study. The influences of the slag composition, the type and dosage of the alkali activator, and the curing conditions on the hydration characteristics and the microstructure of the AASC were discussed. Relatively few research results on the microstructure of AASC are available, and the relevant conclusions are not completely consistent. Moreover, there are many constraints on the development of AASC (e.g., complex composition of raw materials of slag, large shrinkage deformation, and low fluidity). Therefore, further research is required.
The Hong Kong–Zhuhai–Macao Bridge (HZMB) involved the installation of 120 mega-cylinders with a diameter of 22 m, weights up to 513 tonnes, and penetration depths up to 33 m using an eight-vibratory hammer group. Due to the lack of engineering experience on the drivability of large-diameter cylinders under multiple vibratory hammers, predicting the penetration rate and time of steel cylinders is an open challenge that has a considerable impact on the construction control of the HZMB. In this study, the vibratory penetration of large-diameter steel cylinders in the HZMB is investigated based on geological surveys, field monitoring, and drivability analysis. The vibratory penetration rate, installation accuracy, and dynamic responses of the steel cylinders at both the eastern and western artificial islands are analyzed. The dynamic soil resistance has a great influence on the cylinder drivability. However, the current design methods for estimating the vibratory driving soil resistance are proven inaccurate without considering the scale effects. Therefore, a modified method with a normalized effective area ratio A¯r,eff is proposed in this study to calculate the vibratory soil resistance for open-ended thin-wall cylinders under unplugged conditions. Considering the scale effects on the vibratory driving soil resistance, the proposed method leads to closer results to the measured data, providing a reference for future engineering practice.
The electrification of building heating is an effective way to meet the global carbon target. As a clean and sustainable electrified heating technology, air-source heat pumps (ASHPs) are widely used in areas lacking central heating. However, as a major component of space heating, heating terminals might not fit well with ASHP in order to achieve both intermittency and comfort. Therefore, this study proposes a novel radiation-adjustable heating terminal combined with an ASHP to achieve electrification, intermittency, and better thermal comfort. Radiant terminals currently suffer from three major problems: limited maximum heating capacity, inability to freely adapt, and difficulty with combining them with ASHPs. These problems were solved by improving the structural design of the novel terminal (Improvement A–E). Results showed that the maximum heating capacity increased by 23.6% and radiation heat transfer ratio from 10.1% to 30.9% was provided for users with the novel terminal. Further, new flat heat pipe (FHP) design improved stability (compressor oil return), intermittency (refrigerant thermal inertia), and safety (refrigerant leakage risk) by reducing the length of exposed refrigerant pipes. Furthermore, a new phased operation strategy was proposed for the novel terminal, and the adjustability of the terminal was improved. The results can be used as reference information for decarbonizing buildings by electrifying heating terminals.
During the coronavirus disease 2019 (COVID-19) emergency, many hospitals were built or renovated around the world to meet the challenges posed by the rising number of infected cases. Environmental management in the hospital life cycle is vital in preventing nosocomial infection and includes many infection control procedures. In certain urgent situations, a hospital must be completed quickly, and work process approval and supervision must therefore be accelerated. Thus, many works cannot be checked in detail. This results in a lack of work liability control and increases the difficulty of ensuring the fulfillment of key infection prevention measures. This study investigates how blockchain technology can transform the work quality inspection workflow to assist in nosocomial infection control under a fast delivery requirement. A blockchain-based life-cycle environmental management framework is proposed to track the fulfillment of crucial infection control measures in the design, construction, and operation stages of hospitals. The proposed framework allows for work quality checking after the work is completed, when some work cannot be checked on time. Illustrative use cases are selected to demonstrate the capabilities of the developed solution. This study provides new insights into applying blockchain technology to address the challenge of environmental management brought by rapid delivery requirements.