Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: To evaluate the role of mPGES-2 in NAFLD, whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy. CONCLUSION: Our study indicates the pathogenic role of mPGES-2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES-2 inhibition in liver steatosis and steatohepatitis.

African Suid Genomes Provide Insights into the Local Adaptation to Diverse African Environments.

African wild suids consist of several endemic species that represent ancient members of the family Suidae and have colonized diverse habitats on the African continent. However, limited genomic resources for African wild suids hinder our understanding of their evolution and genetic diversity. In this study, we assembled high-quality genomes of a common warthog (Phacochoerus africanus), a red river hog (Potamochoerus porcus), as well as an East Asian Diannan small-ear pig (Sus scrofa). Phylogenetic analysis showed that common warthog and red river hog diverged from their common ancestor around the Miocene/Pliocene boundary, putatively predating their entry into Africa. We detected species-specific selective signals associated with sensory perception and interferon signaling pathways in common warthog and red river hog, respectively, which contributed to their local adaptation to savannah and tropical rainforest environments, respectively. The structural variation and evolving signals in genes involved in T-cell immunity, viral infection, and lymphoid development were identified in their ancestral lineage. Our results provide new insights into the evolutionary histories and divergent genetic adaptations of African suids.

Differences in sex- and age-associated mortality in patients with anti-MDA5-positive dermatomyositis.

OBJECTIVES: The effect of sex and age on the outcomes of patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) remains unclear. This study aimed to investigate the impact of sex and age on the prognosis of patients with MDA5+ DM. METHODS: We included 251 patients (women, 156; men, 95), who were newly diagnosed with MDA5+ DM between 2014 and 2021. The outcome was 6-month all-cause mortality after the diagnosis of interstitial lung disease. Cox regression analysis was used to assess the mortality. Adjusted restricted cubic spline analysis was performed to explore the non-linear relationship between age and outcomes. RESULTS: The 6-month mortality rates of women and men were 36.5% and 46.3%, respectively. Multivariate Cox regression revealed that ≥60 years of age was significantly associated with the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.02-5.78). The trend of the risk of 6-month mortality in men was relatively flat until 54 years and increased rapidly afterwards (hazard ratio, 1.14; 95% confidence interval, 1.01-1.29). In contrast, the 6-month mortality rate showed a low linear increasing trend with age among females. CONCLUSIONS: Patients with MDA5+ DM, who received contemporary treatment, had unfavourable outcomes. The 6-month mortality risk increased with age, particularly in male patients aged >54 years.

Genetic Architecture Underlying Nascent Speciation-The Evolution of Eurasian Pigs under Domestication.

Speciation is a process whereby the evolution of reproductive barriers leads to isolated species. Although many studies have addressed large-effect genetic footprints in the advanced stages of speciation, the genetics of reproductive isolation in nascent stage of speciation remains unclear. Here, we show that pig domestication offers an interesting model for studying the early stages of speciation in great details. Pig breeds have not evolved the large X-effect of hybrid incompatibility commonly observed between "good species." Instead, deleterious epistatic interactions among multiple autosomal loci are common. These weak Dobzhansky-Muller incompatibilities confer partial hybrid inviability with sex biases in crosses between European and East Asian domestic pigs. The genomic incompatibility is enriched in pathways for angiogenesis, androgen receptor signaling and immunity, with an observation of many highly differentiated cis-regulatory variants. Our study suggests that partial hybrid inviability caused by pervasive but weak interactions among autosomal loci may be a hallmark of nascent speciation in mammals.

MYB bi-allelic targeting abrogates primitive clonogenic progenitors while the emergence of primitive blood cells is not affected.

MYB is a key regulator of definitive hematopoiesis and it is dispensable for the development of primitive hematopoietic cells in vertebrates. To delineate definitive versus primitive hematopoiesis during differentiation of human embryonic stem cells, we have introduced reporters into the MYB locus and inactivated the gene by bi-allelic targeting. To recapitulate the early developmental events more adequately, the mutant and wild type human embryonic stem cell lines were differentiated in defined culture conditions without the addition of hematopoietic cytokines. The differentiation of the reporter cell lines demonstrated that MYB is specifically expressed throughout emerging hematopoietic cell populations. Here we show that the disruption of the MYB gene leads to severe defects in the development and proliferation of primitive hematopoietic progenitors while the emergence of primitive blood cells is not affected. We also provide evidence that MYB is essential for neutrophil and T cell development and the upregulation of innate immunity genes during hematopoietic differentiation. Our results suggest that the endothelial origin of primitive blood cells is direct and does not include the intermediate step of primitive hematopoietic progenitors.

Effects of Photoperiod on Acetaminophen-Induced Hepatotoxicity in Mice.

PURPOSE: Acetaminophen (APAP) is a clinically popular analgesic and antipyretic drug, but excessive APAP can cause fatal hepatotoxicity. Many factors affect the degree of APAP-induced liver injury. This study aimed to investigate how circadian rhythm affects the development of APAP-induced hepatotoxicity and to clarify the roles of photoperiod and dietary rhythm on APAP-induced hepatotoxicity in mice. METHODS: APAP-induced hepatotoxicity models were established by intraperitoneal injection of APAP (400 mg/kg) to mice. The mice were then divided into three treatment groups: normal diet, reversed diet, and reversed photoperiod. RESULTS: More severe liver injury was observed at zeitgeber time 12 (ZT12) than at zeitgeber time 0 (ZT0) in all treatment groups, suggesting that photoperiod played a critical role in APAP-induced liver injury. We observed a change in the expression of the circadian gene Per2, which may be responsible for regulation of liver injury by photoperiod. Our results showed negligible change in Per2 expression with diet reversion, whereas Cry1, Cry2, and Dbp expressions were more highly affected by diet reversion than was Per2 expression. Downstream effects including liver enzyme expression, GSH level, and inflammation factors were also examined to identify the mechanism of liver injury. The results indicated that the circadian gene Per2 participated in APAP biometabolism by regulating the expression of Cyp2e1, which may explain the more severe hepatotoxicity at ZT12 than at ZT0. CONCLUSION: APAP-induced hepatotoxicity can be mediated by photoperiod through the circadian gene Per2, suggesting that medicines containing APAP should be administered not only with food but also according to the appropriate photoperiod.

Reduced Severity of Outcome of Recurrent Ipsilateral Transient Cerebral Ischemia Compared with Contralateral Transient Cerebral Ischemia in Rats.

BACKGROUND: To investigate whether prior transient ischemic attack (TIA) had a preconditioning effect on subsequent cerebral infarction in a rat model using middle cerebral artery occlusion (MCAO). METHODS: Thirty-six adult male Sprague-Dawley rats were divided into 3 groups: those with transient (5 minutes) left MCAO (left TIA) (n = 15), those with transient right MCAO (right TIA) (n = 15), and a sham operation group (n = 6). Seven days after the initial transient MCAO, rats in all groups underwent permanent left MCAO. After 24 hours, all rats underwent motor function measurement (the Garcia score and tilting plane test), magnetic resonance imaging, postmortem brain examination, and biomarkers of stroke. RESULTS: Following permanent MCAO, the Garcia score, the brain edema area of T2-weighted images, brain infarction volume, and the level of tumor necrosis factor α mRNA of the ipsilateral and contralateral TIA groups showed no significant difference. The angle of sliding off in the tilting plane test, the mean intensity of the brain edema area of T2-weighted images, levels of matrix metalloproteinase 9, interleukin-1ß, inducible nitric oxide synthase mRNA, and apoptosis-related proteins, BAX, and phosphorylated-p38, were lower in the ipsilateral TIA group compared with the contralateral TIA group. CONCLUSION: The main finding of this study was that a transient, mild, unilateral focus of cerebral ischemia (or TIA) in either the left or right hemisphere, which is then followed by a second unilateral severe and focal ischemic event, results in brain injury. The severity of the brain injury following this second ischemic event will be alleviated when the second insult is ipsilateral to the first TIA.

Betaine reduces serum uric acid levels and improves kidney function in hyperuricemic mice.

Betaine as a dietary alkaloid has attracted the attention of patients with kidney diseases. This study aimed to investigate the effects of betaine on serum uric acid levels and kidney function, and explore their underlying mechanisms in potassium oxonate-induced hyperuricemic mice. Betaine at 5, 10, 20, and 40 mg/kg was orally administered to hyperuricemic mice for 7 days and found to significantly reduce serum uric acid levels and increase fractional excretion of uric acid in hyperuricemic mice in a dose-dependent manner. It effectively restored renal protein level alterations of urate transport-related molecular proteins urate transporter 1, glucose transporter 9, organic anion transporter 1, and ATP-binding cassette subfamily G member 2 in this model, possibly resulting in the enhancement of kidney urate excretion. Moreover, betaine reduced serum creatinine and blood urea nitrogen levels and affected urinary levels of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase as well as upregulated renal protein levels of organic cation/carnitine transporters OCT1, OCTN1, and OCTN2, resulting in kidney function improvement in hyperuricemic mice. The findings from this study provide evidence that betaine has anti-hyperuricemic and nephroprotective actions by regulating protein levels of these renal organic ion transporters in hyperuricemic mice.

AH-DB: collecting protein structure pairs before and after binding.

This work presents the Apo-Holo DataBase (AH-DB, http://ahdb.ee.ncku.edu.tw/ and http://ahdb.csbb.ntu.edu.tw/), which provides corresponding pairs of protein structures before and after binding. Conformational transitions are commonly observed in various protein interactions that are involved in important biological functions. For example, copper-zinc superoxide dismutase (SOD1), which destroys free superoxide radicals in the body, undergoes a large conformational transition from an 'open' state (apo structure) to a 'closed' state (holo structure). Many studies have utilized collections of apo-holo structure pairs to investigate the conformational transitions and critical residues. However, the collection process is usually complicated, varies from study to study and produces a small-scale data set. AH-DB is designed to provide an easy and unified way to prepare such data, which is generated by identifying/mapping molecules in different Protein Data Bank (PDB) entries. Conformational transitions are identified based on a refined alignment scheme to overcome the challenge that many structures in the PDB database are only protein fragments and not complete proteins. There are 746,314 apo-holo pairs in AH-DB, which is about 30 times those in the second largest collection of similar data. AH-DB provides sophisticated interfaces for searching apo-holo structure pairs and exploring conformational transitions from apo structures to the corresponding holo structures.

Exploring the factors influencing public intention for spectator sports consumption based on grounded theory.

Spectator sports consumption serves as a vital component in the development of the sports industry. However, numerous challenges exist in fostering public engagement in this domain. Therefore, in order to explore the factors that influence public participation in spectator sport consumption, this study analyzes the intention to participate in spectator sports consumption from the perspective of consumers. On this basis, Semi-structured interviews were conducted with a sample of 25 members of the public, and three levels of coding were analyzed using the qualitative research method of procedural rooting theory and establish a model on the influence of public intention to participate in spectator sports consumption, and on this basis, we reveal the influence of crucial elements. The results of the study indicate that: Firstly, personal and psychological factors are significant internal drivers, while external drivers cover product and contextual factors. Secondly, the key to filling the attitudinal and behavioral gaps is the depth of perception individually, which is of great importance in increasing public participation. Thirdly, external contextual factors impacting consumer support primarily consist of external incentives, social influences, and urban contextual variables, which also serve a moderating role in the integration model. The results suggest that guiding the public to actively participate in spectator sport consumption should be based on an understanding of individual perceptions, emotions as well as attitudes. This paper develops a model examining public motivation to engage in spectator sports locally in China, pinpoints the primary influencing factors and mechanisms, and presents novel concepts for the sustainable growth of the sports sector.

Study on the gelatinization and digestive characteristics of wheat starch and potato starch under low moisture conditions.

This study explored the gelatinization and digestive characteristics of wheat and potato starches under low moisture conditions using identical processing parameters. The results revealed that potato starch exhibited greater resistance to digestion than wheat starch, with an enzyme hydrolysis rate 18 % to 30 % lower than wheat starch under the same conditions. The analysis of particle size, swelling power, and low-field NMR demonstrated that potato starch required almost 40 % more moisture for full gelatinization than wheat starch, indicating that low-moisture conditions could not meet the significant water demand of potato starch. Additionally, the DSC analysis showed that potato starch had superior thermal stability, with To of 62.13 °C and ΔH of 16.30 (J/g). Subsequently, the microscopy results showed that the partially gelatinized wheat starch had a rough, porous surface, allowing enzymes for direct access to hydrolysis. In contrast, the potato starch had smoother and less damaged particles without visible pores, enzymes had to degrade it progressively, layer by layer. Furthermore, potato starch still exhibited a lower enzyme hydrolysis rate than wheat starch under the same gelatinization levels. Overall, potato starch is more resistant to hydrolysis and gelatinization in low-moisture environments, making potato starch suitable for low-digestibility products like potato biscuits or chips.

Loss of Slc39a12 in hippocampal neurons is responsible for anxiety-like behavior caused by temporomandibular joint osteoarthritis.

Background: An evident association between mood disorders and TMJ dysfunction has been demonstrated in previous studies. This study observed both the behavioral changes and the pathological changes in hippocampal tissue of rats in an animal model of TMJ-OA by injecting MIA into TMJ. Methods: Eighteen SD rats were randomly assigned to the NC group and the MIA groups. A TMJ-OA model was established to assess the HWT in the TMJ region, and the rats were subjected to the OFT and EPM. HE, O-fast green staining, qRT-PCR and immunofluorescence were used to detect condylar damage. Serum and hippocampal oxidative stress levels were detected. Functions of genes obtained by RNA-Seq were investigated using H2O2, ZnCl2 and transfection of siRNA on HT22 cells. Results: Injection of MIA resulted in disorganization of the chondrocyte layer on the condylar surface of rats, with reduced synthesis and increased degradation of the condylar cartilage matrix and reduced HWT. The results of the OFT and EPM showed that the rats in the MIA group developed anxiety-like behavior during the sixth week of MIA injection. Increased Nox4 expression, decreased SOD2 expression, elevated MDA level, and reduced GSH level were detected in serum and hippocampal neurons in the MIA group, with nuclear pyknosis and reduced Nissl bodies observed in neurons. The expression of Slc39a12 in hippocampal neurons of rats in the MIA group decreased. Slc39a12 knockdown in HT22 cells induced increased Nox4 expression, decreased SOD2 expression, increased MDA level, and reduced GSH and intracellular Zn2+. Oxidative stress in HT22 cells after transfection and H2O2 stimulation was reversed when ZnCl2 was added. Conclusion: Loss of Slc39a12 in hippocampal neurons results in cellular oxidative stress, further leading to neuronal damage. This may potentially explain how TMJ-OA triggers anxiety-like behavior in rats.

Fine-scale monitoring of lake ice phenology by synthesizing remote sensed and climatologic features based on high-resolution satellite constellation and modeling.

Lake ice, as a crucial component of the cryosphere, serves as a sensitive indicator of climate change. Fine-scale monitoring of spatiotemporal patterns in lake ice phenology holds significant importance in scientific research and environmental management. However, the rapid and dynamic nature of the freeze-thaw process of lake ice poses challenges to existing methods, resulting in their limited application in small lakes. In this study, we propose a novel approach of investigating ice phenology of lakes in various sizes. We conducted a case study in Hoh Xil, known for its vulnerability to climate change and a wide distribution of small lakes, to analyze the ice phenology of 372 lakes (>1 km2) during 2017-2021. Firstly, ensemble machine-learning model was developed for lake ice identification from Landsat-8/9 and Sentinel-2 A/B imagery. The accuracy evaluation reveals the overall good performance for ice extraction results based on Landsat-8/9 (97.03 %) and Sentinel-2 A/B (96.89 %). Next, the XGBoost models were employed to reconstruct ice coverages on unobserved dates for the freezeup and breakup periods, respectively. Totally, 744 XGBoost models were constructed for the study lakes, and the majority of them perform well. Based on the reconstructed daily ice coverage, phenology parameters could be extracted for examining the spatiotemporal characteristics of ice cover and possible relationships with lake sizes and terrains. From early-October to early-November, the Hoh Xil lakes freeze from the northwest to the southeast, while the breakup period starts in late-March and lasts until late-June. Moreover, the results indicate relatively small variability in freezeup-end dates among lakes, but significant differences in breakup dates, showing a greater sensitivity to temperature variations. Furthermore, ice phenology in small lakes exhibit stronger consistency with subtle climatic fluctuations. The results highlight the significant role of ice phenology in small lakes, as they dominate the overall tendency of ice phenology in Hoh Xil.

Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm.

Cytokine storm (CS) is linked with macrophage dysfunction and acute lung injury (ALI), which can lead to patient mortality. Glycolysis is preferentially exploited by the pro-inflammatory macrophages, in which pyruvate kinase M2 (PKM2) is a critical enzyme. The mechanism underlying the link between CS and ALI involves cell death, with the recently discovered programmed cell death known as ferroptosis being involved. However, the relationship between the glycolysis and ferroptosis in the context of CS-related ALI remains unclear. CS-associated ALI induced by poly I:C (10 mg/kg, i.v) and LPS (5 mg/kg, i.p) (IC: LPS) exhibit significant ferroptosis. Ferrostatin-1 (ferroptosis inhibitor) treatment attenuated IC:LPS­induced mortality and lung injury. Moreover, Alveolar macrophage (AM) from IC:LPS model exhibited enhanced glycolysis and PKM2 translocation. The administration of ML-265(PKM2 monomer/dimer inhibitor) resulted in the formation of a highly active tetrameric PKM2, leading to improved survival and attenuation of ALI. Furthermore, ML-265 treatment decreased ferroptosis and restored the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infection, intracellular expression level of PKM2 were correlated with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation was noticed in CD14+ blood monocytes of lung infection patients with CS. In conclusion, PKM2 is a key regulatory node integrating metabolic reprograming with intra-nuclear function for the regulation of ferroptosis. Targeting PKM2 could be explored as a potential means in the future to prevent or alleviate hyper-inflammatory state or cytokines storm syndrome with aberrant ferroptotic cell death.

Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.

Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.

The Renoprotective and Anti-Inflammatory Effects of Human Urine-Derived Stem Cells on Acute Kidney Injury Animals.

BACKGROUND: Acute Kidney Injury (AKI) is defined as a sudden loss of kidney function, which is often caused by drugs, toxins, and infections. The large spectrum of AKI implies diverse pathophysiological mechanisms. In many cases, AKI can be lethal, and kidney replacement therapy is frequently needed. However, current treatments are not satisfying. Developing novel therapies for AKI is essential. Adult stem cells possess regenerative ability and play an important role in medical research and disease treatment. METHODS: In this study, we isolated and characterized a distinct human urine-derived stem cell, which expressed both proximal tubular cell and mesenchymal stem cell genes as well as certain unique genes. RESULTS: It was found that these cells exhibited robust protective effects on tubular cells and anti- inflammatory effects on macrophages in vitro. In an ischemia-reperfusion-induced acute kidney injury NOD-SCID mouse model, transplantation of USCs significantly protected the kidney morphology and functions in vivo. CONCLUSION: In summary, our results highlighted the effectiveness of USCs in protecting from PTC injury and impeding macrophage polarization, as well as the secretion of pro-inflammatory interleukins, suggesting the potential of USCs as a novel cell therapy in AKI.

Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy.

Background: Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN. Methods: Five DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted. Results: A total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN. Conclusion: Our integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention.

SENP3 facilitates M1 macrophage polarization via the HIF-1α/PKM2 axis in lipopolysaccharide-induced acute lung injury.

M1/M2 macrophage polarization plays a pivotal role in the development of acute lung injury (ALI). The hypoxia-inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis, which functions upstream of macrophage polarization, has been implicated in this process. The function of HIF-1α is known to be tightly regulated by SUMOylation. Upregulation of SUMO-specific peptidase 3 (SENP3), a deSUMOylation enzyme, is induced by reactive oxygen species (ROS), which are abundantly produced during ALI. To explore the links between SENP3, macrophage polarization, and lung injury, we used mice with Senp3 conditional knockout in myeloid cells. In the lipopolysaccharide (LPS)-induced ALI model, we found that in vitro and in vivo SENP3 deficiency markedly inhibited M1 polarization and production of pro-inflammatory cytokines and alleviated lung injury. Further, we demonstrated that SENP3 deficiency suppressed the LPS-induced inflammatory response through PKM2 in a HIF-1α-dependent manner. Moreover, mice injected with LPS after PKM2 inhibitor (shikonin) treatment displayed inhibition of M1 macrophage polarization and reduced lung injury. In summary, this work revealed that SENP3 promotes M1 macrophage polarization and production of proinflammatory cytokines via the HIF-1α/PKM2 axis, contributing to lung injury; thus, SENP3 may represent a potential therapeutic target for ALI treatment.

Comparing Multi-Dimensional fNIRS Features Using Bayesian Optimization-Based Neural Networks for Mild Cognitive Impairment (MCI) Detection.

The diagnosis of mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), is essential for initiating timely treatment to delay the onset of AD. Previous studies have shown the potential of functional near-infrared spectroscopy (fNIRS) for diagnosing MCI. However, preprocessing fNIRS measurements requires extensive experience to identify poor-quality segments. Moreover, few studies have explored how proper multi-dimensional fNIRS features influence the classification results of the disease. Thus, this study outlined a streamlined fNIRS preprocessing method to process fNIRS measurements and compared multi-dimensional fNIRS features with neural networks in order to explore how temporal and spatial factors affect the classification of MCI and cognitive normality. More specifically, this study proposed using Bayesian optimization-based auto hyperparameter tuning neural networks to evaluate 1D channel-wise, 2D spatial, and 3D spatiotemporal features of fNIRS measurements for detecting MCI patients. The highest test accuracies of 70.83%, 76.92%, and 80.77% were achieved for 1D, 2D, and 3D features, respectively. Through extensive comparisons, the 3D time-point oxyhemoglobin feature was proven to be a more promising fNIRS feature for detecting MCI by using an fNIRS dataset of 127 participants. Furthermore, this study presented a potential approach for fNIRS data processing, and the designed models required no manual hyperparameter tuning, which promoted the general utilization of fNIRS modality with neural network-based classification to detect MCI.