Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose-induced cardiomyocyte injury.

BACKGROUND: Diabetic cardiomyopathy (DCM) represents a major cause of heart failure and a large medical burden worldwide. This study screened the potentially regulatory targets of DCM and analyzed their roles in high glucose (HG)-induced cardiomyocyte injury. METHODS: Through GEO database, we obtained rat DCM expression chips and screened differentially expressed genes. Rat cardiomyocytes (H9C2) were induced with HG. 3-hydroxy-3-methylglutarylcoenzyme A synthase 2 (Hmgcs2) and microRNA (miR)-363-5p expression patterns in cells were measured by real-time quantitative polymerase chain reaction or Western blot assay, with the dual-luciferase assay to analyze their binding relationship. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, lactate dehydrogenase assay, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, enzyme-linked immunosorbent assay, and various assay kits were applied to evaluate cell viability, cytotoxicity, apoptosis, inflammation responses, and oxidative burden. RESULTS: Hmgcs2 was the vital hub gene in DCM. Hmgcs2 was upregulated in HG-induced cardiomyocytes. Hmgcs2 downregulation increased cell viability, decreased TUNEL-positive cell number, reduced HG-induced inflammation and oxidative stress. miR-363-5p is the upstream miRNA of Hmgcs2. miR-363-5p overexpression attenuated HG-induced cell injury. CONCLUSIONS: Hmgcs2 had the most critical regulatory role in DCM. We for the first time reported that miR-363-5p inhibited Hmgcs2 expression, thereby alleviating HG-induced cardiomyocyte injury.

Multimodal image fusion-assisted endoscopic evacuation of spontaneous intracerebral hemorrhage.

PURPOSE: Although traditional craniotomy (TC) surgery has failed to show benefits for the functional outcome of intracerebral hemorrhage (ICH). However, a minimally invasive hematoma removal plan to avoid white matter fiber damage may be a safer and more feasible surgical approach, which may improve the prognosis of ICH. We conducted a historical cohort study on the use of multimodal image fusion-assisted neuroendoscopic surgery (MINS) for the treatment of ICH, and compared its safety and effectiveness with traditional methods. METHODS: This is a historical cohort study involving 241 patients with cerebral hemorrhage. Divided into MINS group and TC group based on surgical methods. Multimodal images (CT skull, CT angiography, and white matter fiber of MRI diffusion-tensor imaging) were fused into 3 dimensional images for preoperative planning and intraoperative guidance of endoscopic hematoma removal in the MINS group. Clinical features, operative efficiency, perioperative complications, and prognoses between 2 groups were compared. Normally distributed data were analyzed using t-test of 2 independent samples, Non-normally distributed data were compared using the Kruskal-Wallis test. Meanwhile categorical data were analyzed via the Chi-square test or Fisher's exact test. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. RESULTS: A total of 42 patients with ICH were enrolled, who underwent TC surgery or MINS. Patients who underwent MINS had shorter operative time (p < 0.001), less blood loss (p < 0.001), better hematoma evacuation (p = 0.003), and a shorter stay in the intensive care unit (p = 0.002) than patients who underwent TC. Based on clinical characteristics and analysis of perioperative complications, there is no significant difference between the 2 surgical methods. Modified Rankin scale scores at 180 days were better in the MINS than in the TC group (p = 0.014). CONCLUSIONS: Compared with TC for the treatment of ICH, MINS is safer and more efficient in cleaning ICH, which improved the prognosis of the patients. In the future, a larger sample size clinical trial will be needed to evaluate its efficacy.

Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation.

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.

Effects and molecular mechanism of sugar transporter ESA_RS15745 on desiccation resistance, motility, and biofilm formation of Cronobacter sakazakii.

Cronobacter sakazakii, an important Gram-negative foodborne pathogen, can cause neonatal meningitis and sepsis with high rates of infection and death. Gene ESA_RS15745 encodes a sugar transporter protein, which is not only essential for osmotic pressure maintenance during bacterial growth and reproduction but also associated with their desiccation tolerance, motility, and biofilm formation. Here, a mutant strain of ESA_RS15745 (ΔESA_RS15745) and the complementation strain (cpESA_RS15745) were constructed using a suicide vector knockout and gene complementation. ΔESA_RS15745 was found to have a decrease in its ability to transport maltose and trehalose and resist desiccation, whereas an increase in the ability of motility and biofilm formation, implying that ESA_RS15745 may positively regulate sugar transport and desiccation tolerance and negatively regulate motility and biofilm formation. To further investigate the molecular mechanisms underlying the function of related genes, RNA-seq was performed to explore the differentially expressed genes in the mutants. RNA-seq results showed the upregulation of 114 genes (mainly including those regulating chemotaxis and flagellar motility) and the downregulation of 22 genes (mainly including those regulating sugar transport). qRT-PCR analysis supported the RNA-seq results and showed that ESA_RS15745 may influence the dehydration tolerance though decreasing the intracellular trehalose content and negatively regulate the motility though the chemotactic signaling pathway. In addition, the biofilm formation of C. sakazakii should also be speculated to negatively regulate by ESA_RS15745 by consuming the extracellular carbohydrates concentration and then downregulating the intracellular cyclic diguanosine monophosphate. This study offers a reference for comprehending the molecular mechanism of gene ESA_RS15745 in C. sakazakii.

Adverse perinatal outcomes complicated with gestational diabetes mellitus in preterm mothers and preterm infants.

The incidence rate of gestational diabetes mellitus (GDM) in pregnancy is currently on the increase. GDM is associated with short and long-term adverse outcomes for mothers, fetuses and newborns. The aim of the present study was to compare the incidence of adverse perinatal outcomes in women with and without GDM, in addition to comparing the morbidity and mortality rates of preterm infants born to women with and without GDM. A retrospective analysis of 640 preterm infants admitted to the Neonatal Intensive Care Unit of Qilu Hospital of Shandong University (Qingdao, China) between January 2019 and December 2020 was undertaken in the present study. According to mothers with or without GDM, the preterm infants were divided into the GDM group (n=217) and non-GDM group (n=423). Women with GDM were older (P<0.01) and more of advanced maternal age (≥35 years) or multipara (P<0.001), tended to have an increased risk of gestational hypertension (P<0.05), placenta previa (P<0.005) and polycystic ovarian syndrome (P<0.05). In infants born preterm, those born from mothers with GDM were associated with an increased risk of respiratory distress syndrome (P<0.001) and sepsis (P<0.05). In addition, very low birth weight infants born to mothers with GDM were found to have an increased risk of hypoglycemia (P<0.05) and sepsis (P<0.05). In the logistic regression analysis, RDS was the only condition independently associated with GDM [adjusted odds ratio: 1.699 (95% confidence interval: 1.699-1.699)]. However, there was no significant difference in the risk of mortality among the two groups. In conclusion, data from the present study suggested that GDM is associated with a higher risk of adverse perinatal outcomes in pregnant women and a higher risk of adverse neonatal outcomes in infants born preterm.

Acute and chronic effects of sublethal neonicotinoid thiacloprid to Asian honey bee (Apis cerana cerana).

Pesticide pollution is one of the most important factors for global bee declines. Despite many studies have revealed that the most important Chinese indigenous species，Apis cerana, is presenting a high risk on exposure to neonicotinoids, the toxicology information on Apis cerana remain limited. This study was aimed to determine the acute and chronic toxic effects of thiacloprid (IUPAC name: {(2Z)-3-[(6-Chloro-3-pyridinyl)methyl]-1,3-thiazolidin-2-ylidene}cyanamide) on behavioral and physiological performance as well as genome-wide transcriptome in A. cerana. We found the 1/5 LC50 of thiacloprid significantly impaired learning and memory abilities after both acute and chronic exposure, nevertheless, has no effects on the sucrose responsiveness and phototaxis climbing ability of A. cerana. Moreover, activities of detoxification enzyme P450 monooxygenases and CarE were increased by short-term exposure to thiacloprid, while prolonged exposure caused suppression of CarE activity. Neither acute nor chronic exposure to thiacloprid altered honey bee AChE activities. To further study the potential defense molecular mechanisms in Asian honey bee under pesticide stress, we analyzed the transcriptomes of honeybees in response to thiacloprid stress. The transcriptomic profiles revealed consistent upregulation of immune- and stress-related genes by both acute or chronic treatments. Our results suggest that the chronic exposure to thiacloprid produced greater toxic effects than a single administration to A. cerana. Altogether, our study deepens the understanding of the toxicological characteristic of A. cerana against thiacloprid, and could be used to further investigate the complex molecular mechanisms in Asian honey bee under pesticide stress.

All-natural environmentally degradable poly (butylene terephthalate-co-caprolactone): A theoretical and experimental study of its degradation properties and mechanisms.

The design and production of materials with excellent mechanical properties and biodegradability face significant challenges. Poly (butylene terephthalate-co-caprolactone) copolyesters (PBTCL) is obtained by modifying the engineering plastic polybutylene terephthalate (PBT) with a simple one-pot process using readily biodegradable ε-caprolactone (ε-CL). The material has mechanical properties comparable to those of commercial biodegradable copolyester PBAT. Besides, this copolyester exhibited remarkable degradability in natural environments such as soil and ocean, for example, PBTCL1.91 lost >40 % of its weight after 6 months of immersion in the Bohai Sea. The effect and diversity of specific microorganisms acting on degradation in the ocean were analyzed by 16 s rDNA gene sequencing. Theoretical calculations such as Fukui function and DFT, and experimental studies on water-soluble intermediates and residual matrixes produced after degradation, confirmed that the insertion CL units not only act as active sites themselves susceptible to hydrolysis reactions, but also promote the reactivity of ester bonds between aromatic segments. This work provides insight for the development of novel materials with high performance and environmental degradability.

Micro-hole array sprayer combined with an organic membrane to assist LIBS (MASOM-LIBS): A novel highly sensitive detection method for dissolved trace heavy metals in water.

The development of highly sensitive and rapid detection technology for heavy metal elements in water is of great significance to the monitoring of water environmental pollution, sewage discharge control and other application fields. As an alternative detection method with great potential in the above fields, LIBS technology still has some problems that need to be solved. To improve the sensitivity and efficiency of LIBS detection of trace metals in water, a new method Micro-hole Array Sprayer combined with an Organic Membrane to assist LIBS (MASOM-LIBS) was proposed in this study. In this method, water samples were transformed into a large number of micrometer droplets by a micro-hole array injection device and were sprayed onto a rotating polypropylene organic film. After natural drying, LIBS analysis was performed. The test results of the mixed solution show that plasma with lower electron density and higher electron temperature can be obtained after full drying, the signal intensity will be stronger, and the stability can be reduced to less than 1%. The experimental results of Cu, Cd, Mn, Pb, Cr and Sr as target elements show that the LODs of the MASOM-LIBS method for most elements is less than 0.1 mg/L when the detection time is less than 3 min, which has certain advantages over similar LIBS methods. If the detection time is increased appropriately, the LODs of this method is even expected to be reduced to less than 0.01 mg/L. These results indicate that MASOM-LIBS is a feasible method to improve the sensitivity and speed of the detection of trace heavy elements in liquid samples and can facilitate the wide application of LIBS in water quality monitoring. In view of the short detection time, high sensitivity and low LODs of MASOM-LIBS, this method is expected to be developed into a water trace heavy metal detection technology with fully automatic, real-time, highly sensitive and multi-element detection technology in the future.

Prognostic value of the S100 calcium-binding protein family members in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a crucial public health problem around the world, and the outlook remains bleak. More accurate prediction models are urgently needed because of the great heterogeneity of HCC. The S100 protein family contains over 20 differentially expressed members, which are commonly dysregulated in cancers. In the present study, we analyzed the expression profile of S100 family members in patients with HCC based on the TCGA database. A novel prognostic risk score model, based on S100 family members, was developed using the least absolute shrinkage and selection operator regression algorithm, to analyze the clinical outcome. Our prediction model showed a powerful predictive value (1-year AUC: 0.738; 3-year AUC: 0.746; 5-year AUC: 0.813), while two former prediction models had less excellent performances than ours. And the S100 family members-based subtypes reveal the heterogeneity in many aspects, including gene mutations, phenotypic traits, tumor immune infiltration, and predictive therapeutic efficacy. We further investigated the role of S100A9, one member with the highest coefficient in the risk score model, which was mainly expressed in para-tumoral tissues. Using the Single-Sample Gene Set Enrichment Analysis algorithm and immunofluorescence staining of tumor tissue sections, we found that S100A9 may be associated with macrophages. These findings provide a new potential risk score model for HCC and support further study of S100 family members in patients, especially S100A9.

Fluorescence tracing the degradation process of biodegradable PBAT: Visualization and high sensitivity.

Biodegradable plastics have emerged as a potential solution to the mounting plastic pollution crisis. However, current methods for evaluating the degradation of these plastics are limited in detecting structural changes rapidly and accurately, particularly for PBAT, which contains worrying benzene rings. Inspired by the fact that the aggregation of conjugated groups can endow polymers with intrinsic fluorescence, this work found that PBAT emits a bright blue-green fluoresces under UV irradiation. More importantly, we pioneered a degradation evaluation approach to track the degradation process of PBAT via fluorescence. A blue shift of fluorescence wavelength as the thickness and molecular weight of PBAT film decreased during degradation in an alkali solution was observed. Additionally, the fluorescence intensity of the degradation solution increased gradually as the degradation progressed, and was found to be exponentially correlated with the concentration of benzene ring-containing degradation products following filtration with the correlation coefficient is up to 0.999. This study proposes a promising new strategy for monitoring the degradation process with visualization and high sensitivity.

Preliminary Results of Utrasound-Guided Percutaneous Radiofrequency Ablation in the Treatment of Refractory Non-nodular Hyperthyroidism.

PURPOSE: To assess the safety and efficacy of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of refractory non-nodular hyperthyroidism. METHODS: This was a single-center retrospective study in 9 patients with refractory non-nodular hyperthyroidism (2 males, 7 females; median age, range, 36 years, 14-55 years) who underwent RFA between August 2018 and September 2020. The incidence of post-procedural complications, changes in thyroid volume, thyroid function and the use and dosages of anti-thyroid drugs, were compared pre- and post-RFA. RESULTS: All patients completed the procedure successfully, and no serious complications occurred. Three months after ablation, thyroid volumes were significantly decreased with the mean volumes of the right and left lobes reduced to 45.6% (10.9 ± 2.2 ml/23.9 ± 7.2 ml, p < 0.001) and 50.2% (10.8 ± 7.4 ml/21.5 ± 11.4 ml, p = 0.001) of the volumes within 1 week after ablation. The thyroid function was gradually improved in all patients. At 3 months post-ablation, the levels of FT3 and FT4 were returned to the normal range (FT3, 4.9 ± 1.6 pmol/L vs. 8.7 ± 4.2 pmol/L, p = 0.009; FT4, 13.1 ± 7.2 pmol/L vs. 25.9 ± 12.6 pmol/L, p = 0.038), the TR-Ab level was significantly lower (4.8 ± 3.9 vs. 16.5 ± 16.4 IU/L, p = 0.027), and the TSH level was significantly higher (0.76 ± 0.88 vs. 0.03 ± 0.06, p = 0.031) than that before-ablation. Additionally, three months after RFA, the anti-thyroid medication dosages were reduced to 31.25% compared to baseline (p < 0.01). CONCLUSION: Ultrasound-guided RFA in the treatment of refractory non-nodular hyperthyroidism was safe and effective in this small group of patients with limited follow-up. Further studies with larger cohorts and longer follow-up are needed to validate this potential new application of thyroid thermal ablation.

High-resolution genome mapping and functional dissection of chlorogenic acid production in Lonicera maackii.

Amur honeysuckle (Lonicera maackii) is a widely used medicinal plant of the Caprifoliaceae family that produces chlorogenic acid. Research on this plant mainly focuses on its ornamental value and medicinal compounds, but a reference genome sequence and molecular resources for accelerated breeding are currently lacking. Herein, nanopore sequencing and high-throughput chromosome conformation capture (Hi-C) allowed a chromosome-level genome assembly of L. maackii (2n = 18). A global view of the gene regulatory network involved in the biosynthesis of chlorogenic acid and the dynamics of fruit coloration in L. maackii was established through metabolite profiling and transcriptome analyses. Moreover, we identified the genes encoding hydroxycinnamoyl-CoA quinate transferase (LmHQT) and hydroxycinnamoyl-CoA shikimic/quinate transferase (LmHCT), which localized to the cytosol and nucleus. Heterologous overexpression of these genes in Nicotiana benthamiana leaves resulted in elevated chlorogenic acid contents. Importantly, HPLC analyses revealed that LmHCT and LmHQTs recombinant proteins modulate the accumulation of chlorogenic acid (CGA) using quinic acid and caffeoyl CoA as substrates, highlighting the importance of LmHQT and LmHCT in CGA biosynthesis. These results confirmed that LmHQTs and LmHCT catalyze the biosynthesis of CGA in vitro. The genomic data presented in this study will offer a valuable resource for the elucidation of CGA biosynthesis and facilitating selective molecular breeding.

Impacts of nature reserve policy on regional ecological environment quality: A case study of Sanjiangyuan region.

Uncovering the ecological effectiveness of nature reserve policies will help protect and manage nature reserves in the future. Taking Sanjiangyuan region as an example, we examined the impacts of the spatial layout characteristics of natural reserves on the ecological environment quality by constructing the dynamic degree of land use and land cover change index, and depicted the spatial differences of the ecological effectiveness of natural reserve policies both inside and outside the natural reserves. Combined with ordinary least squares and field survey results, we explored the influencing mechanism of nature reserve policies on ecological environment quality. The results showed that the ecological quality of the whole region of Sanjiangyuan had been improved significantly since the implementation of the nature reserve policies, and that the transformation of unused land into ecological land was the most important type of land use change for the ecological environment quality improvement. The ecological effectiveness of large-scale nature reserves with concentrated and contiguous distribution was obvious, while the ecological effectiveness of small-scale nature reserves with scattered distribution and close to the administrative boundaries was relatively small. Although the ecological effectiveness of nature reserves was better than that of non-reserved areas, the ecological improvement of nature reserves and the surrounding areas was synchronous. The nature reserve policy had significantly improved ecological environment quality by implementing ecological protection and restoration projects in nature reserves. Meanwhile, it had alleviated the pressure of farmers and herdsmen's activities on the ecological environment by taking measures such as grazing restriction and guiding conversion of industry and production. In the future, we should promote the construction of ecosystem integrity protection network system with National Park as the core, strengthen the integrated protection and linkage management of National Park and surrounding areas, and help farmers and herdsmen further broaden their livelihoods.

Effect of birth asphyxia on neonatal blood glucose during the early postnatal life: A multi-center study in Hubei Province, China.

BACKGROUND: Birth asphyxia causes hypoxia or inadequate perfusion to the organs of newborns, leading to metabolism dysfunctions including blood glucose disorders. METHODS: Neonates with and without birth asphyxia were retrospectively recruited from 53 hospitals in Hubei Province from January 1 to December 31, 2018. In summary, 875, 1139, and 180 cases in the control group, the mild asphyxia group, and the severe asphyxia group were recruited, respectively. Neonatal blood glucose values at postnatal 1, 2, 6, and 12 h (time error within 0.5 h was allowed) were gathered from the medical records. RESULTS: The incidence rates of hyperglycemia in the control group, the mild asphyxia group and the severe asphyxia group were 2.97%, 7.90%, and 23.33%, respectively (p < 0.001). Additionally, the incidence rates of hypoglycemia in the three groups above were 3.66%, 4.13%, and 7.78%, respectively (p = 0.042). The blood glucose values of neonates with hypoglycemia in the asphyxia group were lower than in the control group (p = 0.003). Furthermore, the blood glucose values of neonates with hyperglycemia were highest in the severe asphyxia group (p < 0.001). There were 778 and 117 cases with blood glucose records at four predefined time points in the mild and severe asphyxia group, respectively. The incidence of blood glucose disorders in the mild asphyxia group significantly decreased from postnatal 6 h (p＜0.05). However, we found no obvious changes of the incidence of glucose disorders within postnatal 12 h in the severe asphyxia group (p = 0.589). CONCLUSION: Birth asphyxia is likely to cause neonatal blood glucose disorders, both hypoglycemia and hyperglycemia, during the early postnatal life. The neonates with severe asphyxia have higher incidence, worse severity and longer duration of blood glucose disorders than neonates with mild asphyxia.

Acute oral toxicity, apoptosis, and immune response in nurse bees (Apis mellifera) induced by flupyradifurone.

The potential toxicity of flupyradifurone (FPF) to honey bees has been a subject of controversy in recent years. Understanding the effect of pesticides on nurse bees is important because the fitness of nurse bees is critical for in-hive activities, such as larval survival and performing hive maintenance. In order to evaluate the acute oral toxicity of flupyradifurone on nurse bees, flupyradifurone at five different concentrations was selected to feed both larvae and nurse bees. Our results showed that nurse bees were more sensitive to flupyradifurone than larvae (LD50 of the acute oral toxicity of flupyradifurone was 17.72 µg a.i./larva and 3.368 µg a.i./nurse bee). In addition, the apoptotic rates of neurons in mushroom bodies of nurse bees were significantly induced by flupyradifurone at sublethal concentrations (8 mg/L, 20 mg/L, and 50 mg/L) and the median lethal concentration LC50 (125 mg/L). The expression of immune-related genes (Hsp90, Toll-8/Tollo, and defensin) was significantly changed in exposed nurse bees at the field-realistic concentration of flupyradifurone. However, three detoxifying enzyme genes (CYP9Q1, -2, and -3) were not affected by pesticide exposure. Our data suggest that although flupyradifurone had a relatively lower acute oral toxicity than many other common pesticides, exposures to the field-realistic and other sublethal concentrations of flupyradifurone still have cytotoxicity and immune-responsive effects on nurse bees. Therefore, flupyradifurone should be considered for its application in crops.

Altered maturation in brainstem neural conduction in very premature babies with fetal growth restriction.

BACKGROUND: Using maximum length sequence brainstem auditory evoked response (MLS BAER) to study brainstem neural conduction and maturation in fetal growth restriction (FGR) babies born very prematurely and assess the effect of FGR on brainstem neural maturation. METHODS: MLS BAER was recorded and analyzed at a mean 40 week postmenstrual age in babies born at 27-32 week gestation without other major perinatal conditions or problems. The data were compared between babies with FGR (n = 30) and age-matched babies without FGR (n = 34) to define any differences. RESULTS: A notable difference in MLS BAER was found in interpeak intervals between the babies with FGR and those without FGR. The FGR babies manifested significantly shortened I-III interval, moderately prolonged III-V interval, and significantly decreased III-V/I-III interval ratio. The slope of the I-III interval-rate function in FGR babies was moderately decreased, relative to that in the babies without FGR. CONCLUSION: FGR babies born very prematurely are associated with accelerated or precocial neural maturation at caudal brainstem regions, but moderately delayed maturation at rostral brainstem regions. The altered brainstem neural maturation is different from previously reported mildly delayed maturation in FGR babies born less prematurely, and may have important implication for neurodevelopmental outcome. IMPACT: This first MLS BAER study in FGR found that brainstem neural maturation in very premature FGR babies differed from age-matched non-FGR babies. Neural maturation in very premature FGR babies is accelerated or precocial at caudal brainstem regions but moderately delayed at rostral brainstem regions. The altered maturation is different from previously reported mild delay in brainstem neural maturation in FGR babies born less prematurely. FGR exerts a major and differential effect on brainstem neural maturation in babies born very prematurely. This alteration in very premature FGR babies may have important implication for their neurodevelopment.

The clinicopathological significance of thymic epithelial markers expression in thymoma and thymic carcinoma.

BACKGROUND: The classification of thymomas is based on the morphology of epithelial tumor cells and the proportion of lymphocytes. Type A thymomas are composed of the spindle or oval tumor epithelial cells. Tumor cells of B thymomas are epithelioid-shaped with increasing atypia. Type AB thymomas have the features of epithelial tumor cells of A and B thymomas. The diagnosis can be difficult because of the complex morphology. Some novel thymic epithelial markers have been reported in several preclinical studies, but they have not been applied to clinical practice. Here, we investigated the expression of 3 cortical and 3 medullary markers, which are thymoproteasome-specific subunit ß5t (ß5t), thymus-specific serine protease 16 (PRSS16), cathepsin V, autoimmune regulator (AIRE), CD40 and claudin-4. METHODS: Immunohistochemistry was used to analyze 53 cases of thymomas and thymic squamous cell carcinomas (TSCC), aiming to explore the expression of cortical and medullary epithelial markers and their correlation with histological classification, Masaoka-Koga stage, and prognosis. RESULTS: Our results found that for cortical epithelial markers the expression of ß5t, PRSS16, and cathepsin V was higher in type AB and B thymomas than in micronodular thymoma with lymphoid stroma (MNT), and we observed a dramatic increase of ß5t and PRSS16 expression in type AB compared to type A thymomas. In medullary epithelial markers, the expression of AIRE was higher in type A than in B3 thymomas. CD40 and ß5t expression were associated with the Masaoka-Koga stage. High cathepsin V expression was related to a good prognosis and a longer progression-free survival. CONCLUSION: This is the first comprehensive analysis of the role of thymic cortical and medullary epithelial markers as biomarkers for differential diagnosis and prognosis in thymic tumors. Thymic medullary epithelial immunophenotype was found to exhibit in type A, MNT, and TSCC. Type B thymomas primarily exhibited a cortical epithelial immunophenotype. Type AB thymomas showed cortical, medullary, or mixed corticomedullary epithelial immunophenotype. Our results demonstrated that thymic cortical and medullary epithelial markers including ß5t, PRSS16, cathepsin V, and AIRE could be used as ancillary markers in the diagnosis and prognosis of thymic epithelial tumors.

Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells.

The immune regulator galectin-9 (Gal-9) is commonly involved in the regulation of cell proliferation, but with various impacts depending on the cell type. Here, we revealed that Gal-9 expression was persistently increased in Epstein-Barr virus (EBV)-infected primary B cells from the stage of early infection to the stage of mature lymphoblastoid cell lines (LCLs). This sustained upregulation paralleled that of gene sets related to cell proliferation, such as oxidative phosphorylation, cell cycle activation, and DNA replication. Knocking down or blocking Gal-9 expression obstructed the establishment of latent infection and outgrowth of EBV-infected B cells, while exogenous Gal-9 protein promoted EBV acute and latent infection and outgrowth of EBV-infected B cells at the early infection stage. Mechanically, stimulator of interferon gene (STING) activation or signal transducer and activator of transcription 3 (STAT3) inhibition impeded the outgrowth of EBV-infected B cells and promotion of Gal-9-induced lymphoblastoid cell line (LCL) transformation. Accordingly, Gal-9 expression was upregulated by forced EBV nuclear antigen 1 (EBNA1) expression in 293T cells in vitro. Clinical data showed that Gal-9 expression in B-cell lymphomas (BCLs) correlated positively with EBNA1 and disease stage. Targeting Gal-9 slowed LCL tumor growth and metastasis in xenografted immunodeficient mice. These findings highlight an oncogenic role of Gal-9 in EBV-associated BCLs, indicating that Gal-9 boosts the transformation of EBV-infected B cells. IMPORTANCE The cross talk between Epstein-Barr virus (EBV) and the host cell transcriptome assumes important roles in the oncogenesis of EBV-associated malignancies. Here, we first observed that endogenous Gal-9 expression was persistently increased along with an overturned V-type change in antivirus signaling during the immortalization of EBV-transformed B cells. Upregulation of Gal-9 promoted the outgrowth and latent infection of EBV-infected B cells, which was linked to B-cell-origin tumors by suppressing STING signaling and subsequently promoting STAT3 phosphorylation. EBV nuclear antigen EBNA1 induced Gal-9 expression and formed a positive feedback loop with Gal-9 in EBV-infected B cells. Tumor Gal-9 levels were positively correlated with disease stage and EBNA1 expression in patients with B-cell lymphomas (BCLs). Targeting Gal-9 slowed the growth and metastases of LCL tumors in immunodeficient mice. Altogether, our findings indicate that Gal-9 is involved in the lymphomagenesis of EBV-positive BCLs through cross talk with EBNA1 and STING signals.

A self-assembly nano-prodrug for triple-negative breast cancer combined treatment by ferroptosis therapy and chemotherapy.

Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle. Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. STATEMENT OF SIGNIFICANCE: Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.

C-type lectin Mincle initiates IL-17-mediated inflammation in acute exacerbations of idiopathic pulmonary fibrosis.

RATIONALE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has a poor prognosis and high mortality. However, there is limited information regarding the mechanisms of AE-IPF. AIMS: We aimed to explore the function of macrophage-inducible C-type lectin (Mincle) in AE-IPF. METHODS: In the present study, Mincle was detected in the lung tissues of AE-IPF patients. Mincle-deficient (Mincle-/-) mice and wild-type C57BL/6 mice were administered bleomycin (BLM), followed by HSV1 viral infection to establish the AE-IPF model. RESULTS: Mincle was increased in the lung tissues of AE-IPF patients compared with those with stable IPF (P = 0.04) and healthy controls (P = 0.009). The survival rate of the Mincle-/-+BLM+HSV group was higher than that of the WT+BLM+HSV group. The mice in the Mincle-/-+BLM+HSV group exhibited milder inflammation and lower acute lung injury scores (P = 0.008). Mincle was expressed on inflammatory monocytes and neutrophils (CD11b+Gr1 +F4/80-) and monocyte-derived macrophages (Mo-AMs, CD11b+Gr1 +F4/80 +) in the BALF of AE-IPF mice. Mo-AMs were significantly increased in the WT+BLM+HSV group compared with the WT+BLM+PBS (P < 0.0001) and Mincle-/-+BLM+HSV (P = 0.0009) groups. Deletion of Mincle decreased the proportion of Th17 cells and Mo-AMs in the Mincle-/-+BLM+HSV group. CONCLUSIONS: Mincle contributed to acute inflammation in AE-IPF by promoting Th17 differentiation.