Molecular engineering of PETase for efficient PET biodegradation.

The widespread utilization of polyethylene terephthalate (PET) has caused a variety of environmental and health problems. Compared with traditional thermomechanical or chemical PET cycling, the biodegradation of PET may offer a more feasible solution. Though the PETase from Ideonalla sakaiensis (IsPETase) displays interesting PET degrading performance under mild conditions; the relatively low thermal stability of IsPETase limits its practical application. In this study, enzyme-catalysed PET degradation was investigated with the promising IsPETase mutant HotPETase (HP). On this basis, a carbohydrate-binding module from Bacillus anthracis (BaCBM) was fused to the C-terminus of HP to construct the PETase mutant (HLCB) for increased PET degradation. Furthermore, to effectively improve PET accessibility and PET-degrading activity, the truncated outer membrane hybrid protein (FadL) was used to expose PETase and BaCBM on the surface of E. coli (BL21with) to develop regenerable whole-cell biocatalysts (D-HLCB). Results showed that, among the tested small-molecular weight ester compounds (p-nitrophenyl phosphate (pNPP), p-Nitrophenyl acetate (pNPA), 4-Nitrophenyl butyrate (pNPB)), PETase displayed the highest hydrolysing activity against pNPP. HP displayed the highest catalytic activity (1.94 µM(p-NP)/min) at 50 °C and increased longevity at 40 °C. The fused BaCBM could clearly improve the catalytic performance of PETase by increasing the optimal reaction temperature and improving the thermostability. When HLCB was used for PET degradation, the yield of monomeric products (255.7 µM) was ∼25.5 % greater than that obtained after 50 h of HP-catalysed PET degradation. Moreover, the highest yield of monomeric products from the D-HLCB-mediated system reached 1.03 mM. The whole-cell catalyst D-HLCB displayed good reusability and stability and could maintain more than 54.6 % of its initial activity for nine cycles. Finally, molecular docking simulations were utilized to investigate the binding mechanism and the reaction mechanism of HLCB, which may provide theoretical evidence to further increase the PET-degrading activities of PETases through rational design. The proposed strategy and developed variants show potential for achieving complete biodegradation of PET under mild conditions.

Potential of artificial soil preparation for vegetation restoration using red mud and phosphogypsum.

Red mud and phosphogypsum have long been a focus and challenge in global industrial waste management, and their low-cost and large-scale utilization technology has always been an urgent need. This study is based on the strong acid-base neutralization reaction between red mud and phosphogypsum, which contain an elemental composition similar to that of natural soil, red mud itself has characteristic of clay minerals, and other auxiliary materials (i.e. rice husk powder, bentonite, fly ash, polyacrylamide flocculant and microbial suspension) were added, so as to explore the potential of synergistically prepared artificial soil for vegetation restoration. The results showed that the artificial soils exhibited physicochemical characteristics (e.g., pH, moisture content, cation exchange capacity) similar to those of natural soil, along with abundant organic matter, nitrogen, phosphorus, and potassium contents, meeting the growth requirements of plants. The artificial soils were able to support favorable growth of suitable plants (e.g., sunflower, wheat, rye grass), accumulating high levels of diverse enzymatic activities, comparable to those in natural soils (e.g., catalase, urease, phosphatase), or even surpassing natural soils (e.g., sucrase), and rich microorganism communities, such as Cyanobacteria, Proteobacteria, Actinobacteria in the bacteria domain, and Ascomycota in the fungi domain, were initially developed. It's suggested that preparing 1 ton of artificial soil entails synergistic consumption of 613.7 kg of red mud and 244.6 kg of phosphogypsum, accounting for mass proportions of 61.4 % and 24.5 %, respectively. In future, more evaluations on the leaching loss of nutrients and alkalinity and the environmental risks of heavy metals should be conducted to more references for the artificial soil application. In summary, the preparation of artificial soil is a very simple, efficient, scalable and low-cost collaborative resource utilization scheme of red mud and phosphogypsum, which has great potential for vegetation restoration in some places such as tailings field and soil-deficient depression.

Enhancing the Biological Performance of Titanium Alloy through In Situ Modulation of the Surface Nanostructure: Near-Infrared-Responsive Antibacterial Function and Osteoinductivity.

The poor clinical performance of titanium and its alloy implants is mainly attributed to their lack of antibacterial ability and poor osseointegration. The key and challenge lie in how to enhance their osteoinductivity while imparting antibacterial capability. In this study, a titanium oxide metasurface with light-responsive behavior was constructed on the surface of titanium alloy using an alkaline-acid bidirectional hydrothermal method. The effects of the acid type, acid concentration, hydrothermal time, hydrothermal temperature, and subsequent heat treatments on the optical behavior of the metasurface were systematically investigated with a focus on exploring the influence of the metasurface and photodynamic reaction on the osteogenic activity of osteoblasts. Results show that the type of acid and heat treatment significantly affect the light absorption of the titanium alloy surface, with HCl and post-heat-treatment favoring redshift in the light absorption. Under 808 nm near-infrared (NIR) irradiation for 10 min, in vitro antibacterial experiments demonstrate that the antibacterial rate of the metasurface titanium alloy against Staphylococcus aureus and Escherichia coli were 96.87% and 99.27%, respectively. In vitro cell experiments demonstrate that the nanostructure facilitates cell adhesion, proliferation, differentiation, and expression of osteogenic-related genes. Surprisingly, the nanostructure promoted the expression of relevant osteogenic genes of MC3T3-E1 under 808 nm NIR irradiation. This study provides a method for the surface modification of titanium alloy implants.

Three new flavonoids from the roots of Sophora tonkinensis.

Three new flavonoids including two isoflavanones sophortones A and B (1 and 2), and one chalcone sophortone C (3) were isolated from the roots of Sophora tonkinensis. Their structures were established by UV, IR, HRESIMS, and NMR data. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations.

A mechanical-assisted post-bioprinting strategy for challenging bone defects repair.

Bioprinting that can synchronously deposit cells and biomaterials has lent fresh impetus to the field of tissue regeneration. However, the unavoidable occurrence of cell damage during fabrication process and intrinsically poor mechanical stability of bioprinted cell-laden scaffolds severely restrict their utilization. As such, on basis of heart-inspired hollow hydrogel-based scaffolds (HHSs), a mechanical-assisted post-bioprinting strategy is proposed to load cells into HHSs in a rapid, uniform, precise and friendly manner. HHSs show mechanical responsiveness to load cells within 4 s, a 13-fold increase in cell number, and partitioned loading of two types of cells compared with those under static conditions. As a proof of concept, HHSs with the loading cells show an enhanced regenerative capability in repair of the critical-sized segmental and osteoporotic bone defects in vivo. We expect that this post-bioprinting strategy can provide a universal, efficient, and promising way to promote cell-based regenerative therapy.

Coupling dechlorination and catalytic pyrolysis to produce carbon nanotubes from mixed polyvinyl chloride and polyethylene.

The presence of chlorine in polyvinyl chloride (PVC) presents a major challenge for realizing the high-value utilization of real waste plastics. The objective of this research was to develop a chlorine-resistant process for the preparation of carbon nanotubes (CNTs) from mixed plastics containing PVC. This study investigates the influence of PVC content and various dechlorinating agents (CaO, Na2CO3, red mud (RM), ZSM-5, Fe-Al2O3, Fe(OH)3) on CNTs formation. The results showed that PVC content exceeding 5 % significantly inhibits CNTs formation. Employing dechlorinating agents in the pyrolysis process results in a substantial yield of CNTs from mixed plastics containing 10 % PVC. Among the dechlorinating agents, RM proves to be the most effective, leading to the highest carbon yield (at 30 wt%) and superior CNTs quality. Other dechlorinating agents, except for ZSM-5, yield comparable results, although there were some obvious variations of volatiles. Further investigation of the role of dechlorinating agents from the perspective of volatiles evolution was conducted via Py-GC/MS, and found that the dechlorination agent efficiently absorbs the HCl from mixed plastics pyrolysis, while also exhibiting catalytic and regulatory influence on volatile components. These findings offer valuable insights for the development of a chlorine-resistant process in the preparation of CNTs from mixed plastics that contain PVC.

Carbon sequestration in the subsoil and the time required to stabilize carbon for climate change mitigation.

Soils store large quantities of carbon in the subsoil (below 0.2 m depth) that is generally old and believed to be stabilized over centuries to millennia, which suggests that subsoil carbon sequestration (CS) can be used as a strategy for climate change mitigation. In this article, we review the main biophysical processes that contribute to carbon storage in subsoil and the main mathematical models used to represent these processes. Our guiding objective is to review whether a process understanding of soil carbon movement in the vertical profile can help us to assess carbon storage and persistence at timescales relevant for climate change mitigation. Bioturbation, liquid phase transport, belowground carbon inputs, mineral association, and microbial activity are the main processes contributing to the formation of soil carbon profiles, and these processes are represented in models using the diffusion-advection-reaction paradigm. Based on simulation examples and measurements from carbon and radiocarbon profiles across biomes, we found that advective and diffusive transport may only play a secondary role in the formation of soil carbon profiles. The difference between vertical root inputs and decomposition seems to play a primary role in determining the shape of carbon change with depth. Using the transit time of carbon to assess the timescales of carbon storage of new inputs, we show that only small quantities of new carbon inputs travel through the profile and can be stabilized for time horizons longer than 50 years, implying that activities that promote CS in the subsoil must take into consideration the very small quantities that can be stabilized in the long term.

Spatiotemporal co-optimization of agricultural management practices towards climate-smart crop production.

Co-optimization of multiple management practices may facilitate climate-smart agriculture, but is challenged by complex climate-crop-soil management interconnections across space and over time. Here we develop a hybrid approach combining agricultural system modelling, machine learning and life cycle assessment to spatiotemporally co-optimize fertilizer application, irrigation and residue management to achieve yield potential of wheat and maize and minimize greenhouse gas emissions in the North China Plain. We found that the optimal fertilizer application rate and irrigation for the historical period (1995-2014) are lower than local farmers' practices as well as trial-derived recommendations. With the optimized practices, the projected annual requirement of fertilizer, irrigation water and residue inputs across the North China Plain in the period 2051-2070 is reduced by 16% (14-21%) (mean with 95% confidence interval), 19% (7-32%) and 20% (16-26%), respectively, compared with the current supposed optimal management in the historical reference period, with substantial greenhouse gas emission reductions. We demonstrate the potential of spatiotemporal co-optimization of multiple management practices and present digital mapping of management practices as a benchmark for site-specific management across the region.

Immunotherapy and targeted therapy as first-line treatment for advanced gastric cancer.

For patients diagnosed with advanced gastric or gastroesophageal cancer (AGC) that is not amenable to surgical intervention, the standard of care for first-line treatment consists of fluoropyrimidine and platinum-based chemotherapy. The incorporation of novel agents into these standard first-line regimens could potentially improve patient prognosis; options for such augmentations include both immune-based and targeted therapy combinations. To provide a comparative analysis of these different first-line combination treatments, a network meta-analysis was conducted. Outcome measures comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade 3-4 treatment-related adverse events (TRAEs). Data were drawn from 22 randomized controlled trials, encompassing 10,787 patients and 17 distinct treatment regimens. Our findings suggest that FGFR2b-targeted therapy, specifically when used in combination with chemotherapy (bemarituzumab_chemo), exhibited the greatest efficacy. This was followed by immunotherapy-based combination regimens (CPS ≥5, Sintilimab_chemo). Further, targeted combination therapy featuring CLAUDIN 18.2 (zolbetuximab_chemo) appeared beneficial based on individual patient characteristics. In the case of HER2-positive patients, the trastuzumab_chemo regimen is recommended, as most existing studies have excluded this subpopulation. These results have significant implications for both clinical decision-making and patient care in the realm of advanced gastric or gastroesophageal cancer treatment.

Current advances in the structural biology and molecular engineering of PETase.

Poly(ethylene terephthalate) (PET) is a highly useful synthetic polyester plastic that is widely used in daily life. However, the increase in postconsumer PET as plastic waste that is recalcitrant to biodegradation in landfills and the natural environment has raised worldwide concern. Currently, traditional PET recycling processes with thermomechanical or chemical methods also result in the deterioration of the mechanical properties of PET. Therefore, it is urgent to develop more efficient and green strategies to address this problem. Recently, a novel mesophilic PET-degrading enzyme (IsPETase) from Ideonella sakaiensis was found to streamline PET biodegradation at 30°C, albeit with a lower PET-degrading activity than chitinase or chitinase-like PET-degrading enzymes. Consequently, the molecular engineering of more efficient PETases is still required for further industrial applications. This review details current knowledge on IsPETase, MHETase, and IsPETase-like hydrolases, including the structures, ligand‒protein interactions, and rational protein engineering for improved PET-degrading performance. In particular, applications of the engineered catalysts are highlighted, including metabolic engineering of the cell factories, enzyme immobilization or cell surface display. The information is expected to provide novel insights for the biodegradation of complex polymers.

An integrated view of correlated emissions of greenhouse gases and air pollutants in China.

BACKGROUND: Air pollution in China has raised great concerns due to its adverse effects on air quality, human health, and climate. Emissions of air pollutants (APs) are inherently linked with CO2 emissions through fossil-energy consumption. Knowledge of the characteristics of APs and CO2 emissions and their relationships is fundamentally important in the pursuit of co-benefits in addressing air quality and climate issues in China. However, the linkages and interactions between APs and CO2 in China are not well understood. RESULTS: Here, we conducted an ensemble study of six bottom-up inventories to identify the underlying drivers of APs and CO2 emissions growth and to explore their linkages in China. The results showed that, during 1980-2015, the power and industry sectors contributed 61-79% to China's overall emissions of CO2, NOx, and SO2. In addition, the residential and industrial sectors were large emitters (77-85%) of PM10, PM2.5, CO, BC, and OC. The emissions of CH4, N2O and NH3 were dominated by the agriculture sector (46-82%) during 1980-2015, while the share of CH4 emissions in the energy sector increased since 2010. During 1980-2015, APs and greenhouse gases (GHGs) emissions from residential sources generally decreased over time, while the transportation sector increased its impact on recent emissions, particularly for NOx and NMVOC. Since implementation of stringent pollution control measures and accompanying technological improvements in 2013, China has effectively limited pollution emissions (e.g., growth rates of -10% per year for PM and -20% for SO2) and slowed down the increasing trend of carbon emissions from the power and industrial sectors. We also found that areas with high emissions of CO, NOx, NMVOC, and SO2 also emitted large amounts of CO2, which demonstrates the possible common sources of APs and GHGs. Moreover, we found significant correlations between CO2 and APs (e.g., NOx, CO, SO2, and PM) emissions in the top 5% high-emitting grid cells, with more than 60% common grid cells during 2010-2015. CONCLUSIONS: We found significant correlation in spatial and temporal aspects for CO2, and NOx, CO, SO2, and PM emissions in China. We targeted sectorial and spatial APs and GHGs emission hot-spots, which help for management and policy-making of collaborative reductions of them. This comprehensive analysis over 6 datasets improves our understanding of APs and GHGs emissions in China during the period of rapid industrialization from 1980 to 2015. This study helps elucidate the linkages between APs and CO2 from an integrated perspective, and provides insights for future synergistic emissions reduction.

Assembly and recognition mechanisms of glycosylated PEGylated polyallylamine phosphate nanoparticles: A fluorescence correlation spectroscopy and small angle X-ray scattering study.

HYPOTHESIS: Modification of polyallylamine hydrochloride (PAH) with heterobifunctional low molecular weight polyethylene glycol (PEG) (600 and 1395 Da), and subsequent attachment of mannose, glucose, or lactose sugars to PEG, can lead to formation of polyamine phosphate nanoparticles (PANs) with lectin binding affinity and narrow size distribution. EXPERIMENTS: Size, polydispersity, and internal structure of glycosylated PEGylated PANs were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and small angle X-ray scattering (SAXS). Fluorescence correlation spectroscopy (FCS) was used to study the association of labelled glycol-PEGylated PANs. The number of polymer chains forming the nanoparticles was determined from the changes in amplitude of the cross-correlation function of the polymers after formation of the nanoparticles. SAXS and fluorescence cross-correlation spectroscopy were used to investigate the interaction of PANs with lectins: concanavalin A with mannose modified PANs, and jacalin with lactose modified ones. FINDINGS: Glyco-PEGylated PANs are highly monodispersed, with diameters of a few tens of nanometers and low charge, and a structure corresponding to spheres with Gaussian chains. FCS shows that the PANs are single chain nanoparticles or formed by two polymer chains. Concanavalin A and jacalin show specific interactions for the glyco-PEGylated PANs with higher affinity than bovine serum albumin.

Antisenescence ZIF-8/Resveratrol Nanoformulation with Potential for Enhancement of Bone Fracture Healing in the Elderly.

Accumulation of senescent cells in the elderly impairs bone homeostasis. It is important to alleviate cell senescence and scavenge excessive oxidative stress for enhanced bone fracture healing in elderly patients. In this study, resveratrol (RSV), an antioxidant drug, was encapsulated in a biocompatible zeolitic imidazolate framework-8 (ZIF-8) nanoparticle to protect it from oxidation and improve its bioavailability. Cells responsible for bone healing, including osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), macrophages, and endothelial cells, were used to evaluate the regulatory role of the nanoformulation in the alleviation of cellular senescence and promotion of cell functions. It was proved that the nanoformulation sustainably released RSV with well-preserved bioactivity and improved bioavailability. Cell experiments confirmed that ZIF-8/RSV was capable of alleviating the senescence of cells [human osteoblasts (HOBs), BMSCs, H2O2-induced senescent vascular endothelial cells (HUVECs)] and scavenging excessive intracellular reactive oxygen species (ROS). Excitingly, the ZIF-8/RSV improved the osteogenic ability of senescent osteoblasts and promoted macrophage M2 polarization. In addition, the ZIF-8/RSV also enhanced the angiogenic function of senescent HUVECs. More importantly, the ZIF-8/RSV nanoformulation outperformed the REV alone, indicating the critical role of encapsulation using ZIF-8. These findings suggest that the ZIF-8/RSV nanoformulation exhibits potential for bone fracture treatment in elderly patients.

Reproductive variance can drive behavioral dynamics.

The concept of fitness is central to evolution, but it quantifies only the expected number of offspring an individual will produce. The actual number of offspring is also subject to demographic stochasticity-that is, randomness associated with birth and death processes. In nature, individuals who are more fecund tend to have greater variance in their offspring number. Here, we develop a model for the evolution of two types competing in a population of nonconstant size. The fitness of each type is determined by pairwise interactions in a prisoner's dilemma game, and the variance in offspring number depends upon its mean. Although defectors are preferred by natural selection in classical population models, since they always have greater fitness than cooperators, we show that sufficiently large offspring variance can reverse the direction of evolution and favor cooperation. Large offspring variance produces qualitatively new dynamics for other types of social interactions, as well, which cannot arise in populations with a fixed size or with a Poisson offspring distribution.

Impacts of bariatric surgery on adverse liver outcomes: a systematic review and meta-analysis.

BACKGROUND: Bariatric surgery has been reported to improve degeneration, inflammation, and fibrosis in nonalcoholic fatty liver disease, but the effects of bariatric surgery on the associated clinical outcomes is not known. OBJECTIVES: This work aimed to assess the impacts of bariatric surgery on adverse liver outcomes in people with obesity. SETTING: An electronic search was performed on EMBASE, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL). METHODS: The primary outcome was the incidence of adverse liver outcomes following bariatric surgery. Liver cancer, cirrhosis, liver transplantation, liver failure, and liver-related mortality were defined as adverse hepatic outcomes. RESULTS: We analyzed data from 18 studies comprising 16,800,287 post bariatric surgical patients and 10,595,752 control patients. We found that bariatric surgery reduced the risk of adverse liver outcomes in people with obesity (hazard ratio [HR] = .33, 95% confidence interval [CI] = .31-.34; I2 = 98.1%). The subgroup analysis showed that bariatric surgery reduced the risk of nonalcoholic cirrhosis (HR = .07, 95% CI = .06-.08; I2 = 99.3%) and liver cancer (HR = .37, 95% CI = .35-.39; I2 = 97.8%), although bariatric surgery may also increase the risk of postoperative alcoholic cirrhosis (HR = 1.32, 95% CI = 1.35-1.59). CONCLUSIONS: This systematic review and meta-analysis revealed that bariatric surgery lowered the incidence of adverse hepatic outcomes. However, bariatric surgery may also increase the risk of alcoholic cirrhosis after surgery. Future randomized controlled trials are required to further investigate the effects of bariatric surgery on liver of people with obesity.

Enhanced mild-temperature photothermal therapy by pyroptosis-boosted ATP deprivation with biodegradable nanoformulation.

BACKGROUND: Mild-temperature photothermal therapy (mild PTT) is a safe and promising tumor therapeutic modality by alleviating the damage of healthy tissues around the tumor due to high temperature. However, its therapeutic efficiency is easily restricted by heat shock proteins (HSPs). Thus, exploitation of innovative approaches of inhibiting HSPs to enhance mild PTT efficiency is crucial for the clinical application of PTT. RESULTS: Herein, an innovative strategy is reported: pyroptosis-boosted mild PTT based on a Mn-gallate nanoformulation. The nanoformulation was constructed via the coordination of gallic acid (GA) and Mn2+. It shows an acid-activated degradation and releases the Mn2+ and GA for up-regulation of reactive oxygen species (ROS), mitochondrial dysfunction and pyroptosis, which can result in cellular ATP deprivation via both the inhibiton of ATP generation and incresed ATP efflux. The reduction of ATP and accumulation of ROS provide a powerful approach for inhibiting the expression of HSPs, which enables the nanoformulation-mediated mild PTT. CONCLUSIONS: Our in-vitro and in-vivo results demonstrate that this strategy of pyroptosis-assited PTT can achieve efficient mild PTT efficiency for osteosarcoma therapy.

Fe-Doped Carbon Dots as NIR-II Fluorescence Probe for In Vivo Gastric Imaging and pH Detection.

Carbon dots (CDs) with excellent cytocompatibility, tunable optical properties, and simple synthesis routes are highly desirable for use in optical bioimaging. However, the majority of existing CDs are triggered by ultraviolet/blue light, presenting emissions in the visible/first near-infrared (NIR-I) regions, which do not allow deep tissue penetration. Emerging research into CDs with NIR-II emission in the red region has generated limited designs with poor quantum yield, restricting their in vivo imaging applications due to low penetration depth. Developing novel CDs with NIR-II emissions and high quantum yield has significant and far-reaching applications in bioimaging and photodynamic therapy. Here, it is developed for the first time Fe-doped CDs (Fe-CDs) exhibiting the excellent linear relationship between 900-1200 nm fluorescence-emission and pH values, and high quantum yield (QY-1.27%), which can be used as effective probes for in vivo NIR-II bioimaging. These findings demonstrate reliable imaging accuracy in tissue as deep as 4 mm, reflecting real-time pH changes comparable to a standard pH electrode. As an important example application, the Fe-CDs probe can non-invasively monitor in vivo gastric pH changes during the digestion process in mice, illustrating its potential applications in aiding imaging-guided diagnosis of gastric diseases or therapeutic delivery.

Thyroid-Stimulating Hormone Levels within the Trimester-Specific Reference Intervals Are Correlated with Non-High-Density Lipoprotein Cholesterol and Remnant Cholesterol Concentrations in Pregnant Women.

OBJECTIVE: Thyroid-stimulating hormone (TSH) levels are associated with serum lipid concentrations in the general nonpregnant population. Here, we aimed to establish trimester-specific reference intervals and to explore the associations of their variations within the specific reference intervals during pregnancy. METHODS: Trimester-specific reference intervals were established according to the Clinical and Laboratory Standard Institute EP28-A3c guidelines using a direct sampling method based on a large prospective cohort. After making one-to-one matches, correlation analyses between TSH and lipid index levels, especially within the reference intervals, were conducted. RESULT: A total of 1648 pregnant women for TSH and 2045 subjects for lipids were recruited to establish the trimester-specific reference intervals. The upper reference limit (90% confidence interval) of TSH for pregnant women in the first trimester is 3.95 (3.66-4.29) mIU/L, which is very close to the default value (4.0 mIU/L) recommended by the American Thyroid Association in 2017. Apart from triglyceride and high-density lipoprotein cholesterol, TSH levels were positively associated with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), and remnant cholesterol (RC) either in the entire range or within the specific reference intervals. Of note, the positive correlations between TSH and non-HDL-C and RC were, albeit similarly weak (r < 0.25), relatively more robust (P < .001). CONCLUSION: In this study, we showed positive correlations between TSH and lipid components within trimester-specific reference intervals, highlighting the need for the integrated management of pregnant women over age 35 and with nonoptimal lipid status in China.

Analysis of m6A methylation patterns and tumor microenvironment in endometrial cancer.

BACKGROUND: The N6-methyladenosine (m6A) modification is the most common epigenetic modification in eukaryotic mRNA. In recent years, lots of studies have shown that the tumor microenvironment (TME) plays a critical role in tumor growth and development. However, there are few studies on the interaction between m6A methylation and the TME in uterine corpus endometrial carcinoma (UCEC). METHODS: Three distinct m6A modification patterns were based on 21 m6A regulators of UCEC patients and tumor-free individuals. We investigated the relationship between m6A modification patterns and associated features of the TME. Differentially expressed genes were selected and the m6A score was established to evaluate the prognosis and immunotherapeutic efficacy of UCEC patients. RESULTS: We identified three different m6A modification patterns. The TME infiltrating characteristics were highly consistent with tumors with three distinct immune phenotypes. Besides, our analysis showed that the m6A score was shown to be useful in predicting clinical outcomes. Patients with the low m6A score seemed to have a better prognosis, a stronger immunotherapeutic response, and a higher tumor mutation burden. CONCLUSION: Our study explored the influence of m6A modification and TME on the prognosis of cancer patients, which will contribute to the discovery of immunotherapy strategies to improve their prognosis.

Nicotinamide Mononucleotide Alleviates Osteoblast Senescence Induction and Promotes Bone Healing in Osteoporotic Mice.

Combating the accumulated senescent cells and the healing of osteoporotic bone fractures in the older remains a significant challenge. Nicotinamide mononucleotide (NMN), a precursor of NAD+, is an excellent candidate for mitigating aging-related disorders. However, it is unknown if NMN can alleviate senescent cell induction and enhance osteoporotic bone fracture healing. Here we show that NMN treatment partially reverses the effects of tumor necrosis factor-alpha (TNF-α) on human primary osteoblasts (HOBs): senescent cell induction, diminished osteogenic differentiation ability, and intracellular NAD+ and NADH levels. Mechanistically, NMN restores the mitochondrial dysfunction in HOBs induced by TNF-α evidenced by increased mitochondrial membrane potential and reduced reactive oxidative species and mitochondrial mass. NMN also increases mitophagy activity by down-regulating P62 expression and up-regulating light chain 3B-II protein expression. In addition, the cell senescence protective effects of NMN on HOBs are mitigated by a mitophagy inhibitor (Bafilomycin A1). In vivo, NMN supplementation attenuates senescent cell induction in growth plates, partially prevents osteoporosis in an ovariectomized mouse model, and accelerates bone healing in osteoporotic mice. We conclude that NMN can be a novel and promising therapeutic candidate to enhance bone fracture healing capacity in the older.