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During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of redox regulation in sperm development and maturation remain largely elusive. In this study, we report that thioredoxin-glutathione reductase (TXNRD3), a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation, regulates redox homeostasis to support male fertility. Using Txnrd3-/- mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility under conditions of TXNRD3 deficiency. We find that mitochondria develop more defined cristae during capacitation in wildtype sperm. Furthermore, we show that absence of TXNRD3 alters thiol redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization. [ABSTRACT FROM AUTHOR]

Extreme value theory can analyze the extreme changes of financial market returns, and it is an effective financial risk management model. The distribution characteristics of financial assets' returns are the core content of all financial models. The assumptions about the fluctuation behavior of returns and its distribution characteristics are of great theoretical and practical significance for the measurement and management of financial risks. We compare the estimates of value at risk by the peak over threshold model with that by the traditional variance-covariance method. During downturns, the peak over threshold model based value at risk estimates is higher relative to that by the traditional variance-covariance approach. At the same time, this paper conducts statistical analysis of basic data through data collection and combines the establishment of statistical methods to study the practical effects of various factors on carbon productivity in China. In addition, this paper constructs a low-carbon economic neural network model based on particle swarm optimization to study carbon emissions. Finally, on the basis of analysis and research, this paper puts forward policy recommendations for China's future low-carbon development model, and then provides reference for guiding the development of China's future low-carbon model and provides theoretical basis for subsequent related research. [ABSTRACT FROM AUTHOR]

Macroeconomics is a very complex and huge system. With the improvement of China's market economy, it is of great theoretical significance and practical value to apply quantitative economics methods and models to study the macroeconomic state and forecast the economic development trend. The development of regional economy is restricted by natural conditions and social and humanistic conditions, and it is a complex system with many factors and levels. By using grey system theory, data processing can reduce its randomness and strengthen the inherent trend of data, so it is possible to use as few data as possible to establish a model describing economic system. Through empirical test, the author analyses the main factors of unbalanced regional economic development and puts forward the comparative advantages of regional development. According to the simulation results, the predicted results are stable and reliable. The conclusion of the study has a certain reference value for the formulation of macroeconomic policies. By strengthening the guidance of government classification, the regional economic disparity will be narrowed continuously. [ABSTRACT FROM AUTHOR]

Calcium signaling is critical for successful fertilization. In spermatozoa, calcium influx into the sperm flagella mediated by the sperm-specific CatSper calcium channel is necessary for hyperactivated motility and male fertility. CatSper is a macromolecular complex and is repeatedly arranged in zigzag rows within four linear nanodomains along the sperm flagella. Here, we report that the Tmem249-encoded transmembrane (TM) domain-containing protein, CATSPERθ is essential for the CatSper channel assembly during sperm tail formation. CATSPERθ facilitates the channel assembly by serving as a scaffold for a pore-forming subunit CATSPER4. CATSPERθ is specifically localized at the interface of a CatSper dimer and can self-interact, suggesting its potential role in CatSper dimer formation. Male mice lacking CATSPERθ are infertile because the sperm lack the entire CatSper channel from sperm flagella, rendering sperm unable to hyperactivate, regardless of their normal expression in the testis. In contrast, genetic abrogation of any of the other CatSper TM subunits results in loss of CATSPERθ protein in the spermatid cells during spermatogenesis. CATSPERθ might act as a checkpoint for the properly assembled CatSper channel complex to traffic to sperm flagella. This study provides insights into the CatSper channel assembly and elucidates the physiological role of CATSPERθ in sperm motility and male fertility. [ABSTRACT FROM AUTHOR]

We investigated how innate sensing by the mannose receptor (MR) influences the development of antifungal immunity. We demonstrate that MR senses mannan on the surface of attenuated Blastomyces dermatitidis vaccine yeast and that MR(-/-) mice demonstrate impaired vaccine immunity against lethal experimental blastomycosis, compared with wild-type control mice. Using naive Blastomyces-specific transgenic CD4(+) T cells, we found that MR regulates differentiation of naive T cells into T-helper type 17 (Th17) effector cells, which are essential in vaccine immunity against systemic dimorphic fungi. Thus, MR regulates differentiation of Th17 cells and is required to induce vaccine immunity against lethal pulmonary blastomycosis. [ABSTRACT FROM AUTHOR]

Vaccine immunity to the endemic mycoses of North America requires Thl7 cells, but the pattern recognition receptors and signaling pathways that drive these protective responses have not been defined. We show that C-type lectin receptors exert divergent contributions to the development of antifungal Thl7 cells and vaccine resistance against Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides posadasii. Acquired immunity to II. dermatitidis requires Dectin-2, whereas vaccination against H. capsulatum and C. posadasii infection depends on innate sensing by Dectin-1 and Dectin-2, but not Mincie. Tracking Ag-specific T cells in vivo established that the Card9 signaling pathway acts indispensably and exclusively on differentiation of Thl7 cells, while leaving intact their activation, proliferation, survival, and migration. Whereas Card9 signaling is essential, C-type lectin receptors offer distinct and divergent contributions to vaccine immunity against these endemic fungal pathogens. Our work provides new insight into innate immune mechanisms that drive vaccine immunity and Thl7 cells. [ABSTRACT FROM AUTHOR]

Background: Hepatic progenitor cells (HPC), a cell compartment capable of differentiating into hepatocytic and biliary lineages, may give rise to the formation of intermediate hepatobiliary cells (IHBC) or ductular reactions (DR). Aims: The aim of this study was to analyse the gene expression profiles of DR in cirrhosis and further investigate novel proteins expressed by HPC and their intermediate progeny. Methods: DR in hepatitis B virus (HBV)-positive cirrhotic liver tissues adjacent to hepatocellular carcinoma and interlobular bile ducts (ILBDs) in normal liver tissues were isolated by laser capture microdissection and then subjected to microarray analysis. Differential gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry on serial sections. HPC and their intermediate progeny were recognized by immunostaining with hepatocytic and biliary markers [HepPar1, cytokeratin (CK)7, CK19, neural cell adhesion molecule (NCAM), epithelial cell adhesion molecule (EpCAM)]. Results: A total of 88 genes showed upregulation in DR compared with ILBDs. Gene ontology analyses revealed that these upregulated genes were mostly associated with cell adhesion, immune response and the metabolic process. Contactin associated protein-like 2 (CNTNAP2) was first confirmed to be a novel protein expressed in a subpopulation of DR that was positive for CK7, NCAM or EpCAM. In addition, immunoreactivity for CNTNAP2 was also noted in a subset of isolated CK7-positive HPC as well as some ductular IHBC positive for CK19 and HepPar1 in DR. Conclusion: CNTNAP2 is specifically associated with the emergence of ductular populations and may be identified as a novel protein for defining a subset of HPC and their intermediate progeny in cirrhosis. [ABSTRACT FROM AUTHOR]

Candida albicans, a commensal organism and a pathogen of humans, can switch stochastically between a white phase and an opaque phase without an intermediate phase. The white and opaque phases have distinct cell shapes and gene expression programs. Once switched, each phase is stable for many cell divisions. White-opaque switching is under a1-α2 repression and therefore only happens in a or α cells. Mechanisms that control the switching are unknown. Here, we identify Wor1 (white-opaque regulator 1) as a master regulator of white-opaque switching. The deletion of WOR1 blocks opaque cell formation. The ectopic expression of WOR1 converts all cells to stable opaque cells in a or α cells. In addition, the ectopic expression of WOR1 in a/α cells is sufficient to induce opaque cell formation. Importantly, WOR1 expression displays an all-or-none pattern. It is undetectable in white cells, and it is highly expressed in opaque cells. The ectopic expression of Wor1 induces the transcription of WOR1 from the WOR1 locus, which correlates with the switch to opaque phase. We present genetic evidence for feedback regulation of WOR1 transcription. The feedback regulation explains the bistable and stochastic nature of white-opaque switching. [ABSTRACT FROM AUTHOR]

Lung 4D computed tomography (4D-CT), which is a time-resolved CT data acquisition, performs an important role in explicitly including respiratory motion in treatment planning and delivery. However, the radiation dose is usually reduced at the expense of inter-slice spatial resolution to minimize radiation-related health risk. Therefore, resolution enhancement along the superior–inferior direction is necessary. In this paper, a super-resolution (SR) reconstruction method based on a patch low-rank matrix reconstruction is proposed to improve the resolution of lung 4D-CT images. Specifically, a low-rank matrix related to every patch is constructed by using a patch searching strategy. Thereafter, the singular value shrinkage is employed to recover the high-resolution patch under the constraints of the image degradation model. The output high-resolution patches are finally assembled to output the entire image. This method is extensively evaluated using two public data sets. Quantitative analysis shows that the proposed algorithm decreases the root mean square error by 9.7%–33.4% and the edge width by 11.4%–24.3%, relative to linear interpolation, back projection (BP) and Zhang et al’s algorithm. A new algorithm has been developed to improve the resolution of 4D-CT. In all experiments, the proposed method outperforms various interpolation methods, as well as BP and Zhang et al’s method, thus indicating the effectivity and competitiveness of the proposed algorithm. [ABSTRACT FROM AUTHOR]

Most previous efforts in developing computer-aided detection (CADe) of colonic polyps apply similar measures or parameters to detect polyps regardless of their locations under an implicit assumption that all the polyps reside in a similar local environment, e.g. on a relatively flat colon wall. In reality, this implicit assumption is frequently invalid, because the haustral folds can have a very different local environment from that of the relatively flat colon wall. We conjecture that this assumption may be a major cause of missing the detection of polyps, especially small polyps (<10 mm linear size) located on the haustral folds. In this paper, we take the concept of adaptiveness and present an adaptive paradigm for CADe of colonic polyps. Firstly, we decompose the complicated colon structure into two simplified sub-structures, each of which has similar properties, of (1) relatively flat colon wall and (2) ridge-shaped haustral folds. Then we develop local environment descriptions to adaptively reflect each of these two simplified sub-structures. To show the impact of the adaptiveness of the local environment descriptions upon the polyp detection task, we focus on the local geometrical measures of the volume data for both the detection of initial polyp candidates (IPCs) and the reduction of false positives (FPs) in the IPC pool. The experimental outcome using the local geometrical measures is very impressive such that not only the previously-missed small polyps on the folds are detected, but also the previously miss-removed small polyps on the folds during FP reduction are retained. It is expected that this adaptive paradigm will have a great impact on detecting the small polyps, measuring their volumes and volume changes over time, and optimizing their management plan. [ABSTRACT FROM AUTHOR]

Thioredoxin/glutathione reductase (TXNRD3) is a selenoprotein composed of thioredoxin reductase and glutaredoxin domains. This NADPH-dependent thiol oxidoreductase evolved through gene duplication within the Txnrd family, is expressed in the testes, and can reduce both thioredoxin and glutathione in vitro; however, the function of this enzyme remains unknown. To characterize the function of TXNRD3 in vivo, we generated a strain of mice bearing deletion of Txnrd3 gene. We show that these Txnrd3 knockout mice are viable and without discernable gross phenotypes, and also that TXNRD3 deficiency leads to fertility impairment in male mice. We found that Txnrd3 knockout animals exhibited a lower fertilization rate in vitro, a sperm movement phenotype, and an altered thiol redox status in sperm cells. Proteomic analyses further revealed a broad range of substrates reduced by TXNRD3 during sperm maturation, presumably as a part of sperm quality control. Taken together, these results show that TXNRD3 plays a critical role in male reproduction via the thiol redox control of spermatogenesis. [ABSTRACT FROM AUTHOR]

Background: Orthotopic liver transplantation is the only effective treatment for liver failure but limited with shortage of available donor organs. Recent studies show promising results of mesenchymal stem cells (MSCs)-based therapies.Methods: We systematically investigate the therapeutic effects of MSCs or MSC-conditioned medium (MSC-CM) in ameliorating fulminant hepatic failure (FHF) and chronic liver fibrosis in mice. In addition, extensive flow cytometry analysis of spleens from vehicle and MSC- and MSC-CM-treated mice was applied to reveal the alteration of inflammatory state.Results: In FHF model, MSCs treatment reduced remarkably the death incidents; the analysis of gross histopathology showed that control livers were soft and shrunken with extensive extravasated blood, which was gradually reduced at later time points, while MSC-treated livers showed gross pathological changes, even 24 h after MSC infusion, and hematoxylin and eosin staining revealed dramatical hepatocellular death with cytoplasmic vacuolization suppressed by MSCs treatment; flow cytometry analysis of total lymphocytes showed that macrophages (F4/80) infiltrated into control livers more than MSC-treated livers; by contrast, MSC-CM partially ameliorates FHF. In chronic liver injury model, MSC and MSC-CM both suppressed fibrogenesis and necroinflammatory, and the later was better; activation of hepatic stellate cells (α-SMA) was inhibited; glycogen synthesis and storage (indicated by periodic acid-Schiff -staining) was improved; liver regeneration (Ki67) was promoted while liver apoptosis (TUNEL) was reduced. In the in vitro, MSCs promote macrophage line RAW264.7 apoptosis and MSC-CM promotes apoptosis and inhibits proliferation of HSC line LX-2. We also found that MSCs and MSC-CM could improve spleen; MSC-CM increased levels of Th2 and Treg cells, and reduced levels of Th17 cells, whereas levels of Th1 cells were unchanged; comparatively, MSC treatment did not affect Th17 and Treg cells and only slightly alters inflammatory state; MSC and MSC-CM treatment both substantially down-regulated macrophages in the spleens.Conclusion: Both MSCs and MSC-CM exert therapeutic effects by acting on various key cells during the pathogenesis of FHF and chronic fibrosis, stimulating hepatocyte proliferation and suppressing apoptosis, down-regulating infiltrating macrophages, converting CD4(+) T lymphocyte system into an anti-inflammatory state, and facilitating hepatic stellate cell death. [ABSTRACT FROM AUTHOR]

Candida albicans is a polymorphic human opportunistic pathogen in which the Swi–Snf complex functions as an activator whereas Tup1 acts as a general repressor during the yeast-hyphae transition. In Saccharomyces cerevisiae, the interplay between the Swi–Snf complex and the Tup1–Ssn6 repressive complex regulates the balance between active and repressed chromatin structures of a number of genes. To study the interplay between Candida albicans Swi1 and Tup1 and their effects on morphogenesis, we analyzed phenotypes of swi1/ swi1, tup1/ tup1 and swi1/ swi1 tup1/ tup1 mutants under various growth conditions. The swi1/ swi1 mutant failed to form true hyphae, whereas the tup1/ tup1 mutant exhibited constitutive filamentous growth. Deletion of SWI1 in the tup1/ tup1 mutant completely blocked hyphal growth under all the conditions examined. Under aerobic conditions, the swi1/ swi1 tup1/ tup1 mutant most resembled the swi1/ swi1 mutant in phenotype, actin polarization and gene expression pattern. In invaded agar, the double mutant showed similar phenotypes as the swi1/ swi1 mutant, while under embedded conditions, it grew as a pseudohypha-like form different from that of the wild-type strain, swi1/ swi1 or tup1/ tup1 mutants. These results suggest that Swi1 may play a dominant role by antagonizing the repressive effect of the Tup1 on hyphal development in C. albicans. [ABSTRACT FROM AUTHOR]

Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of macrophage-inducible C-type lectin (Mincle) for host defense against Pneumocystis. Binding assays implementing soluble Mincle carbohydrate recognition domain fusion proteins demonstrated binding to intact Pneumocystis carinii as well as to organism homogenates, and they purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with PCP expressed increased Mincle mRNA levels. Mouse macrophages overexpressing Mincle displayed increased binding to P. carinii life forms and enhanced protein tyrosine phosphorylation. The binding of P. carinii to Mincle resulted in activation of FcRg-mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase after P. carinii challenge, critical in downstream inflammatory signaling. Mincle-deficient CD4-depleted (Mincle-/-) mice showed a significant defect in organism clearance from the lungs with higher organism burdens and altered lung cytokine responses during Pneumocystis murina pneumonia. Interestingly, Mincle-/- mice did not demonstrate worsened survival during PCP compared with wild-type mice, despite the markedly increased organism burdens. This may be related to increased expression of anti-inflammatory factors such as IL-1Ra during infection in the Mincle-/- mice. Of note, the P. murina-infected Mincle-/- mice demonstrated increased expression of known C-type lectin receptors Dectin-1, Dectin-2, and MCL compared with infected wild-type mice. Taken together, these data support a significant role for Mincle in Pneumocystis modulating host defense during infection. [ABSTRACT FROM AUTHOR]

To solve the problem of correction of magnetotelluric (MT) static shift, we quantise factors that influence geological environments and observation conditions and study MT static shift according to 3D MT numerical forward modelling and field tests with real data collection. We find that static shift distortions affect both the apparent resistivity and the impedance phase. The distortion results are also related to the frequency. On the basis of synthetic and real data analysis, we propose the concept of generalised static shift resistivity (GSSR) and a new method for correcting MT static shift. The approach is verified by studying 2D inversion models using synthetic and real data. [ABSTRACT FROM AUTHOR]

Plumbagin (PL, 5-hydroxy-2-methyl-1,4-naphthoquinone) is a herbal compound derived from medicinal plants of the Droseraceae, Plumbaginaceae, Dioncophyllaceae, and Ancistrocladaceae families. Reports have shown that PL exerts immunomodulatory activity and may be a novel drug candidate for immune-related disease therapy. However, its effects on dendritic cells (DCs), the most potent antigen-presenting cells (APCs), remain unclear. In this study, we demonstrate that PL inhibits the differentiation, maturation, and function of human monocyte-derived DCs. PL can also restrict the expression of Th1- and Th17-polarizing cytokines in mDC. In addition, PL suppresses DCs both in vitro and in vivo, as demonstrated by its effects on the mouse DC line DC2.4 and mice with experimental autoimmune encephalomyelitis (EAE), respectively. Notably, PL ameliorated the clinical symptoms of EAE, including central nervous system (CNS) inflammation and demyelination. Our results demonstrate the immune suppressive and anti-inflammatory properties of PL via its effects on DCs and suggest that PL could be a potential treatment for DC-related autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]