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Abstract Background Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index—a comprehensive measure of biological aging in a nationally representative cohort of community‐dwelling older adults. Methods We conducted a population‐based, cross‐sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65 years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non‐frail (FI ≤ 0.15), pre‐frail (0.15 0.25). Serum UA levels were quantified through a colorimetric enzymatic assay. Results After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non‐frail counterparts (P

Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Abstract Background Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases. Methods Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR. Results The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process. Conclusion This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.

Cell-laden structures play a pivotal role in various tissue engineering applications, particularly in tissue restoration. Interactions between cells within bioprinted structures are crucial for successful tissue development and regulation of stem cell fate through intricate cell-to-cell signaling pathways. In this study, we developed a new technique that combines polyethylene glycol (PEG)-infused submerged bioprinting with a stretching procedure. This approach facilitated the generation of fully aligned collagen structures consisting of myoblasts and a low concentration (2 wt%) of collagen to efficiently encourage muscle tissue regeneration. By adjusting several processing parameters, we obtained biologically safe and mechanically stable cell-laden collagen filaments with uniaxial alignment. Notably, the cell filaments exhibited markedly elevated cellular activities compared to those exhibited by conventional bioprinted filaments, even at similar cell densities. Moreover, when we implanted structures containing adipose stem cells into mice, we observed a significantly increased level of myogenesis compared to that in normally bioprinted struts. Thus, this promising approach has the potential to revolutionize tissue engineering by fostering enhanced cellular interactions and promoting improved outcomes in regenerative medicine.

Abstract While the impacts of climate change on global food security have been studied extensively, the capability of emerging tools that couple land surface processes and crop growth in reproducing inter‐annual yield variability at regional scale remains to be tested rigorously. In this study, we analyzed the effects of weather variations between years (1999–2019) on regional crop productivity for two agriculturally managed regions with contrasting climate and cropping conditions: the German state of North Rhine‐Westphalia (DE‐NRW) and the Australian state of Victoria (AUS‐VIC), using the latest version of the Community Land Model (CLM5) and the WFDE5 (WATCH Forcing Data methodology applied to ECMWF reanalysis version 5) reanalysis. Overall, the simulation results were able to reproduce the total annual crop yields of certain crops, while also capturing the differences in total yield magnitudes between the domains. However, the simulations showed limitations in correctly capturing inter‐annual differences of crop yield compared to official yield records, which resulted in relatively low correlation coefficients between 0.07 and 0.39 in AUS‐VIC and between 0.11 and 0.42 in DE‐NRW. The mean absolute deviation of simulated winter wheat yields was up to 4.6 times lower compared to state‐wide records from 1999 to 2019. Our results suggest the following limitations of CLM5: (a) limitations in simulating yield responses from plant hydraulic stress; (b) errors in simulating soil moisture contents compared to satellite‐derived data; and (c) errors in the representation of cropland in general, for example, crop parameterizations and human influences.

Abstract Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression.

Abstract Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.

Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management.In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.

Farm-level seasonal irrigation water usage is often highly variable across time and space in an irrigation district. Identifying the driving factors of this variation can help researchers and managers understand the underlying efficiency of water usage, identify the sources of water waste and develop best irrigation practices to facilitate the development of more efficient and sustainable irrigated cropping systems. This study explored driving factors for the seasonal irrigation water usage across an irrigation district in south-eastern Australia, using extensive climate, soil, cropping and water use data from 312 farms (a total of 1099 annual crop water use records). It focused on three irrigated crops (corn/maize, cotton and rice) for 2011–2019. Factors considered included climate, soils, irrigation practices and water allocation, from which key driving factors and their effects on the seasonal irrigation water usage were identified. A Bayesian hierarchical model averaging approach was developed to determine key predictors and estimate seasonal irrigation water usage. The Bayesian hierarchical modelling framework allowed seasonal irrigation water usage to be estimated at all crop-farm-year observation points simultaneously while also enabling different key predictors to be selected for different crop types. Results showed that the seasonal irrigation water usage was mainly driven by irrigation practices and soil, but the water use of different crop types was driven by different subsets of irrigation and soil predictors. Modelling was undertaken in natural log space and the model showed reasonable accuracy in estimating the seasonal irrigation water usage (R2 = 0.62). Our model is considered useful in 1) identifying drivers of variation of the seasonal irrigation water usage across time and space, and 2) suggesting potential adjustments to irrigation practices and quantifying their benefits to reduce irrigation water usage.

Background CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated. Methods KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis. Results CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of β-nicotinamide adenine dinucleotide (NAD+), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1). Conclusion Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD+ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Abstract Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.

Abstract Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases.

Abstract Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

Abstract Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.

Abstract The fabrication of highly porous cell-loaded structures in tissue engineering applications has been a challenging issue because non-porous cell-laden struts can cause severe cell necrosis in the middle region owing to poor transport of nutrients and oxygen. In this study, we propose a versatile handheld 3D printer for the effective fabrication of porous cell-laden methacrylated gelatin (GelMa) with high porosity (≈97%) by air injection and a bubble-making system using mesh filters through which a mixture of air/GelMa bioink is passed. In particular, the pore size and foamability of the cell constructs could be manipulated using various processing parameters (rheological properties of GelMa, filter size and number, and air-bioink volume ratio). To demonstrate the feasibility of the cell construct as a tissue engineering substitute for muscle regeneration, in vitro cellular activities and in vivo regeneration ability of human adipose stem cells were assessed. The in vitro results demonstrated that the human adipose stem cells (hASCs) fabricated using the handheld 3D printer were alive and well-proliferated. Furthermore, the in vivo results showed that the hASCs-constructs directly printed from the handheld 3D printer showed significant restoration of functionality and efficient muscle regeneration in the volumetric muscle loss model of mice. Based on these results, the fabrication method of the porous cell-laden construct could be a promising tool for regenerating muscle tissues.

Abstract Three-dimensional (3D) bioprinting is a highly effective technique for fabricating cell-loaded constructs in tissue engineering. However, the versatility of fabricating precise and complex cell-loaded hydrogels is limited owing to the poor crosslinking ability of cell-containing hydrogels. Herein, we propose an optic-fiber-assisted bioprinting (OAB) process to efficiently crosslink methacrylated hydrogels. By selecting appropriate processing conditions for the photo-crosslinking technique, we fabricated biofunctional cell-laden structures including methacrylated gelatin (Gelma), collagen, and decellularized extracellular matrix. To apply the method to skeletal muscle regeneration, cell-laden Gelma constructs were processed with a functional nozzle having a topographical cue and an OAB process that could induce a uniaxial alignment of C2C12 and human adipose stem cells (hASCs). Significantly higher degrees of cell alignment and myogenic activities in the cell-laden Gelma structure were observed compared with those in the cell construct that was printed using a conventional crosslinking method. Moreover, an in vivo regenerative potential was observed in volumetric muscle defects in a mouse model. The hASC-laden construct significantly induced greater muscle regeneration than the cell construct without topographical cues. Based on the results, the newly designed bioprinting process can prove to be highly effective in fabricating biofunctional cell-laden constructs for various tissue engineering applications.

Abstract A simple predictive biomarker for fatty liver disease is required for individuals with insulin resistance. Here, we developed a supervised machine learning-based classifier for fatty liver disease using fecal 16S rDNA sequencing data. Based on the Kangbuk Samsung Hospital cohort (n = 777), we generated a random forest classifier to predict fatty liver diseases in individuals with or without insulin resistance (n = 166 and n = 611, respectively). The model performance was evaluated based on metrics, including accuracy, area under receiver operating curve (AUROC), kappa, and F1-score. The developed classifier for fatty liver diseases performed better in individuals with insulin resistance (AUROC = 0.77). We further optimized the classifiers using genetic algorithm. The improved classifier for insulin resistance, consisting of ten microbial genera, presented an advanced classification (AUROC = 0.93), whereas the improved classifier for insulin-sensitive individuals failed to distinguish participants with fatty liver diseases from the healthy. The classifier for individuals with insulin resistance was comparable or superior to previous methods predicting fatty liver diseases (accuracy = 0.83, kappa = 0.50, F1-score = 0.89), such as the fatty liver index. We identified the ten genera as a core set from the human gut microbiome, which could be a diagnostic biomarker of fatty liver diseases for insulin resistant individuals. Collectively, these findings indicate that the machine learning classifier for fatty liver diseases in the presence of insulin resistance is comparable or superior to commonly used methods.

Abstract Background Muscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone‐induced muscle wasting. Methods The dexamethasone‐induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied in vivo in wild‐type and PDK4 knockout mice treated with dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis. Results Knockdown of PDK4 was found to prevent glucocorticoid‐induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271 ± 0.102 vs 2.163 ± 0.192, ****P

How dietary restriction increases longevity is still not fully understood. Here, the authors demonstrate that L-threonine is an essential mediator of dietary restriction that prevents age-induced ferroptosis and that dietary supplementation promotes healthy ageing.

Abstract For over a century, numerous proposals for increasing available water in central Australia have been raised, inspired in part by the natural occurrence of the ephemeral lake, Kati Thanda‐Lake Eyre. It has also been proposed that additional rainfall generated by the lake would spread beyond the lake itself, potentially opening up large tracts of uncultivated land to dryland agriculture. Here we use a climate model to examine how adding a permanent lake to Australia's arid center might influence local and regional precipitation. Locally, evaporative cooling from the lake increases low‐level divergence, suppressing precipitation. Regionally, additional moisture from the lake is spread thinly over the Australian continent, resulting in little change to total precipitation. Overall, our results do not support the assertion that maintaining a large inland lake like Kati Thanda‐Lake Eyre in central Australia would significantly increase precipitation, either locally or regionally.

Abstract Climate model estimates show significant groundwater depletion during the 20th century, consistent with global mean sea level (GMSL) budget analysis. However, prior to the Argo float era, in the early 2000’s, there is little information about steric sea level contributions to GMSL, making the role of groundwater depletion in this period less certain. We show that a useful constraint is found in observed polar motion (PM). In the period 1993–2010, we find that predicted PM excitation trends estimated from various sources of surface mass loads and the estimated glacial isostatic adjustment agree very well with the observed. Among many contributors to the PM excitation trend, groundwater storage changes are estimated to be the second largest (4.36 cm/yr) toward 64.16°E. Neglecting groundwater effects, the predicted trend differs significantly from the observed. PM observations may also provide a tool for studying historical continental scale water storage variations.

Sarcopenic obesity is defined as the coexistence of sarcopenia and obesity in the same individual, characterized by of the co-presence of body fat accumulation and muscle loss. This condition is currently a major concern as it is associated with frailty and disabilities such as cardiovascular disease, fractures, dementia, cancer, and increased all-cause mortality. Particularly, older individuals remain at risk of sarcopenic obesity. Progress at several levels is needed to improve the global prognostic outlook for this condition, including the elaboration and implementation of a more uniform definition that may favor the identification and specification of prevalence by age group. Furthermore, improvements in the understanding of the pathogenesis of sarcopenic obesity may lead to the development of more specific therapeutic interventions to improve prognosis. We reviewed the knowledge on sarcopenic obesity and its associations with cardiovascular diseases and mortality.

Background: Frankincense, a resin derived from trees of the Boswellia genus, has been used as an incense and a type of herbal medicine for treating inflammatory diseases such arthritis, chronic bowel illness, and asthma. While endometriosis is a well-known inflammatory gynecological illness caused by the ectopic attachment and development of uterine tissue over the menstrual cycle, the impact of frankincense on this illness is poorly understood. The purpose of this study was to explore the effects of frankincense on endometriosis. Methods: We used a network pharmacological assessment, in vitro and in vivo investigations with a human endometriotic cell line as well as a syngeneic uterine transfer mouse model. High-performance liquid chromatographic analysis was used to compare water-extracted frankincense (Fr) to its reference compounds and validate the sample. Results: A network pharmacological analysis suggested a positive effect of Fr on endometriosis. Fr relieved endometriosis by reducing ectopic endometrial adherence and development, according to both in vivo and in vitro models. We suggested that the ER stress/p53-apoptosis and chemokine-migration/adhesion pathways underlie Fr's anti-endometriotic action using RNA sequencing and bioinformatic analysis. Conclusion: This study revealed the potential effect of Fr on endometriosis using an experimental investigation. Fr may have the potential to be an effective and safe treatment for endometriosis.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Targeted therapy against the epidermal growth factor receptor (EGFR) is a promising treatment approach for NSCLC. However, resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge in its clinical management. EGFR mutation elevates the expression of hypoxia-inducible factor-1 alpha to upregulate the production of glycolytic enzymes, increasing glycolysis and tumor resistance. The inhibition of glycolysis can be a potential strategy for overcoming EGFR-TKI resistance and enhancing the effectiveness of EGFR-TKIs. In this review, we specifically explored the effectiveness of pyruvate dehydrogenase kinase inhibitors and lactate dehydrogenase A inhibitors in combating EGFR-TKI resistance. The aim was to summarize the effects of these natural products in preclinical NSCLC models to provide a comprehensive understanding of the potential therapeutic effects. The study findings suggest that natural products can be promising inhibitors of glycolytic enzymes for the treatment of EGFR-TKI-resistant NSCLC. Further investigations through preclinical and clinical studies are required to validate the efficacy of natural product-based glycolytic inhibitors as innovative therapeutic modalities for NSCLC.

Abstract Background Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle‐specific CR6‐interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass. Methods MKO mice with lower muscle OxPhos were fed a normal chow or high‐fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM‐derived CXCL12 (C–X–C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche‐resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation. Results MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response‐related genes in the extensor digitorum longus (P

Volumetric muscle loss (VML) is associated with a severe loss of muscle tissue that overwhelms the regenerative potential of skeletal muscles. Tissue engineering has shown promise for the treatment of VML injuries, as evidenced by various preclinical trials. The present study describes the fabrication of a cell-laden GelMa muscle construct using an in situ crosslinking (ISC) strategy to improve muscle functionality. To obtain optimal biophysical properties of the muscle construct, two UV exposure sources, UV exposure dose, and wall shear stress were evaluated using C2C12 myoblasts. Additionally, the ISC system showed a significantly higher degree of uniaxial alignment and myogenesis compared to the conventional crosslinking strategy (post-crosslinking). To evaluate the in vivo regenerative potential, muscle constructs laden with human adipose stem cells were used. The VML defect group implanted with the bio-printed muscle construct showed significant restoration of functionality and muscular volume. The data presented in this study suggest that stem cell-based therapies combined with the modified bioprinting process could potentially be effective against VML injuries.

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons. Furthermore, Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction. Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss. Thus, Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.

Abstract Background Sarcopenia is defined as muscle wasting, characterized by a progressive loss of muscle mass and function due to ageing. Diagnosis of sarcopenia typically involves both muscle imaging and the physical performance of people exhibiting signs of muscle weakness. Despite its worldwide prevalence, a molecular method for accurately diagnosing sarcopenia has not been established. Methods We develop an artificial intelligence (AI) diagnosis model of sarcopenia using a published transcriptome dataset comprising patients from multiple ethnicities. For the AI model for sarcopenia diagnosis, we use a transcriptome database comprising 17 339 genes from 118 subjects. Among the 17 339 genes, we select 27 features as the model inputs. For feature selection, we use a random forest, extreme gradient boosting and adaptive boosting. Using the top 27 features, we propose a four‐layer deep neural network, named DSnet‐v1, for sarcopenia diagnosis. Results Among isolated testing datasets, DSnet‐v1 provides high sensitivity (100%), specificity (94.12%), accuracy (95.83%), balanced accuracy (97.06%) and area under receiver operating characteristics (0.99). To extend the number of patient data, we develop a web application (http://sarcopeniaAI.ml/), where the model can be accessed unrestrictedly to diagnose sarcopenia if the transcriptome is available. A focused analysis of the top 27 genes for their differential or co‐expression with other genes implied the potential existence of race‐specific factors for sarcopenia, suggesting the possibility of identifying causal factors of sarcopenia when a more extended dataset is provided. Conclusions Our new AI model, DSnet‐v1, accurately diagnoses sarcopenia and is currently available publicly to assist healthcare providers in diagnosing and treating sarcopenia.

Endometriosis is a gynecological disease prevalent in women of reproductive age, and it is characterized by the ectopic presence and growth of the eutopic endometrium. The pathophysiology and diagnostic biomarkers of endometriosis have not yet been comprehensively determined. To discover molecular markers and pathways underlying the pathogenesis of endometriosis, we identified differentially expressed genes (DEGs) in three Gene Expression Omnibus microarray datasets (GSE11691, GSE23339, and GSE7305) and performed gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) network analyses. We also validated the identified genes via immunohistochemical analysis of tissues obtained from patients with endometriosis or healthy volunteers. A total of 118 DEGs (79 upregulated and 39 downregulated) were detected in each dataset with a lower (fold change) FC cutoff (log2|FC| > 1), and 17 DEGs (11 upregulated and six downregulated) with a higher FC cutoff (log2|FC| > 2). KEGG and GO functional analyses revealed enrichment of signaling pathways associated with inflammation, complement activation, cell adhesion, and extracellular matrix in endometriotic tissues. Upregulation of seven genes (C7, CFH, FZD7, LY96, PDLIM3, PTGIS, and WISP2) out of 17 was validated via comparison with external gene sets, and protein expression of four genes (LY96, PDLIM3, PTGIS, and WISP2) was further analyzed by immunohistochemistry and western blot analysis. Based on these results, we suggest that TLR4/NF-κB and Wnt/frizzled signaling pathways, as well as estrogen receptors, regulate the progression of endometriosis. These pathways may be therapeutic and diagnostic targets for endometriosis.

Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI.Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI

BackgroundPancreatic cancer is one of the most fatal malignancies of the gastrointestinal cancer, with a challenging early diagnosis due to lack of distinctive symptoms and specific biomarkers. The exact etiology of pancreatic cancer is unknown, making the development of reliable biomarkers difficult. The accumulation of patient-derived omics data along with technological advances in artificial intelligence is giving way to a new era in the discovery of suitable biomarkers.MethodsWe performed machine learning (ML)-based modeling using four independent transcriptomic datasets, including GSE16515, GSE62165, GSE71729, and the pancreatic adenocarcinoma (PAC) dataset of the Cancer Genome Atlas. To find candidates for circulating biomarkers, we exported expression profiles of 1,703 genes encoding secretory proteins. Integrating three transcriptomic datasets into either a training or test set, ML-based modeling distinguishing PAC from normal was carried out. Another ML-model classifying long-lived and short-lived patients with PAC was also built to select prognosis-associated features. Finally, circulating level of SCG5 in the plasma was determined from the independent cohort (non-tumor = 25 and pancreatic cancer = 25). We also investigated the impact of SCG5 on adipocyte biology using recombinant protein.ResultsThree distinctive ML-classifiers selected 29-, 64- and 18-featured genes, recognizing the only common gene, SCG5. As per the prediction of ML-models, the SCG5 transcripts was significantly reduced in PAC and decreased further with the progression of the tumor, indicating its potential as a diagnostic as well as prognostic marker for PAC. External validation of SCG5 using plasma samples from patients with PAC confirmed that SCG5 was reduced significantly in patients with PAC when compared to controls. Interestingly, plasma SCG5 levels were correlated with the body mass index and age of donors, implying pancreas-originated SCG5 could regulate energy metabolism systemically. Additionally, analyses using publicly available Genotype-Tissue Expression datasets, including adipose tissue histology and pancreatic SCG5 expression, further validated the association between pancreatic SCG5 expression and the size of subcutaneous adipocytes in humans. However, we could not observe any definite effect of rSCG5 on the cultured adipocyte, in 2D in vitro culture.ConclusionCirculating SCG5, which may be associated with adipopenia, is a promising diagnostic biomarker for PAC.

The out-of-phase rainfall and temperature and deep root system make the sequential connection between past rainfall events, soil water storage, and forest growth response complicated and temporally extended in asynchronous climates with Mediterranean-type settings. Unfortunately, these location-specific deep-soil water stores are rarely measured due to logistic and financial constraints, especially in the forest. Therefore, at a large spatio-temporal scale, forest growth relationship to growth drivers is still unknown in these ecosystems, limiting our knowledge to understand the functioning of these forests and their links with hydrological processes. Although process-based water balance models can analyze vegetation growth response to the input climate forcing, they rely upon some significant assumptions regarding plants access to deep soil water storage. Thus, this study aims to understand how the out-of-phase rainfall events affect the current ecosystem growth response, represented by the observed Normalized Difference Vegetation Index (NDVI), across the landscape. We have used an empirical approach on long term observed data without any assumption on access to deep-soil water stores. We estimated time lags between forest growth and rainfall events using a lagged correlation analysis applied to monthly anomalies of NDVI and rainfall against their climatological averages over 2002–2018. The study found that the forests in asynchronous climates exhibit unexpectedly long (10–25 months) memory to rain, and this memory has a systematic pattern across the landscape, which we contend has highlighted three things: 1) the forest in the middle aridity (∼3–4.5) range are relatively more sensitive to changes in the short-term rainfall than the forest in lower (5) aridity regions, could be due to rapid depletion of relatively small soil water storage in between the storms, 2) the variable memory of forest to rain across the landscape can be an indicator of soil depth/rooting depth, and 3) the variable sized location specific antecedent rainfall windows can explain significant variability in forest growth status in asynchronous climates, thus these rainfall windows can be employed to forecast forest growth with a lead time (>4 months).

Due to the limited availability of Root-Zone Soil Moisture (RZSM) information at the regional scale, this paper explores the use of thermal infrared remote sensing to estimate RZSM in agricultural fields. This study presents the Crop Water Stress Index (CWSI) derived from thermal infrared data used as an indicator to estimate root zone soil moisture. Theoretical limits were calculated using canopy and air temperature difference, which is related to vapor pressure deficit. An empirical model was developed using continuous remotely sensed optical, thermal infrared data with limited meteorological data collected from a wheat site, the Dookie experimental farm, Victoria, Australia during 2012 and 2013. Linear and exponential models predicting RZSM using CWSI were constructed and compared in two different cropping seasons. Cross-validation results demonstrate that the linear model predicted RZSM with an error of 3.9% in 2012 and 5.3% in 2013 cropping seasons. The proposed method is applied to another root-zone soil moisture dataset collected during 2002–04 cropping seasons from a corn field site in the Optimizing Production Inputs for Economic and Environmental Enhancement (OPE3) site in the USA. Validation results showed that the model produces reasonable RZSM estimates, except for the high rainfall distribution during cropping seasons even though the crop types of the calibration and validation sites were different. The efficacy of canopy temperature in RZSM estimations was demonstrated using Dookie and OPE3 RZSM dataset. The potential limitation is that sparse vegetation in the initial growth stages produces negative values in CWSI due to the dominant soil surface. Overall, the results support the potential role of the theoretical crop water stress index in root-zone soil moisture estimations.

As the fundamental regulator of energy exchange in the vegetation–soil–atmosphere circulation system, soil moisture is a key parameter for drought monitoring and is indispensable to the land surface hydrological processes. In order to overcome the constraints of the Perpendicular Drought Index, PDI (performs poorly over the fields with dense vegetation and hard to construct the soil line), and the Temperature Vegetation Drought Index, TVDI (requires similar atmospheric forcing and large enough dimension of mapping area), in soil moisture monitoring, a new drought index (Normalized Temperature Drought Index, NTDI) is proposed to explore the spatiotemporal changes of soil moisture by substituting red and near-infrared reflectances with vegetation index and normalized land surface temperature on the basis of the PDI framework. Victoria, Australia, was selected as the study area as it experiences many severe droughts and has been affected for more than ten years. Time series of satellite-based data were applied to evaluate the effectiveness and applicability of the NTDI at the regional scale. Results indicated that the expression of the soil line representing the water condition of the bare soil is easier to obtain in the new trapezoid framework and has good fits with the coefficients of determination (R2) of more than 0.8. Compared with PDI, TVDI and Modified PDI (MPDI) at the cropping sites, NTDI exhibits a relatively better performance in soil moisture monitoring for most days where the R2 achieved can reach to more than 0.7 on DOY 242, 254 and 272. Meanwhile, spatial–temporal mappings of the four drought indices from satellite data were conducted, and the NTDI presented the slightly seasonal variation and effectively described the real spatial characteristics of regional drought. Overall, the NTDI seems to a viable approach and can provide insight into spatial and temporal soil moisture monitoring at different scales.

Soil moisture is an important data which can be used for crop growth estimation, drought prediction, irrigation, and development of hydrological model. However, it is difficult to obtain soil moisture data from inaccessible area or very large area using only general field campaign. For this reason, many soil moisture retrieval algorithms have been developed based on satellite remote sensing technique. It should be noted that both satellite images and ground-based data for the region of interest are required to effectively develop the soil moisture retrieval algorithm using satellite images. Thus, Korea aerospace research institute, KARI, have collected ground-based data containing soil moisture, soil temperature, and crop height in collaboration with the university of Melbourne from wheat cropping fields in Australia which are suitable for the development of soil moisture retrieval algorithm. The ground-based data was collected from wheat cropping fields containing various types of soils for about 7 months from May 2019 to November 2019.

The world is facing the new challenges of an aging population, and understanding the process of aging has therefore become one of the most important global concerns. Sarcopenia is a condition which is defined by the gradual loss of skeletal muscle mass and function with age. In research and clinical practice, sarcopenia is recognized as a component of geriatric disease and is a current target for drug development. In this review we define this condition and provide an overview of current therapeutic approaches. We further highlight recent findings that describe key pathophysiological phenotypes of this condition, including alterations in muscle fiber types, mitochondrial function, nicotinamide adenine dinucleotide (NAD+) metabolism, myokines, and gut microbiota, in aged muscle compared to young muscle or healthy aged muscle. The last part of this review examines new therapeutic avenues for promising treatment targets. There is still no accepted therapy for sarcopenia in humans. Here we provide a brief review of the current state of research derived from various mouse models or human samples that provide novel routes for the development of effective therapeutics to maintain muscle health during aging.

Abstract Background Perturbation in cell adhesion and growth factor signalling in satellite cells results in decreased muscle regenerative capacity. Cdon (also called Cdo) is a component of cell adhesion complexes implicated in myogenic differentiation, but its role in muscle regeneration remains to be determined. Methods We generated inducible satellite cell‐specific Cdon ablation in mice by utilizing a conditional Cdon allele and Pax7 CreERT2. To induce Cdon ablation, mice were intraperitoneally injected with tamoxifen (tmx). Using cardiotoxin‐induced muscle injury, the effect of Cdon depletion on satellite cell function was examined by histochemistry, immunostaining, and 5‐ethynyl‐2'‐deoxyuridine (EdU) incorporation assay. Isolated myofibers or myoblasts were utilized to determine stem cell function and senescence. To determine pathways related to Cdon deletion, injured muscles were subjected to RNA sequencing analysis. Results Satellite cell‐specific Cdon ablation causes impaired muscle regeneration with fibrosis, likely attributable to decreased proliferation, and senescence, of satellite cells. Cultured Cdon‐depleted myofibers exhibited 32 ± 9.6% of EdU‐positive satellite cells compared with 58 ± 4.4% satellite cells in control myofibers (P < 0.05). About 32.5 ± 3.7% Cdon‐ablated myoblasts were positive for senescence‐associated β‐galactosidase (SA‐β‐gal) while only 3.6 ± 0.5% of control satellite cells were positive (P < 0.001). Transcriptome analysis of muscles at post‐injury Day 4 revealed alterations in genes related to mitogen‐activated protein kinase signalling (P < 8.29 e−5) and extracellular matrix (P < 2.65 e−24). Consistent with this, Cdon‐depleted tibialis anterior muscles had reduced phosphorylated extracellular signal‐regulated kinase (p‐ERK) protein levels and expression of ERK targets, such as Fos (0.23‐fold) and Egr1 (0.31‐fold), relative to mock‐treated control muscles (P < 0.001). Cdon‐depleted myoblasts exhibited impaired ERK activation in response to basic fibroblast growth factor. Cdon ablation resulted in decreased and/or mislocalized integrin β1 activation in satellite cells (weak or mislocalized integrin1 in tmx = 38.7 ± 1.9%, mock = 21.5 ± 6%, P < 0.05), previously linked with reduced fibroblast growth factor (FGF) responsiveness in aged satellite cells. In mechanistic studies, Cdon interacted with and regulated cell surface localization of FGFR1 and FGFR4, likely contributing to FGF responsiveness of satellite cells. Satellite cells from a progeria model, Zmpste24−/− myofibers, showed decreased Cdon levels (Cdon‐positive cells in Zmpste24−/− = 63.3 ± 11%, wild type = 90 ± 7.7%, P < 0.05) and integrin β1 activation (weak or mislocalized integrin β1 in Zmpste24−/− = 64 ± 6.9%, wild type = 17.4 ± 5.9%, P < 0.01). Conclusions Cdon deficiency in satellite cells causes impaired proliferation of satellite cells and muscle regeneration via aberrant integrin and FGFR signalling.

Abstract Background Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator‐activated receptor γ coactivator α (PGC‐1α) inducers and report its potential as a drug for muscle wasting. Methods The effects of indoprofen treatment on dexamethasone‐induced atrophy in mice and in 3‐phosphoinositide‐dependent protein kinase‐1 (PDK1)‐deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic‐related and oxidative metabolism‐related proteins. Young, old, and disuse‐induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results In young (3‐month‐old) and aged (22‐month‐old) mice, indoprofen treatment activated oxidative metabolism‐related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP‐activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC‐1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short‐term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen‐induced AKT/S6K activation and hypertrophic response. Conclusions Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC‐1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases.

Abstract The Integrated Multi‐satellitE Retrievals for Global Precipitation Measurement mission (IMERG) aims to deliver the “best” precipitation estimation from space and has attracted much attention. The Version 05 of IMERG products including the near‐real‐time “Early” and “Late” run products (IMERG‐E and IMERG‐L, respectively), and the post‐real‐time “Final” run IMERG product (IMERG‐F) are assessed at both national and basin scales against gauge observations over Mainland China for a 4‐year period (from April 2014 to March 2018). As control products for comparison, their predecessor Tropical Rainfall Measurement Mission (TRMM) Multi‐satellite Precipitation Analysis (TMPA) products (i.e., TMPA‐RT and TMPA‐V7) are also employed. Components analysis confirms the best performance of IMERG‐F among the five SPEs in three different categories. All five SPEs feature increasing bias and root mean square difference (RMSD) with increasing daily gauge total precipitation, and such issue is less pronounced for IMERG‐F—as evidenced by the lowest bias and RMSD across all precipitation rates. Besides, compared to TMPA, IMERG products exhibit better accuracy in detecting real precipitation evens, especially for light‐to‐medium rain (

Purpose We evaluated the relationship of cancer-associated fibroblasts (CAFs) and desmoplastic reactions with cancer invasiveness and long-term outcomes in patients with colorectal cancer (CRC). Methods Histologic evaluation of mature CAFs and desmoplasia was performed by observing the collagen fiber structure and fibroblast cytomorphology in the intratumoral stroma and invasive front of CRC tissues. Cancer-cell invasiveness was evaluated using lymphatic invasion, vascular invasion, perineural invasion, tumor budding, and tumor growth patterns. Overall survival and systemic recurrence were analyzed. A network analysis was performed between CAF maturation, desmoplastic reaction, and cancer invasiveness. Results The proportions of mature CAFs in the intratumoral stroma and the invasive front were 57.6% and 60.3%, respectively. Epidermal growth factor receptor (EGFR) overexpression was significantly higher in the mature CAFs in the invasive front as compared to immature CAFs. Lymphatic invasion increased as the number of mature fibroblasts in the intratumoral stroma increased. Tumor budding was observed in almost half of both mature and immature stroma samples and occurred more frequently in infiltrating tumors. On network analysis, well-connected islands were identified that was associated with EGFR overexpression, CAF maturation, and infiltrating tumor growth patterns leading to tumor budding. Conclusion The maturity of CAFs and desmoplastic reactions were associated with cancer invasion. However, the cytomorphologic characteristics of CAFs were insufficient as an independent prognostic factor for patients with CRC.

X-band KOMPSAT-5 provides a good perspective for soil moisture retrieval at high-spatial resolution over arid and semi-arid areas. In this paper, an intercomparison of KOMPSAT-5 and C-band Sentinel-1 radar data in soil moisture retrieval was conducted over agricultural fields in Wimmera, Victoria, Australia. Optical images from Sentinel-2 were also used to calculate the scattering contribution of vegetation. This study employed a new semi-empirical vegetation scattering model with a linear association of soil moisture with observed backscatter coefficient and vegetation indices. The Combined Vegetation Index (CVI) was proposed and first used to parameterize vegetation water content. As a result, the vegetation scattering model was developed to monitor soil moisture based on remotely sensed data and ground measurements. Application of the algorithm over dryland wheat field sites demonstrated that the estimated satellite-based soil moisture contents have good linear relationships with the ground measurements. The correlation coefficients (R) are 0.862 and 0.616, and the root mean square errors (RMSEs) have the values of 0.020 cm3/cm3 and 0.032 cm3/cm3 at X- and C-bands, respectively. Furthermore, the validation results also indicated that X-band provided higher consistent accuracy for soil moisture inversion than C-band. These results showed significant promise in retrieving soil moisture using KOMPSAT-5 and Sentinel-1 remotely sensed data at high-spatial resolution over agricultural fields, with subsequent uses for crop growth and yield estimation.

We performed targeted metabolomics with machine learning (ML)-based interpretation to identify metabolites that distinguish the progression of nonalcoholic fatty liver disease (NAFLD) in a cohort. Plasma metabolomics analysis was conducted in healthy control subjects (n = 25) and patients with NAFL (n = 42) and nonalcoholic steatohepatitis (NASH, n = 19) by gas chromatography-tandem mass spectrometry (MS/MS) and liquid chromatography-MS/MS as well as RNA sequencing (RNA-seq) analyses on liver tissues from patients with varying stages of NAFLD (n = 12). The resulting metabolomic data were subjected to routine statistical and ML-based analyses and multi-omics interpretation with RNA-seq data. We found 6 metabolites that were significantly altered in NAFLD among 79 detected metabolites. Random-forest and multinomial logistic regression analyses showed that eight metabolites (glutamic acid, cis-aconitic acid, aspartic acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, myristoleic acid, and tyrosine) could distinguish the three groups. Then, the recursive partitioning and regression tree algorithm selected three metabolites (glutamic acid, isocitric acid, and aspartic acid) from these eight metabolites. With these three metabolites, we formulated an equation, the MetaNASH score that distinguished NASH with excellent performance. In addition, metabolic map construction and correlation assays integrating metabolomics data into the transcriptome datasets of the liver showed correlations between the concentration of plasma metabolites and the expression of enzymes governing metabolism and specific alterations of these correlations in NASH. Therefore, these findings will be useful for evaluation of altered metabolism in NASH and understanding of pathophysiologic implications from metabolite profiles in relation to NAFLD progression.

Missing data and low data quality are common issues in field observations of actual evapotranspiration (ETa) from eddy-covariance systems, which necessitates the need for gap-filling techniques to improve data quality and utility for further analyses. A number of models have been proposed to fill temporal gaps in ETa or latent heat flux observations. However, existing gap-filling approaches often use multi-variate models that rely on relationships between ETa and other meteorological and flux variables, highlighting a critical lack of parsimonious gap-filling models. This study aims to develop and evaluate parsimonious approaches to fill gaps in ETa observations. We adapted three gap-filling models previously used for other meteorological variables but never applied to infill sub-daily ETa or flux observations from eddy-covariance systems before. All three models are solely based on the observed diurnal patterns in the ETa data, which infill gaps in sub-daily data with sinusoidal functions (Sinusoidal), smoothing functions (Smoothing) and pattern matching (MaxCor) approaches, respectively. We presented a systematic approach for model evaluation, considering multiple patterns of data gaps during different times of the day. The three gap-filling models were evaluated together with another benchmarking gap-filling model, mean diurnal variation (MDV) that has been commonly used and has similar data requirement. We used a case study with field measurements from an EC system over summer 2020–2021, at a maize field in southeastern Australia. We identified the MaxCor model as the best gap-filling model, which informs the diurnal pattern of the day to infill by using another day with similar temporal patterns and complete data. Following the MaxCor model, the MDV and the Sinusoidal models show comparable performances. We further discussed the infilling models in terms of their dependence on data availability and their suitability for different practical situations. The MaxCor model relies on high data availability for both days with complete data and the available records within each day to infill. The Sinusoidal model does not rely on any day with complete data, which makes it the ideal choice in situations where days with complete records are limited.

The forecast of warmer weather, and reduced precipitation and streamflow under climate change makes freshwater biota particularly vulnerable to being exposed to temperature extremes. Given the importance of temperature to regulate vital physiological processes, the availability of discrete cold-water patches (CWPs) in rivers to act as potential thermal refugia is critical to support freshwater ecosystem function. Being able to predict their spatial distribution at riverscape scales is the first step to understanding the capacity to maintain thermal refuges and to inform future river management strategies. Novel Unmanned Aerial Vehicle (UAV)-based Thermal Infra-Red (TIR) imagery technologies provide an opportunity to assess riverscape stream temperature. On the example of a 50 km linear length of the groundwater-dominated Upper Ovens River (Australia), this study presents a methodology addressing critical challenges in UAV-based TIR and optical data acquisition, processing, and interpretation. Our methodological approach generated 49 georeferenced high-resolution TIR and optical orthomosaicked imagery sets. The imagery sets allowed us to identify river-length longitudinal patterns of temperature and to detect, characterize, and classify 260 CWPs. Both stream and CWPs temperatures increased but presented considerable variability with downstream distance. CWPs were non-uniformly distributed along the riverscape, with emergent hyporheic water types dominating, followed by deep pools, shading, side channels, and tributaries. We found associations between CWPs and key physical controls including land use, riparian vegetation, longitudinal and lateral CWP location, and CWP area size, illustrating processes acting at multiple spatial scales. This study provides a basis for future works on the thermal associations with physical controls over a riverscape, and it highlights the major challenges and limitations of the use of UAV-based TIR and optical imagery to be used in future applications. In conjunction with studies of thermally linked ecological processes, the predictions of CWPs can help prioritize river restoration measures as effective climate adaptation tools.

Mapping irrigated areas using remotely sensed imagery has been widely applied to support agricultural water management; however, accuracy is often compromised by the in-field heterogeneity of and interannual variability in crop conditions. This paper addresses these key issues. Two classification methods were employed to map irrigated fields using normalized difference vegetation index (NDVI) values derived from Landsat 7 and Landsat 8: a dynamic thresholding method (method one) and a random forest method (method two). To improve the representativeness of field-level NDVI aggregates, which are the key inputs in our methods, a Gaussian mixture model (GMM)-based filtering approach was adopted to remove noncrop pixels (e.g., trees and bare soils) and mixed pixels along the field boundary. To improve the temporal transferability of method one we dynamically determined the threshold value to account for the impact of interannual weather variability based on the dynamic range of NDVI values. In method two an innovative training sample pool was designed for the random forest modeling to enable automatic calibration for each season, which contributes to consistent performance across years. The irrigated field mapping was applied to a major irrigation district in Australia from 2011 to 2018, for summer and winter cropping seasons separately. The results showed that using GMM-based filtering can markedly improve field-level data quality and avoid up to 1/3 of omission errors for irrigated fields. Method two showed superior performance, exhibiting consistent and good accuracy (kappa > 0.9) for both seasons. The classified maps in wet winter seasons should be used with caution, because rainfall alone can largely meet plant water requirements, leaving the contribution of irrigation to the surface spectral signature weak. The approaches introduced are transferable to other areas, can support multiyear irrigated area mapping with high accuracy, and significantly reduced model development effort.

M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.

Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty acid. Therefore, the thermogenesis of BAT may be harnessed to treat obesity and related diseases. In mice and humans, BAT levels decrease with aging, and the underlying mechanism is elusive. Here, we compared the transcriptomic profiles of both young and aged BAT in response to thermogenic stimuli. The profiles were extracted from the GEO database. Intriguingly, aging does not cause transcriptional changes in thermogenic genes but upregulates several pathways related to the immune response and downregulates metabolic pathways. Acute severe CE upregulates several pathways related to protein folding. Chronic mild CE upregulates metabolic pathways, especially related to carbohydrate metabolism. Our findings provide a better understanding of the effects of aging and metabolic responses to thermogenic stimuli in BAT at the transcriptome level.

Background and objectives: The purpose of this study was to confirm the effect of Galgeunhwanggeumhwangryeon-tang (GGRT) on the skin barrier integrity and inflammation in an atopic dermatitis-like animal model. Materials and Methods: The model was established using lipid barrier elimination (LBE) in BALB/c mice. Ceramide 3B, a control drug, and GGRT were applied to the skin of LBE mice. Gross observation and histological examination were combined with measurement of skin score, trans-epidermal water loss, and pH. The expression of filaggrin, kallikrein-related peptidase 7 (KLK7), protease-activated receptor-2 (PAR-2), thymic stromal lymphopoietin (TSLP), and interleukin 4 (IL-4) was examined. Results: The effect of GGRT on atopic dermatitis was estimated in silico using two individual gene sets of human atopic dermatitis. In animal experiments, GGRT treatment reduced atopic dermatitis-like symptoms, as confirmed via gross and histological observations, skin score, pH change, and trans-epidermal water loss. The expression level of filaggrin increased in the skin of GGRT-treated mice compared to that in the LBE group. The expression levels of KLK7, PAR2, TSLP, and IL-4 were decreased in GGRT-treated mice skin compared to those in LBE mice. Conclusions: We demonstrated that GGRT restored the skin barrier and reduced inflammatory reactions in a murine model of atopic dermatitis.

The conventional Land Surface Temperature (LST)–Normalized Difference Vegetation Index (NDVI) trapezoid model has been widely used to retrieve vegetation water stress. However, it has two inherent limitations: (1) its complex and computationally intensive parameterization for multi-temporal observations and (2) deficiency in canopy water content information. We tested the hypothesis that an improved water stress index could be constructed by the representation of canopy water content information to the LST–NDVI trapezoid model. Therefore, this study proposes a new index that combines three indicators associated with vegetation water stress: canopy temperature through LST, canopy water content through Surface Water Content Index (SWCI), and canopy fractional cover through NDVI in one temporally transferrable index. Firstly, a new optical space of SWCI–NDVI was conceptualized based on the linear physical relationship between shortwave infrared (SWIR) and soil moisture. Secondly, the SWCI–NDVI feature space was parameterized, and an index d(SWCI, NDVI) was computed based on the distribution of the observations in the SWCI–NDVI spectral space. Finally, standardized LST (LST/long term mean of LST) was combined to d(SWCI, NDVI) to give a new water stress index, Temperature Vegetation Water Stress Index (TVWSI). The modeled soil moisture from the Australian Water Resource Assessment—Landscape (AWRA-L) and Soil Water Fraction (SWF) from four FLUXNET sites across Victoria and New South Wales were used to evaluate TVWSI. The index TVWSI exhibited a high correlation with AWRA-L soil moisture (R2 of 0.71 with p < 0.001) and the ground-based SWF (R2 of 0.25–0.51 with p < 0.001). TVWSI predicted soil moisture more accurately with RMSE of 21.82 mm (AWRA-L) and 0.02–0.04 (SWF) compared to the RMSE ranging 28.98–36.68 mm (AWRA-L) and 0.03–0.05 (SWF) were obtained for some widely used water stress indices. The TVWSI could also be a useful input parameter for other environmental models.