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To date, the complete natural history of pancreatic steatosis is unknown. This study aimed to investigate the association of fatty pancreas (FP) in the incidence of metabolic syndrome and its components among Chinese patients with a 5-year follow-up.Three independent cross-sectional surveys were carried out in 2013, 2015, and 2018. Fatty pancreas was diagnosed via transabdominal sonography. Logistic regression analysis was used to estimate the correlation between FP and metabolic syndrome. New cases of metabolic syndrome and its components were estimated by Cox proportional hazards models.At baseline, 12,551 individuals classified into FP (n = 1010) and non-FP (n = 11,541) groups were finally enrolled. In cross-sectional analyses, odds ratio of FP was 2.378 (95% confidence interval [CI], 2.085-2.713; P0.001). In longitudinal analyses, FP was associated with the occurrence of metabolic syndrome (hazard ratio [HR], 3.179; 95% CI, 2.197-4.6; P0.001), type 2 diabetes mellitus (HR, 13.99; 95% CI, 7.865-24.883; P0.001), nonalcoholic fatty liver disease (HR, 31.843; 95% CI, 7.73-131.171; P0.001), and hypertension (HR, 12.801; 95% CI, 7.323-22.38; P0.001).Pancreatic steatosis is strongly associated with the occurrence of metabolic syndrome and its components such as hypertension and diabetes.

Common in fungal extracellular membrane (CFEM) domain is unique in fungal proteins and some of which contribute to iron acquisition in yeast. However, their roles in iron acquisition remain largely unknown in filamentous fungi. In this study, 12 CFEM-containing proteins were bioinformatically identified in the filamentous entomopathogenic fungus Beauveria bassiana, and the roles of 11 genes were genetically characterized. Transmembrane helices were critical for their association with intracellular membranes, and their number varied among proteins. Eleven CFEM genes significantly contribute to vegetative growth under iron starvation and virulence. Notably, the virulence of most disruptants could be significantly weakened by a decrease in iron availability, in which the virulence of ΔBbcfem7 and 8 strains was partially recovered by exogenous hemin. ΔBbcfem7 and 8 mutants displayed defective competitiveness against the sister entomopathogenic fungus Beauveria brongniartii. All 11 disruptants displayed impaired growth in the antagonistic assay with the saprotrophic fungus Aspergillus niger, which could be repressed by exogenous ferric ions. These findings not only reveal the systematic contributions of CFEM proteins to acquire two forms of iron (i.e. heme and ferric ion) in the entire lifecycle of entomopathogenic fungi but also help to better understand the mechanisms of fungus-host and inter-fungus interactions.

Lectins are characterized of the carbohydrate-binding ability and play comprehensive roles in fungal physiology (e.g., defense response, development and host–pathogen interaction). Beauveria bassiana, a filamentous entomopathogenic fungus, has a lectin-like protein containing a Fruit Body_domain (BbLec1). BbLec1 could bind to chitobiose and chitin in fungal cell wall. BbLec1 proteins interacted with each other to form multimers, and translocated into eisosomes. Further, the interdependence between BbLec1 and the eisosome protein PliA was essential for stabilizing the eisosome architecture. To test the BbLec1 roles in B. bassiana, we constructed the gene disruption and complementation mutants. Notably, the BbLec1 loss resulted in the impaired cell wall in mycelia and conidia as well as conidial formation capacity. In addition, disruption of BbLec1 led to the reduced cytomembrane integrity and the enhanced sensitivity to osmotic stress. Finally, ΔBbLec1 mutant strain displayed the weakened virulence when compared with the wild-type strain. Taken together, BbLec1 traffics into eisosome and links the functionality of eisosome to development and virulence of B. bassiana.

COVID‐19 is a serious respiratory disease. The ever‐increasing number of cases is causing heavier loads on the health service system. Using 38 blood test indicators on the first day of admission for the 422 patients diagnosed with COVID‐19 (from January 2020 to June 2021) to construct different machine learning (ML) models to classify patients into either mild or severe cases of COVID‐19. All models show good performance in the classification between COVID‐19 patients into mild and severe disease. The area under the curve (AUC) of the random forest model is 0.89, the AUC of the naive Bayes model is 0.90, the AUC of the support vector machine model is 0.86, and the AUC of the KNN model is 0.78, the AUC of the Logistic regression model is 0.84, and the AUC of the artificial neural network model is 0.87, among which the naive Bayes model has the best performance. Different ML models can classify patients into mild and severe cases based on 38 blood test indicators taken on the first day of admission for patients diagnosed with COVID‐19., Highlights 1.Different machine learning models are used to classify mild and severe cases of COVID‐19 patients.2.38 blood sample indicators are used for the machine learning models.3.Five most significant indicators are identified.

Acetyl-coenzyme A (CoA) synthetase (Acs) links cellular metabolism and physiology by catalyzing acetate and CoA into acetyl-CoA. However, the biological roles of Acs are not well studied in entomopathogenic fungi. In this study, two Acs proteins (BbAcs1 and BbAcs2) was functionally characterized in the filamentous insect pathogenic fungus Beauveria bassiana. BbAcs1 and BbAcs2 localize in cytoplasm and peroxisome, respectively. BbAcs1 contributes to vegetative growth on fatty acids as carbon source, and BbAcs2 did not. Both genes did not contribute to fungal response to stresses. The BbAcs1 loss conferred a slight influence on conidiation, and did not result in the defects in blastospore formation. On the contrary, BbAcs2 significantly contributes to lipid metabolism in germlings, blastospore formation, and virulence. The results indicated that Acs2 played a more predominant role than Acs1 in B. bassiana, which links the acetyl-CoA metabolism with the lifestyle of entomopathogenic fungi.

The maternal‐foetal interface is an immune‐privileged site where the semi‐allogeneic embryo is protected from attacks by the maternal immune system. Uterine macrophages are key players in establishing and maintaining pregnancy, and the dysregulation of the M1‐M2 subpopulation balance causes abortion. We separated two distinct mouse uterine macrophage subpopulations during early pregnancy, CD45+F4/80+CD206− M1‐like (M1) and CD45+F4/80+CD206+ M2‐like (M2) cells. The M1 preponderance was significantly exaggerated at 6 hours after lipopolysaccharide (LPS) treatment, and adoptive transfer of M2 macrophages partially rescued LPS‐induced abortion. RNA sequencing analysis of mouse uterine M2 versus M1 revealed 1837 differentially expressed genes (DEGs), among which 629 was up‐regulated and 1208 was down‐regulated. Histone deacetylase 9 (Hdac9) was one of the DEGs and validated to be significantly up‐regulated in uterine M2 as compared with M1. Remarkably, this differential expression profile between M1 and M2 was also evident in primary splenic macrophages and in vitro polarized murine peritoneal, bone marrow–derived and RAW 264.7 macrophages. In Hdac9/HDAC9 knockout RAW 264.7 and human THP‐1–derived macrophages, the expression of M1 differentiation markers was unchanged or decreased whereas M2 markers were increased compared with the wild‐type cells, and these effects were unrelated to compromised proliferation. Furthermore, Hdac9/HDAC9 ablation significantly enhanced the phagocytosis of fluorescent microspheres in M2 Raw 264.7 cells yet decreased the capacity of THP‐1‐derived M1 macrophages. The above results demonstrate that Hdac9/HDAC9 deficiency exaggerates M2 macrophage polarization in mouse and human macrophages, which may provide clues for our understanding of the epigenetic regulation on macrophage M1/M2 polarization in maternal‐foetal tolerance.

Purpose Obese individuals have an increased risk of hypothyroidism. This study investigated the sex-specific association between obesity phenotypes and the development of hypothyroidism. Methods The study population was derived from a health management cohort in Shandong Provincial Hospital from 2012 to 2016. In total, 9011 baseline euthyroid adults were included and classified into four groups according to obesity phenotype: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). The median follow-up time was 1.92 (1.00–2.17) years. Incidence density was evaluated and a generalized estimation equation method was used to investigate the associations between obesity phenotypes and the development of hypothyroidism. Results The incidence densities of hypothyroidism in males with a consistent obesity phenotype were 12.19 (8.62–16.76), 15.87 (11.39–21.56), 14.52 (6.74–27.57), and 19.88 (14.06–27.34) per 1000 person-years in the MHNO, MHO, MUNO, and MUO groups, respectively. After adjusting for confounding factors, compared with the MHNO phenotype, the MHO, MUNO, and MUO phenotypes were independent risk factors for developing hypothyroidism in males. In the subgroup analysis, the MHO and MUO phenotypes were independent risk factors for developing hypothyroidism in males under 55 years, while the MUNO phenotype was an independent risk factor in males over 55 years. The MHO, MUNO, and MUO phenotypes were not independent risk factors for hypothyroidism in females. Conclusion Both obesity and metabolic abnormities are associated with a higher risk of hypothyroidism in males. The underlying mechanism of the sex and age differences in this association needs further investigation.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Exercise is a therapeutic strategy for preventing NAFLD. However, the underlying molecular mechanisms by which NAFLD can be ameliorated through exercise are still not clear. This study investigates the mechanisms by which exercise suppresses NAFLD development induced by a high-fat diet (HFD) in mice. Male 6-week-old C57BL/6J mice were fed a normal diet or HFD for 12 weeks and then induced to swim or remain sedentary for 8 weeks. Histomorphology, inflammatory factors, fat metabolizing enzymes, fibrosis, and steatosis were determined in HFD-fed mouse liver, and levels of hepatic enzymes and molecules in the related pathways were analyzed. NAFLD mice showed evident steatosis, fibrosis, and liver injury, and an increased expression of HMGCS2, Wnt3a/ β-catenin, and phosphorylated (p)-AMPK in the liver. Exercise significantly attenuated these symptoms and downregulated the level of Wnt3a/β-catenin in lipotoxic liver tissue. Inhibition of HMGCS2 expression decreased the activation of the Wnt3a/β-catenin pathway and lowered p-AMPK in palmitate-treated HepG2. Our results suggest that exercise prevents NAFLD-associated liver injury, steatosis, and fibrosis. Exercise-mediated hepatoprotection was achieved partly via the blocking of the upregulation of HMGCS2 and the attenuation of the Wnt3a/β-catenin pathway.

Autophagy is a conserved intracellular recycling mechanism, in which autophagy-related genes 12 and 16 (ATG12 and ATG16) function in a complex controlling the ubiquitin-like conjugation system. In the insect-pathogenic fungus Beauveria bassiana, ATG12 and ATG16 were functionally characterized. Disruption of BbATG12 or BbATG16 resulted in the absence of autophagic bodies under starvation stress. ΔBbATG12 and ΔBbATG16 mutant strains displayed similar defects in asexual development (conidiation and blastospore formation) and tolerance to oxidative stress. ΔBbATG16 strain exhibited the impaired growth on the media with gelatin or chitin as a single nitrogen source, and ΔBbATG12 displayed decreased growth on the media with sucrose, fructose or maltose as a single carbon source. Both BbATG12 and BbATG16 were required for fungal virulence. BbATG16 mutation had more effects on fungal virulence than BbATG12 in topical infection assay, although both genes had similar contributions to fungal virulence in intrahemocoel injection assay. This study indicates that BbATG12 and BbATG16 mediate diverse biological functions in addition to their convergent roles in autophagy.

Insulin resistance (IR) is a major metabolic risk factor even before the onset of hyperglycemia. Recently, berberine (BBR) is found to improve hyperglycemia and IR. In this study, we investigated whether BBR could improve IR independent of hyperglycemia. Acute insulin-resistant state was induced in rats by systemic infusion of intralipid (6.6%). BBR was administered via different delivery routes before or after the beginning of a 2-h euglycemic-hyperinsulinemic clamp. At the end of experiment, rats were sacrificed, gastrocnemius muscle was collected for detecting mitochondrial swelling, phosphorylation of Akt and AMPK, as well as the mitochondrial permeability regulator cyclophilin D (CypD) protein expression. We showed that BBR administration markedly ameliorated intralipid-induced IR without affecting blood glucose, which was accompanied by alleviated mitochondrial swelling in skeletal muscle. We used human skeletal muscle cells (HSMCs), AML12 hepatocytes, human umbilical vein endothelial cells, and CypD knockout mice to investigate metabolic and molecular alternations. In either HSMCs or AML12 hepatocytes, BBR (5 μM) abolished palmitate acid (PA)-induced increase of CypD protein levels. In CypD-deficient mice, intralipid-induced IR was greatly attenuated and the beneficial effect of BBR was diminished. Furthermore, we demonstrated that the inhibitory effect of BBR on intralipid-induced IR was mainly mediated by skeletal muscle, but not by intestine, liver, or microvasculature; BBR administration suppressed intralipid-induced upregulation of CypD expression in skeletal muscle. These results suggest that BBR alleviates intralipid-induced IR, which is related to the inhibition of CypD protein expression in skeletal muscle.

Summary The ten-eleven translocation factor TET1 and its conferred epigenetic modification 5-hydroxymethylcytosine (5hmC) have important roles in maintaining the pluripotent state of embryonic stem cells (ESCs). We previously showed that TET1 is also essential to maintain the stem cell state of trophoblast stem cells (TSCs). Here, we establish an integrated panel of absolute 5hmC levels, genome-wide DNA methylation and hydroxymethylation patterns, transcriptomes, and TET1 chromatin occupancy in TSCs and differentiated trophoblast cells. We show that the combined presence of 5-methylcytosine (5mC) and 5hmC correlates with transcriptional activity of associated genes. Hypoxia can slow down the global loss of 5hmC that occurs upon differentiation of TSCs. Notably, unlike in ESCs and epiblast cells, most TET1-bound regions overlap with active chromatin marks and TFAP2C binding sites and demarcate putative trophoblast enhancer regions. These chromatin modification and occupancy patterns are highly informative to identify novel candidate regulators of the TSC state., Highlights • 5hmC to 5mC ratios correlate with gene activity in TS cells • TS cell differentiation-associated loss of 5hmC is slowed down in hypoxia • TET1 binding in TS cells forms long-range interactions with key trophoblast genes • Intergenic TET1 binding sites in TS cells demarcate putative trophoblast enhancers, TET1 and its conferred epigenetic modification 5-hydroxymethylation are critical for maintaining pluripotency of embryonic stem cells. In this article, Senner and colleagues describe in-depth the role of this modification, in conjunction with DNA methylation, in trophoblast stem cells, and determine a distinct role for TET1 in demarcating putative trophoblast enhancers and thereby establishing trophoblast-specific gene networks.

© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.Oxidative stress (OS)-induced mitochondrial damage and the subsequent osteoblast dysfunction contributes to the initiation and progression of osteoporosis. Notoginsenoside R1 (NGR1), isolated from Panax notoginseng, has potent antioxidant effects and has been widely used in traditional Chinese medicine. This study aimed to investigate the protective property and mechanism of NGR1 on oxidative-damaged osteoblast. Osteoblastic MC3T3-E1 cells were pretreated with NGR1 24 h before hydrogen peroxide administration simulating OS attack. Cell viability, apoptosis rate, osteogenic activity and markers of mitochondrial function were examined. The role of C-Jun N-terminal kinase (JNK) signalling pathway on oxidative injured osteoblast and mitochondrial function was also detected. Our data indicate that NGR1 (25 μM) could reduce apoptosis as well as restore osteoblast viability and osteogenic differentiation. NGR1 also reduced OS-induced mitochondrial ROS and restored mitochondrial membrane potential, adenosine triphosphate production and mitochondrial DNA copy number. NGR1 could block JNK pathway and antagonize the destructive effects of OS. JNK inhibitor (SP600125) mimicked the protective effects of NGR1while JNK agonist (Anisomycin) abolished it. These data indicated that NGR1 could significantly attenuate OS-induced mitochondrial damage and restore osteogenic differentiation of osteoblast via suppressing JNK signalling pathway activation, thus becoming a promising agent in treating osteoporosis.

Human trophoblast syncytialization is one of the most important yet least understood events during placental development. In this study, we found that detyrosinated α-tubulin (detyr-α-tub), which is negatively regulated by tubulin tyrosine ligase (TTL), was elevated during human placental cytotrophoblast fusion. Correspondingly, relatively high expression of TTL protein was observed in first-trimester human placental cytotrophoblast cells, but fusing trophoblast cells exhibited much lower levels of TTL. Notably, fusion of preeclamptic cytotrophoblast cells was compromised but could be partially rescued by knockdown of TTL levels. Mechanistically, chronic downregulation of TTL in trophoblast cells resulted in significantly elevated expression of detyr-α-tub. Restoration of detyr-α-tub thus contributed to the cell surface localization of the fusogenic protein Syncytin-2 and the gap junction protein Connexin 43 (Cx43), which in turn promoted successful fusion between trophoblast cells. Taken together, the results suggest that tubulin detyrosination plays an essential role in human trophoblast fusogenic protein aggregation and syncytialization. Insufficient tubulin detyrosination leads to defects in syncytialization and potentially to the onset of preeclampsia.

Autophagy is a sophisticated mechanism for maintaining cellular homeostasis, in which E1-like enzyme (ATG7) controls the activation of ubiquitin-like conjugation system in the autophagy pathway. In the insect pathogenic fungus Beauveria bassiana, a yeast ortholog of ATG7 was identified and functionally analyzed. Ablation of BbATG7 gene blocks the autophagic process under starvation stress. The mutant ΔBbATG7 exhibited impaired growth on the media with chitin as single nitrogen source. On rich media, gene loss did not cause notable effect on vegetative growth, but resulted in a considerable reduction in conidiation (71.6%) and blastospore yield (61.1%) in the mutant. In addition, the ΔBbATG7 mutant displayed increased sensitivity to stress caused by menadione and Congo red. The virulence of ΔBbATG7 mutant was significantly attenuated as indicated in topical and intrahemocoel injection assays. Our study indicates that BbATG7 contributes to B. bassiana virulence via regulating autophagy pathway and playing non-autophagic functions in the infection cycle.

Aims Peroxins Pex5 and Pex7 belong to the peroxisomal import machinery and recognize proteins containing peroxisomal targeting signal (PTS) type 1 and type 2, respectively. This study seeks to characterize these two peroxins in the entomopathogenic fungus Beauveria bassiana. Methods and results The orthologs of Pex5 and Pex7 in B. bassiana (BbPex5 and BbPex7) were functionally analyzed via protein localization and gene disruption. BbPex5 and BbPex7 were associated with peroxisome and specifically required for PTS1 and PTS2 pathways, respectively, which were demonstrated to be involved in development, tolerance to oxidative stress and virulence. ΔBbPex5 mutant displayed additionally defectives that were undetected in ΔBbPex7 in vegetative growth and resistance to osmotic and cell wall-perturbing stresses. Notably, Woronin body major protein Hex1 with PTS1 linked this organelle to the development and virulence of B. bassiana, which indicates that Woronin body is associated with the roles of PTS1 pathway. Conclusion Both PTS1 and PTS2 pathways are involved in broad physiological process, and the PTS1 pathway acts as a main peroxisomal import pathway. Significance and impact of the study This study shows the functional divergence of different peroxins and improves our understanding of organellar physiology involved in biocontrol potential of the entomopathogenic fungi.

To evaluate the accuracy of 6D computed-derived implant guides made in China, in order to provide methods and basis for reducing deviation.3D rapid prototyping technique was used to fabricate implant guides for auxiliary surgical implantation in edentulous patients, and the position deviation between the preoperative design and the actual implant was measured. Sixteen edentulous patients with 172 implantation sites were measured. In 10 patients, six implants were implanted in the maxilla, 4 implants in the mandible, and 6 implants were implanted both in the maxilla and mandible of 6 patients. A total of 28 implants were tilted implant in 14 patients. Preoperative cone-beam CT(CBCT) data were imported into the 6D Dental Planning Software to design and make the implant guides. Digital guides were used to assist implant placement. Preoperative design and postoperative CBCT were imported into the software for 3D reconstruction and registration, and then exported to Geomagic Studio software for analysis to obtain the deviation between the preoperative design and the implantation, so as to analyze the accuracy of the guides. The differences were analyzed by SPSS 25.0 software package with paired t-test and single factor analysis of variance.The distance deviation of implant neck center point was (0.83±0.27) mm and the horizontal deviation was (0.60±0.21) mm. The distance deviation of implant bottom center point was (1.11±0.35) mm, and the vertical deviation was (0.45±0.19) mm. The angle deviation was (3.16±1.73)°.The 6D computed-derived implant guides made in China can improve the accuracy and efficiency of implant surgery for edentulous patients and obtain a better long-term clinical effect to meet clinical requirements well. Since the deviation is similar to other implant guide plate systems that reported aborad, it must be taken into account in the process of clinical design, in order to avoid risks and unnecessary complications. This method is worthy of wide clinical application.

Conidial maturation and germination are highly coupled physiological processes in filamentous fungi that are critical for the pathogenicity of mycopathogens. Compared to the mechanisms involved in conidial germination, those of conidial reserves during maturation are less understood. The insect-pathogenic fungus Beauveria bassiana, as a representative species of filamentous fungi, is important for applied and fundamental research. In addition to its conserved roles in fungal adaptation to iron status, the bZIP transcription factor HapX acts as a master regulator involved in conidial virulence and regulates fatty acid/lipid metabolism. Further investigation revealed that the Δ9-fatty acid desaturase gene (Ole1) is a direct downstream target of HapX. This study reveals the HapX-Ole1 pathway involved in the fatty acid/lipid accumulation associated with conidial maturation and provides new insights into the startup mechanism of infection caused by spores from pathogenic fungi., In pathogenic filamentous fungi, conidial germination not only is fundamental for propagation in the environment but is also a critical step of infection. In the insect mycopathogen Beauveria bassiana, we genetically characterized the role of the basic leucine zipper (bZIP) transcription factor HapX (BbHapX) in conidial nutrient reserves and pathogen-host interaction. Ablation of BbHapX resulted in an almost complete loss of virulence in the topical inoculation and intrahemocoel injection assays. Comparative transcriptomic analysis revealed that BbHapX is required for fatty acid (FA)/lipid metabolism, and biochemical analyses indicated that BbHapX loss caused a significant reduction in conidial FA contents. Exogenous oleic acid could partially or completely restore the impaired phenotypes of the ΔBbHapX mutant, including germination rate, membrane integrity, vegetative growth, and virulence. BbHapX mediates fungal iron acquisition which is not required for desaturation of stearic acid. Additionally, inactivation of the Δ9-fatty acid desaturase gene (BbOle1) generated defects similar to those of the ΔBbHapX mutant; oleic acid also had significant restorative effects on the defective phenotypes of the ΔBbOle1 mutant. A gel retarding assay revealed that BbHapX directly regulated the expression of BbOle1. Lipidomic analyses indicated that both BbHapX and BbOle1 contributed to the homeostasis of phospholipids with nonpolar tails derived from oleic acid; therefore, exogenous phospholipids could significantly restore membrane integrity. These data reveal that the HapX-Ole1 pathway contributes to conidial fatty acid/lipid reserves and that there are important links between the lipid biology and membrane functionality involved in the early stages of infection caused by B. bassiana. IMPORTANCE Conidial maturation and germination are highly coupled physiological processes in filamentous fungi that are critical for the pathogenicity of mycopathogens. Compared to the mechanisms involved in conidial germination, those of conidial reserves during maturation are less understood. The insect-pathogenic fungus Beauveria bassiana, as a representative species of filamentous fungi, is important for applied and fundamental research. In addition to its conserved roles in fungal adaptation to iron status, the bZIP transcription factor HapX acts as a master regulator involved in conidial virulence and regulates fatty acid/lipid metabolism. Further investigation revealed that the Δ9-fatty acid desaturase gene (Ole1) is a direct downstream target of HapX. This study reveals the HapX-Ole1 pathway involved in the fatty acid/lipid accumulation associated with conidial maturation and provides new insights into the startup mechanism of infection caused by spores from pathogenic fungi.

The placenta is crucial for a successful pregnancy and the health of both the fetus and the pregnant woman. However, how the human trophoblast lineage is regulated, including the categorization of the placental cell subtypes is poorly understood. Here we performed single-cell RNA sequencing (RNA-seq) on sorted placental cells from first- and second-trimester human placentas. New subtypes of cells of the known cytotrophoblast cells (CTBs), extravillous trophoblast cells (EVTs), Hofbauer cells, and mesenchymal stromal cells were identified and cell-type-specific gene signatures were defined. Functionally, this study revealed many previously unknown functions of the human placenta. Notably, 102 polypeptide hormone genes were found to be expressed by various subtypes of placental cells, which suggests a complex and significant role of these hormones in regulating fetal growth and adaptations of maternal physiology to pregnancy. These results document human placental trophoblast differentiation at single-cell resolution and thus advance our understanding of human placentation during the early stage of pregnancy.

Multiple exopolysaccharides (EPSs) have been isolated from various organisms in extreme environments and have yielded a variety of activities. The present study evaluated the immunomodulatory capabilities of an EPS (termed PH-EPS) derived from the fungus Paecilomyces lilacinus PH0016, which was isolated from a tropical and hyperhaline environment in southern China. The macrophage RAW 264.7 cell line was used to investigate the mechanism of PH-EPS-induced macrophage activation. The results indicated that RAW 264.7 macrophages were activated by PH-EPS, in an effect slightly inferior to lipopolysaccharide (LPS), as evidenced by secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and nitric oxide (NO), and by significantly increased phagocytosis in the cells treated with PH-EPS. Nuclear factor (NF)-κB p65 was significantly translocated into the nucleus in the PH-EPS-treated cells. In addition, expression of inducible NO synthase (iNOS) and IκB-α degradation were enhanced in PH-EPS-treated cells. The phosphorylation levels of p38, JNK and ERK were also significantly increased in the PH-EPS-treated cells. Furthermore, IL-1β and TNF-α production was markedly decreased in PH-EPS-treated cells when the mitogen-activated protein kinase (MAPK) pathways were blocked by the inhibitor Dectin-1 and by antibodies against Toll-like receptor 4 (TLR4). The present results indicated that PH-EPS from Paecilomyces lilacinus possessed the capability of activating RAW 264.7 cells via the TLR4/NF-κB/MAPKs signaling pathway.

The Mbp1 protein functions as a DNA-binding protein in the MluI cell cycle box-binding complex and plays significant roles in yeast development. In this study, an ortholog of yeast Mbp1, BbMbp1, was characterized in a filamentous insect mycopathogen, Beauveria bassiana. BbMbp1 plays an important role in morphological changes under aerial and liquid environments. On the aerial surface, BbMbp1 was indispensable for the biogenesis of conidiophores and conidiation. Under submerged conditions, the ∆BbMbp1 mutant displayed abnormal spore-producing structures, with a dramatic decrease in blastospore yield (~95%). The virulence of the ∆BbMbp1 mutant was notably weakened, which might be due to the defect in in vivo blastospore formation in the insect. Moreover, disruption of BbMbp1 resulted in a substantial reduction in hyphal growth on cadavers. Comparative transcriptomics revealed that BbMbp1 mediated different transcriptomes during the formation processes of conidia and blastospores. Yeast one-hybrid assays demonstrated that BbMbp1 was required for transcriptional control of a cell wall protein gene, BbCwp, and an integral membrane protein gene, BbImp that played significant roles in conidiation and blastospore formation respectively. Our results demonstrate that BbMbp1 contributes to the morphological transitions in the pathogenic and saprophytic growth of B. bassiana via different genetic pathways.

The syncytiotrophoblast (STB) plays a key role in maintaining the function of the placenta during human pregnancy. However, the molecular network that orchestrates STB development remains elusive. The aim of this study was to obtain broad and deep insight into human STB formation via transcriptomics. We adopted RNA sequencing (RNA-Seq) to investigate genes and isoforms involved in forskolin (FSK)-induced fusion of BeWo cells. BeWo cells were treated with 50 μM FSK or dimethyl sulfoxide (DMSO) as a vehicle control for 24 and 48 h, and the mRNAs at 0, 24 and 48 h were sequenced. We detected 28,633 expressed genes and identified 1902 differentially expressed genes (DEGs) after FSK treatment for 24 and 48 h. Among the 1902 DEGs, 461 were increased and 395 were decreased at 24 h, whereas 879 were upregulated and 763 were downregulated at 48 h. When the 856 DEGs identified at 24 h were traced individually at 48 h, they separated into 6 dynamic patterns via a K-means algorithm, and most were enriched in down–even and up–even patterns. Moreover, the gene ontology (GO) terms syncytium formation, cell junction assembly, cell fate commitment, calcium ion transport, regulation of epithelial cell differentiation and cell morphogenesis involved in differentiation were clustered, and the MAPK pathway was most significantly regulated. Analyses of alternative splicing isoforms detected 123,200 isoforms, of which 1376 were differentially expressed. The present deep analysis of the RNA-Seq data of BeWo cell fusion provides important clues for understanding the mechanisms underlying human STB formation.

Type 2 diabetes mellitus, obesity and hepatic steatosis showed a strong correlation with metabolic syndrome. However, data on the influence of pancreatic steatosis on metabolic syndrome are lacking.Our aim is to perform the prevalence of pancreatic steatosis in adults and its association with metabolic syndrome in a Chinese population.This was a cross-sectional study, randomly selected. A total of 1190 health examination subjects were recruited. Pancreatic steatosis or hepatic steatosis was diagnosed via trans-abdominal sonography. The clinical and metabolic parameters were compared between the two groups, and their associations with pancreatic steatosis were examined.The prevalence of pancreatic steatosis was 30.7%. The presence of pancreatic steatosis was significantly increased by age, gender, central obesity, hepatic steatosis, hypertriglyceridemia and hyperglycemia. In the logistic regression analysis, age (P 0.05), central obesity (P 0.01), diabetes (P 0.05), hypertriglyceridemia (P 0.05) and hepatic steatosis (P 0.01) were independently associated with pancreatic steatosis. The number of the parameters of the metabolic syndrome in pancreatic steatosis group was more than that in non-pancreatic steatosis group [(2.5 ± 1.1) vs (1.4 ± 1.2)] (P 0.01).The pancreatic steatosis is strongly associated with the parameters of metabolic syndrome, such as central obesity, diabetes, and hepatic steatosis.

The placental syncytiotrophoblast, which is formed by the fusion of cytotrophoblast cells, is indispensable for the establishment and maintenance of normal pregnancy. The human endogenous retrovirus envelope glycoprotein syncytin-2 is the most important player in mediating trophoblast cell-cell fusion as a fusogen. We constructed expression plasmids of wild-type and 21 single-amino-acid substitution mutants of syncytin-2, including 10 N-glycosylation sites individually silenced by mutagenizing N to Q, 1 naturally occurring single-nucleotide polymorphism (SNP) N118S that introduced an N-glycosylation site, and another 10 non-synonymous SNPs located within important functional domains. We observed that syncytin-2 was highly fusogenic and that the mutants had different capacities in merging 293T cells. Of the 21 mutants, N133Q, N312Q, N443Q, C46R (in the CXXC motif) and R417H (in the heptad repeat region and immunosuppressive domain) lost their fusogenicity, whereas N332Q, N118S, T367M (in the fusion peptide), V483I (in the transmembrane domain) and T522M (in the cytoplasmic domain) enhanced the fusogenic activity. We also proved that N133, N146, N177, N220, N241, N247, N312, N332 and N443 were all glycosylated in 293T cells. A co-immunoprecipitation assay showed compromised interaction between mutants N443Q, C46R, T367M, R417H and the receptor MFSD2A, whereas N118S was associated with more receptors. We also sequenced the coding sequence of syncytin-2 in 125 severe pre-eclamptic patients and 272 normal pregnant Chinese women. Surprisingly, only 1 non-synonymous SNP T522M was found and the frequencies of heterozygous carriers were not significantly different. Taken together, our results suggest that N-glycans at residues 133, 312, 332 and 443 of syncytin-2 are required for optimal fusion induction, and that SNPs C46R, N118S, T367M, R417H, V483I and T522M can alter the fusogenic function of syncytin-2.

Sixty-one endophytic fungus strains with different colony morphologies were isolated from the leaves, stems and roots of Tephrosia purpurea with colonization rates of 66.95%, 37.50%, and 26.92%, respectively. Based on internal transcribed spacer sequence analysis, 61 isolates were classified into 16 genera belonging to 3 classes under the phylum Ascomycota. Of the 61 isolates, 6 (9.84%) exhibited antifungal activity against one or more indicator plant pathogenic fungi according to the dual culture test. Isolate TPL25 had the broadest antifungal spectrum of activity, and isolate TPL35 was active against 5 plant pathogenic fungi. Furthermore, culture filtrates of TPL25 and TPL35 exhibited greater than 80% growth inhibition against Sclerotinia sclerotiorum. We conclude that the endophytic fungal strains TPL25 and TPL35 are promising sources of bioactive compounds.

Plasma corticosteroid-binding globulin (CBG) transports cortisol but high progesterone levels at the maternal-fetal interface can displace cortisol from its steroid-binding site. A secretion-deficient CBG mutant (A51V) in ∼1 of 36 Chinese causes low circulating CBG levels.Assess the implications of a CBG deficiency on pregnancy outcomes.From 1978 Chinese women screened at 12-16 weeks' gestation, 50 A51V carriers were identified and 46 were followed with 60 controls throughout pregnancy. Blood samples from another 2051 pregnant women were obtained at term to determine the secondary sex ratio (SSR) of newborns in an extended cohort (n = 101) of A51V mothers.Among women recruited at 12-16 weeks' gestation, serum CBG increased progressively during pregnancy but was lower (P.0001) in heterozygous A51V carriers than controls. Two women homozygous for A51V had very low serum CBG but their pregnancies progressed normally. The A51V mothers did not differ from controls in body mass index, gestational age at delivery, duration of parturition, blood pressure, gravidity, infant birth weight and size, or placental weights, and reported no unusual clinical symptoms. Peripheral CBG and progesterone levels correlated (r = 0.459) during first and second trimesters. Progesterone levels were much higher in intervillous blood and correlated (r = 0.637) with CBG levels. A female-skewed SSR in newborns of A51V mothers (0.77) differed (P.05) from the SSR (1.17) in a reference cohort.CBG influences progesterone levels in peripheral blood and at the maternal-fetal interface. The female-skewed SSR suggests that male fetal survival is compromised in CBG-deficient mothers.

The placenta has numerous functions, such as transporting oxygen and nutrients and building the immune tolerance of the fetus. Cell fusion is an essential process for placental development and maturation. In human placental development, mononucleated cytotrophoblast (CTB) cells can fuse to form a multinucleated syncytiotrophoblast (STB), which is the outermost layer of the placenta. Nephrin is a transmembrane protein that belongs to the Ig superfamily. Previous studies have shown that nephrin contributes to the fusion of myoblasts into myotubes in zebrafish and mice, presenting a functional conservation with itsDrosophilaortholog sticks and stones. However, whether nephrin is involved in trophoblast syncytialization remains unclear. In this study, we report that nephrin was localized predominantly in the CTB cells and STB of human placenta villi from first trimester to term pregnancy. Using a spontaneous fusion model of primary CTB cells, the expression of nephrin was found to be increased during trophoblast cell fusion. Moreover, the spontaneous syncytialization and the expression of syncytin 2, connexin 43, and human chorionic gonadotropin beta were significantly inhibited by nephrin-specific siRNAs. The above results demonstrate that nephrin plays an important role in trophoblast syncytialization.

Recent advancements in brain imaging technologies have facilitated the understanding on several neurological deficits. Increased cases of cerebral infarction have led scientists to focus their researches on the related topics. Silent cerebral infarctions commonly known as silent strokes are one of the poorly understood neurological deficit which still lacks a clear definition. Cerebral infarction is more apparently found in patients with silent cerebral infarction. In this paper, the concept of silent cerebral infarction was studied, and the pathology and etiology were analysed. The patients were selected as the research objects, and their cerebrovascular function was detected. The paper also analyses the correlation between risk factors and better treatment options were also discussed to make certain contributions to the progress of medicine.

Proper differentiation of trophoblast cells in the human placenta is a prerequisite for a successful pregnancy, and dysregulation of this process may lead to malignant pregnancy outcomes, such as preeclampsia. Finding specific markers for different types of trophoblast cells is essential for understanding trophoblast differentiation. Here, we report that placenta-specific protein 8 (PLAC8) is specifically expressed in the interstitial extravillous trophoblast cells (iEVTs) on the fetomaternal interface. Using model systems, including placental villi-decidua co-culture, iEVTs induction by using primary trophoblast cells or explants, etc., we found that PLAC8 promotes invasion and migration of iEVTs. Mechanistically, time-lapse imaging, GTPase activity assay, co-immunoprecipitation and RNA-seq studies show that PLAC8 increases the Cdc42 and Rac1 activities, and further induces the formation of filopodia at the leading edge of the migratory trophoblast cells. More interestingly, PLAC8 is significantly upregulated under hypoxia and expression of PLAC8 is higher in iEVTs from preeclamptic placentas when compared with those from the normal control placentas. Together, PLAC8 is a new marker for iEVTs and plays an important role in promoting trophoblast invasion and migration., Highlighted Article: Oxygen tension-dependent expression of placenta-specific protein 8 positively regulates trophoblast invasion and migration partially through upregulating the activation of Rac1 and Cdc42.

Working principle and advantages of tube in hydroforming with radical crushing were described and introduced briefly. The research status of deformation behaviors of tube in hydroforming with radical crushing with the tube cross-section shape was made into triangle, rectangle or trapezoid were reviewed in this paper. Finally, the development trend and burning questions of tube in hydroforming with radical crushing were predicted.