Publications by authors named "Jintao Xu"

31 Publications

CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis.

mBio 2021 Jul 27:e0107621. Epub 2021 Jul 27.

Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.

Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45CD11bLy6C inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4 T cells and CD8 T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4 T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01076-21DOI Listing
July 2021

Silicone Oil-Based Nanoadjuvants as Candidates for a New Formulation of Intranasal Vaccines.

Vaccines (Basel) 2021 Mar 8;9(3). Epub 2021 Mar 8.

Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland.

Many conventional vaccines are administered via a needle injection, while most pathogens primarily invade the host via mucosal surfaces. Moreover, protective IgA antibodies are insufficiently induced by parenteral vaccines. Mucosal immunity induces both local and systemic response to pathogens and typically lasts for long periods of time. Therefore, vaccination via mucosal routes has been increasingly explored. However, mucosal vaccines require potent adjuvants to become efficacious. Despite many efforts to develop safe and robust adjuvants for mucosal vaccines, only a few have been approved for use in human formulations. The aim of our study was to design, develop and characterize new silicone oil-based nanoadjuvant candidates for intranasal vaccines with potential to become mucosal adjuvants. We have developed an array of nanoadjuvant candidates (NACs), based on well-defined ingredients. NAC1, 2 and 3 are based on silicone oil, but differ in the used detergents and organic solvents, which results in variations in their droplet size and zeta potential. NACs' cytotoxicity, Tumor Necrosis Factor α (TNF-α) induction and their effect on antigen engulfment by immune cells were tested in vitro. Adjuvant properties of NACs were verified by intranasal vaccination of mice together with ovalbumin (OVA). NACs show remarkable stability and do not require any special storage conditions. They exhibit bio-adhesiveness and influence the degree of model protein engulfment by epithelial cells. Moreover, they induce high specific anti-OVA IgG antibody titers after two intranasal administrations. Nanoadjuvant candidates composed of silicone oil and cationic detergents are stable, exhibit remarkable adjuvant properties and can be used as adjuvants for intranasal immunization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines9030234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999606PMC
March 2021

Multivalent butyrylcholinesterase inhibitor discovered by exploiting dynamic combinatorial chemistry.

Bioorg Chem 2021 Mar 27;108:104656. Epub 2021 Jan 27.

School of Pharmacy, Jiangsu University, 301 Xuefu Rd., Zhenjiang, China. Electronic address:

In this study, we report the generation of a polymer-based dynamic combinatorial library (DCL) incorporating exchangeable side chains using acylhydrazone formation reaction. In combination with tetrameric butyrylcholinesterase (BChE), the most potent binding side chain was identified, and the information obtained was further used for the synthesis of a multivalent BChE inhibitor. In the in vitro biological evaluation, this multivalent inhibitor exhibited not only better inhibitory effect than the commercial reference but also high selectivity on BChE over acetylcholinesterase (AChE).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.104656DOI Listing
March 2021

Origin of Magnetically Induced Optical Transmission of Magnetic Nanocomposite Films.

Polymers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

School of Mechanical and Electrical Engineering, University of Electronic Science and Technology of China, Chengdu 611731, China.

Herein, we present an investigation on the origin of the magnetically induced optical transmission of composite films comprised of polydimethylsiloxane and magnetic nanofillers via experiment and simulation. Structured and unstructured films were used in the study, which were fabricated with and without magnetic fields, respectively. Altered optical transmittance was observed from both types of films when they were subjected to an external magnetic field. Numerical analyses were performed to investigate the effect of the particle movement under magnetic field and the film magnetostriction on the film optical transmittance. The simulation results show that the changed light transmission under magnetic field is mainly due to a variation in the film thickness resulting from the film magnetostriction. The ellipsometric analysis results confirm the altered film thickness in response to the external magnetic field, and the measurements of the film magnetostrictive stresses validate that there is magnetostriction in the magnetic composite films. Additionally, it is indicated that there might be some relationship between the magnetically induced optical transmission and the film magnetostrictive stress under certain conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/polym12112533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693415PMC
October 2020

Corrigendum: Sho1 and Msb2 Play Complementary but Distinct Roles in Stress Responses, Sexual Differentiation, and Pathogenicity of .

Front Microbiol 2020 24;11:1956. Epub 2020 Sep 24.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

[This corrects the article DOI: 10.3389/fmicb.2018.02958.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2020.01956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542305PMC
September 2020

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis.

Sci Adv 2020 Jun 17;6(25):eaba2502. Epub 2020 Jun 17.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.

Cryptococcal meningoencephalitis (CM) is the major cause of infection-related neurological death, typically seen in immunocompromised patients. However, T cell-driven inflammatory response has been increasingly implicated in lethal central nervous system (CNS) immunopathology in human patients and murine models. Here, we report marked up-regulation of the chemokine receptor CXCR3 axis in human patients and mice with CM. CXCR3 deletion in mice improves survival, diminishes neurological deficits, and limits neuronal damage without suppressing fungal clearance. CD4 T cell accumulation and T1 skewing are reduced in the CNS but not spleens of infected CXCR3 mice. Adoptive transfer of WT, but not CXCR3 CD4 T cells, into CXCR3 mice phenocopies the pathology of infected WT mice. Collectively, we found that CXCR3CD4 T cells drive lethal CNS pathology but are not required for fungal clearance during CM. The CXCR3 pathway shows potential as a therapeutic target or for biomarker discovery to limit CNS inflammatory damages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aba2502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299622PMC
June 2020

Identification and synthesis of an efficient multivalent E. coli heat labile toxin inhibitor A dynamic combinatorial chemistry approach.

Bioorg Med Chem 2020 05 13;28(9):115436. Epub 2020 Mar 13.

School of Pharmacy, Jiangsu University, Zhenjiang, China. Electronic address:

A polymer based dynamic combinatorial library (DCL) was generated through condensation between aldehyde functionalized linear poly(glycidol) (APG) and galactose containing acylhydrazide derivatives. Pentameric E. coli heat labile enterotoxin B subunit (LTB) was subsequently applied to the DCL as external stimulus, resulting in amplification of a specific acylhydrazone side chain that was further used for the synthesis of a multivalent LTB inhibitor. In the in vitro biological evaluation, this inhibitor exhibited strong inhibition properties as well as low cytotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2020.115436DOI Listing
May 2020

Identification of key genes related to seedlessness by genome-wide detection of structural variation and transcriptome analysis in 'Shijiwuhe' pear.

Gene 2020 May 17;738:144480. Epub 2020 Feb 17.

Center of Pear Engineering Technology Research, State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China. Electronic address:

Seedless fruits are highly marketable because they are easier to eat than fruits with seeds. 'Shijiwuhe' is a seedless pear cultivar that is a mutant derived from an F1 hybridization population ('Bartlett' x 'Yali'). Little is known about the key genes controlling seedless pear fruit. In this study, field experiments revealed that seedless 'Shijiwuhe' pear was not due to parthenocarpy, and that it was self-incompatible. Single nucleotide polymorphisms (SNPs), small insertions and deletions (InDels) and structural variations (SVs) were characterized using DNA sequencing data between 'Shijiwuhe' and parental cultivars. A total of 1498 genes were found to be affected by SV and over 50% of SVs were located in promoter regions. Transcriptome analysis was conducted at three time points (4, 8, and 12 days after cross-pollination) during early fruit development of 'Shijiwuhe', 'Bartlett', and 'Yali'. In total, 1438 differentially expressed genes (DEGs) were found between 'Shijiwuhe' and parental cultivars 'Bartlett' and 'Yali'. We found 1193 SVs that caused differential expression of genes at 4 DACP. Among them, over 100 genes were in pathways related to seed nutrition and energy storage and 41 candidate genes encoded several important transcription factors, such as MYB, WRKY, NAC, and bHLH, which might play important roles in seed development. The qRT-PCR results also confirmed that the candidate genes with SVs showed differential expression between 'Shijiwuhe' pear and 'Bartlett' or 'Yali'. This study, which combined field experiments, SV detection, and transcriptome analysis might provide an effective way to predict the candidate genes regulating the seedless trait and important gene resources for genetic improvement of pear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2020.144480DOI Listing
May 2020

Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization.

Sci Adv 2019 12 4;5(12):eaaw9051. Epub 2019 Dec 4.

Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.

Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of adaptive immunity remains unknown. We report that DCs matured with IFNγ and TNFα or matured in the lungs during invasive fungal infection with endogenous TNFα acquired a stable TNFα-dependent DC1 program, rendering them resistant to both antigen- and cytokine-induced alternative activation. TNFα-programmed DC1 had increased association of H3K4me3 with DC1 gene promoter regions. Furthermore, MLL1 inhibition blocked TNFα-mediated DC1 phenotype stabilization. During IFI, TNFα-programmed DC1s were required for the development of sustained T1/T17 protective immunity, and bone marrow pre-DCs exhibited TNFα-dependent preprogramming, supporting continuous generation of programmed DC1 throughout the infection. TNFα signaling, associated with epigenetic activation of DC1 genes particularly via H3K4me3, critically contributes to generation and sustenance of type 1/17 adaptive immunity and the immune protection against persistent infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aaw9051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892624PMC
December 2019

Development of a multivalent acetylcholinesterase inhibitor via dynamic combinatorial chemistry.

Int J Biol Macromol 2020 May 20;150:1184-1191. Epub 2019 Nov 20.

School of Pharmacy, Jiangsu University, Zhenjiang 212013, China. Electronic address:

In this study, we report the generation of a polymer based dynamic combinatorial library (DCL) using aldehyde-functionalized linear poly(glycidol) and hydrazide derivatives as initial building blocks. In combination with tetrameric acetylcholinesterase (AChE), a certain type of amplified acylhydrazone side chain is identified and further used for the synthesis of a multivalent AChE inhibitor. The cytotoxicity and inhibition properties of the multivalent inhibitor are evaluated, and the results indicate superior bioactivity compared to the commercial reference Edrophonium chloride.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2019.10.127DOI Listing
May 2020

TNF-α-Producing Exerts Protective Effects on Host Defenses in Murine Pulmonary Cryptococcosis.

Front Immunol 2019 26;10:1725. Epub 2019 Jul 26.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, United States.

Tumor necrosis factor alpha (TNF-α) plays a critical role in the control of cryptococcal infection, and its insufficiency promotes cryptococcal persistence. To explore the therapeutic potential of TNF-α supplementation as a booster of host anti-cryptococcal responses, we engineered a strain expressing murine TNF-α. Using a murine model of pulmonary cryptococcosis, we demonstrated that TNF-α-producing strain enhances protective elements of host response including preferential T-cell accumulation and improved Th1/Th2 cytokine balance, diminished pulmonary eosinophilia and alternative activation of lung macrophages at the adaptive phase of infection compared to wild type strain-infected mice. Furthermore, TNF-α expression by enhanced the fungicidal activity of macrophages . Finally, mice infected with the TNF-α-producing strain showed improved fungal control and considerably prolonged survival compared to wild type strain-infected mice, but could not induce sterilizing immunity. Taken together, our results support that TNF-α expression by an engineered strain while insufficient to drive complete immune protection, strongly enhanced protective responses during primary cryptococcal infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.01725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677034PMC
October 2020

Sho1 and Msb2 Play Complementary but Distinct Roles in Stress Responses, Sexual Differentiation, and Pathogenicity of .

Front Microbiol 2018 4;9:2958. Epub 2018 Dec 4.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

The high-osmolarity glycerol response (HOG) pathway is pivotal in environmental stress response, differentiation, and virulence of , which causes fatal meningoencephalitis. A putative membrane sensor protein, Sho1, has been postulated to regulate HOG pathway, but its regulatory mechanism remains elusive. In this study, we characterized the function of Sho1 with relation to the HOG pathway in . Sho1 played minor roles in osmoresistance, thermotolerance, and maintenance of membrane integrity mainly in a HOG-independent manner. However, it was dispensable for cryostress resistance, primarily mediated through the HOG pathway. A mucin-like transmembrane (TM) protein, Msb2, which interacts with Sho1 in , was identified in , but found not to interact with Sho1. codeletion with further decreased osmoresistance and membrane integrity, but not thermotolerance, of Δ mutant, indicating that both factors play to some level redundant but also discrete roles in . Sho1 and Msb2 played redundant roles in promoting the filamentous growth in sexual differentiation in a Cpk1-independent manner, in contrast to the inhibitory effect of the HOG pathway in the process. However, both factors contributed independently to Cpk1 phosphorylation during vegetative growth and endoplasmic reticulum (ER) stress response. Finally, Sho1 and Msb2 play distinct but complementary roles in the pulmonary virulence of . Overall, Sho1 and Msb2 play complementary but distinct roles in stress response, differentiation, and pathogenicity of .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2018.02958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288190PMC
December 2018

Cone-beam evaluation of pharyngeal airway space in adult skeletal Class II patients with different condylar positions.

Angle Orthod 2019 03 20;89(2):312-316. Epub 2018 Nov 20.

Objectives: To test the null hypothesis that there is no significant difference in pharyngeal airway space among adult skeletal Class II patients with different condylar positions using cone-beam computed tomography (CBCT).

Materials And Methods: The CBCT records of 60 patients with skeletal Class II malocclusion (ANB angle ≥ 4°, Wits ≥ 0) were selected from the CBCT database. According to the condyle position, the patients were divided in three groups: anterior group (CD ≤ -12%), centric group (-12% ≤ CD ≤ +12%), and posterior group (CD ≥ +12%). Three-dimensional (3D) pharyngeal airway models were reconstructed using InvivoDental software 5.1.3. The volume and area of the pharyngeal airway space were measured in the 3D airway model.

Results: The volume and area of the pharyngeal airway space in the centric group were significantly smaller than those in the posterior group ( P < .01). The volume and area of the pharyngeal airway space were smallest in the anterior group and significantly increased in the centric and posterior groups ( P < .001).

Conclusions: The null hypothesis was rejected. Significant differences were noted in pharyngeal airway space among adult skeletal Class II patients with different condylar positions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2319/040518-253.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120870PMC
March 2019

Structural and Comparative Analysis of the Complete Chloroplast Genome of -"Wild Plants with a Tiny Population"-and Three Other Species.

Int J Mol Sci 2018 Oct 20;19(10). Epub 2018 Oct 20.

Institute of Forest Biotechnology, Forestry College, Agricultural University of Hebei, Baoding 071000, China.

is a valuable wild resource of in the Rosaceae. Due to its limited distribution and population decline, it has been listed as one of the "wild plants with a tiny population" in China. To date, few studies have been conducted on . This paper offers a systematic review of , providing a basis for the conservation and restoration of resources. In this study, the chloroplast genomes of two different genotypes of , Maxin. cv. Jingbaili, L. cv. Early Red Comice, and were sequenced, compared and analyzed. The two genotypes showed a typical tetrad chloroplast genome, including a pair of inverted repeats encoding the same but opposite direction sequences, a large single copy (LSC) region, and a small single copy (SSC) region. The length of the chloroplast genome of HB-1 was 159,935 bp, 46 bp longer than that of the chloroplast genome of HB-2. The lengths of the SSC and IR regions of the two genotypes were identical, with the only difference present in the LSC region. The GC content was only 0.02% higher in HB-1. The structure and size of the chloroplast genome, the gene species, gene number, and GC content of were similar to those of the other three species. The IR boundary of the two genotypes of showed a similar degree of expansion. To determine the evolutionary history of within the genus and the Rosaceae, 57 common protein-coding genes from 36 Rosaceae species were analyzed. The phylogenetic tree showed a close relationship between the genera and , and the relationship between HB-1 and HB-2 was the closest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19103262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214102PMC
October 2018

How to Determine the Patient's Head and Neck Posture during Computed Tomography Scanning?

Am J Respir Crit Care Med 2018 11;198(9):1238

1 Hebei Medical University Shijiazhuang, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201805-0977LEDOI Listing
November 2018

The role of upper airway morphology in apnea versus hypopnea predominant obstructive sleep apnea patients: an exploratory study.

Authors:
Jintao Xu

Br J Radiol 2018 07 5;91(1088):20180363. Epub 2018 Jun 5.

1 Department of Orthodontics, College of Stomatology, Hebei Medical University , Shijiazhuang, Hebei , PR China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1259/bjr.20180363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209479PMC
July 2018

CD4 T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Meningoencephalitis.

mBio 2017 11 21;8(6). Epub 2017 Nov 21.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA

is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4 T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIV-positive (HIV+) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45 leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-γ)-producing CD4 T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4 cells significantly impaired IFN-γ production, CD8 T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4 T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections. CNS infection with the fungal pathogen often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIV+ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with anti-inflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and addresses the urgent need for animal models to investigate the specific cellular and molecular mechanisms underlying cryptococcal disease in order to better treat treat patients with CNS infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01415-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698549PMC
November 2017

Letters From Our Readers.

Angle Orthod 2017 11;87(6):925

Department of Orthodontics, College of Stomatology Hebei Medical University, Shijiazhuang, China e-mail:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2319/0003-3219-87.6.925DOI Listing
November 2017

Exploitation of Scavenger Receptor, Macrophage Receptor with Collagenous Structure, by Promotes Alternative Activation of Pulmonary Lymph Node CD11b Conventional Dendritic Cells and Non-Protective Th2 Bias.

Front Immunol 2017 28;8:1231. Epub 2017 Sep 28.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, United States.

Macrophage receptor with collagenous structure (MARCO) contributes to fungal containment during the early/innate phase of cryptococcal infection; however, its role in adaptive antifungal immunity remains unknown. Using a murine model of cryptococcosis, we compared host adaptive immune responses in wild-type and MARCO mice throughout an extended time course post-infection. Unlike in early infection, MARCO deficiency resulted in improved pulmonary fungal clearance and diminished cryptococcal dissemination during the efferent phase. Improved fungal control in the absence of MARCO expression was associated with enhanced hallmarks of protective Th1-immunity, including higher frequency of pulmonary TNF-α-producing T cells, increased cryptococcal-antigen-triggered IFN-γ and TNF-α production by splenocytes, and enhanced expression of M1 polarization genes by pulmonary macrophages. Concurrently, we found lower frequencies of IL-5- and IL-13-producing T cells in the lungs, impaired production of IL-4 and IL-10 by cryptococcal antigen-pulsed splenocytes, and diminished serum IgE, which were hallmarks of profoundly suppressed efferent Th2 responses in MARCO-deficient mice compared to WT mice. Mechanistically, we found that MARCO expression facilitated early accumulation and alternative activation of CD11b conventional DC (cDC) in the lung-associated lymph nodes (LALNs), which contributed to the progressive shift of the immune response from Th1 toward Th2 at the priming site (LALNs) and local infection site (lungs) during the efferent phase of cryptococcal infection. Taken together, our study shows that MARCO can be exploited by the fungal pathogen to promote accumulation and alternative activation of CD11b cDC in the LALN, which in turn alters Th1/Th2 balance to promote fungal persistence and dissemination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624996PMC
September 2017

Effect of CO on growth and toxicity of Alexandrium tamarense from the East China Sea, a major producer of paralytic shellfish toxins.

Harmful Algae 2017 09 14;68:240-247. Epub 2017 Sep 14.

The Key Laboratory of Marine Environment and Ecology, Ministry of Education, Ocean University of China, Qingdao 266100, China; Laboratory of Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200,China. Electronic address:

In recent decades, the frequency and intensity of harmful algal blooms (HABs), as well as a profusion of toxic phytoplankton species, have significantly increased in coastal regions of China. Researchers attribute this to environmental changes such as rising atmospheric CO levels. Such addition of carbon into the ocean ecosystem can lead to increased growth, enhanced metabolism, and altered toxicity of toxic phytoplankton communities resulting in serious human health concerns. In this study, the effects of elevated partial pressure of CO (pCO) on the growth and toxicity of a strain of Alexandrium tamarense (ATDH) widespread in the East and South China Seas were investigated. Results of these studies showed a higher specific growth rate (0.31±0.05day) when exposed to 1000μatm CO, (experimental), with a corresponding density of (2.02±0.19)×10cellsL, that was significantly larger than cells under 395μatm COcontrol). These data also revealed that elevated pCO primarily affected the photosynthetic properties of cells in the exponential growth phase. Interestingly, measurement of the total toxin content per cell was reduced by half under elevated CO conditions. The following individual toxins were measured in this study: C1, C2, GTX1, GTX2, GTX3, GTX4, GTX5, STX, dcGTX2, dcGTX3, and dcSTX. Cells grown in 1000μatm CO showed an overall decrease in the cellular concentrations of C1, C2, GTX2, GTX3, GTX5, STX, dcGTX2, dcGTX3, and dcSTX, but an increase in GTX1 and GTX4. Total cellular toxicity per cell was measured revealing an increase of nearly 60% toxicity in the presence of elevated CO compared to controls. This unusual result was attributed to a significant increase in the cellular concentrations of the more toxic derivatives, GTX1 and GTX4.Taken together; these findings indicate that the A. tamarense strain ATDH isolated from the East China Sea significantly increased in growth and cellular toxicity under elevated pCO levels. These data may provide vital information regarding future HABs and the corresponding harmful effects as a result of increasing atmospheric CO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hal.2017.08.008DOI Listing
September 2017

RIPK3/Fas-Associated Death Domain Axis Regulates Pulmonary Immunopathology to Cryptococcal Infection Independent of Necroptosis.

Front Immunol 2017 1;8:1055. Epub 2017 Sep 1.

PLA Key Laboratory of Mycosis, Department of Dermatology and Venereology, Changzheng Hospital, Shanghai, China.

Fas-associated death domain (FADD) and receptor interacting protein kinase 3 (RIPK3) are multifunctional regulators of cell death and immune response. Using a mouse model of cryptococcal infection, the roles of FADD and RIPK3 in anti-cryptococcal defense were investigated. Deletion of RIPK3 alone led to increased inflammatory cytokine production in the -infected lungs, but in combination with FADD deletion, it led to a robust Th1-biased response with M1-biased macrophage activation. Rather than being protective, these responses led to paradoxical expansion and rapid clinical deterioration in and mice. The increased mortality of and even more accelerated mortality in mice was attributed to profound pulmonary damage due to neutrophil-dominant infiltration with prominent upregulation of pro-inflammatory cytokines. This phenomenon was partially associated with selective alterations in the apoptotic frequency of some leukocyte subsets, such as eosinophils and neutrophils, in infected mice. In conclusion, our study shows that RIPK3 in concert with FADD serve as physiological "brakes," preventing the development of excessive inflammation and Th1 bias, which in turn contributes to pulmonary damage and defective fungal clearance. This novel link between the protective effect of FADD and RIPK3 in antifungal defense and sustenance of immune homeostasis may be important for the development of novel immunomodulatory therapies against invasive fungal infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585137PMC
September 2017

Scavenger Receptor MARCO Orchestrates Early Defenses and Contributes to Fungal Containment during Cryptococcal Infection.

J Immunol 2017 05 15;198(9):3548-3557. Epub 2017 Mar 15.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;

The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen , remains unknown. Using a mouse model of infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO mice was accompanied by impaired recruitment of Ly6C monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during infection. Lastly, we found that MARCO was involved in phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1700057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423401PMC
May 2017

Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection.

mBio 2016 07 12;7(4). Epub 2016 Jul 12.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA

Unlabelled: Anti-tumor necrosis factor alpha (anti-TNF-α) therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including Cryptococcus neoformans infection. Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-α signaling results in the development of nonprotective immunity against C. neoformans We found that transient depletion of TNF-α inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of C. neoformans during the adaptive phase of the immune response. Higher fungal burdens in TNF-α-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-α depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4(+) T cells in the lung-associated lymph nodes (LALN) of C. neoformans-infected mice. These defects in LALN T cell responses were preceded by a dramatic shift from a classical toward an alternative activation of dendritic cells (DC) in the LALN of TNF-α-depleted mice. Taken together, our results indicate that early TNF-α signaling is required for optimal DC activation, and the initial Th17 response followed by Th1 transcriptional prepolarization of T cells in the LALN, which further drives the development of protective immunity against cryptococcal infection in the lungs. Thus, administration of anti-TNF-α may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1/Th17 responses for their containment and clearance.

Importance: Increased susceptibility to invasive fungal infections in patients on anti-TNF-α therapies underlines the need for understanding the cellular effects of TNF-α signaling in promoting protective immunity to fungal pathogens. Here, we demonstrate that early TNF-α signaling is required for classical activation and accumulation of DC in LALN of C. neoformans-infected mice. Subsequent transcriptional initiation of Th17 followed by Th1 programming in LALN results in pulmonary accumulation of gamma interferon- and interleukin-17A-producing T cells and effective fungal clearance. All of these crucial steps are severely impaired in mice that undergo anti-TNF-α treatment, consistent with their inability to clear C. neoformans This study identified critical interactions between cells of the innate immune system (DC), the emerging T cell responses, and cytokine networks with a central role for TNF-α which orchestrate the development of the immune protection against cryptococcal infection. This information will be important in aiding development and understanding the potential side effects of immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.00510-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958242PMC
July 2016

Intracellular β-glucosidases CEL1a and CEL1b are essential for cellulase induction on lactose in Trichoderma reesei.

Eukaryot Cell 2014 Aug 30;13(8):1001-13. Epub 2014 May 30.

State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Jinan, Shandong, People's Republic of China

Lactose (1,4-O-β-d-galacto-pyranosyl-d-glucose) induces cellulolytic enzymes in Trichoderma reesei and is in fact one of the most important soluble carbon sources used to produce cellulases on an industrial level. The mechanism underlying the induction is, however, not fully understood. In this study, we investigated the cellular functions of the intracellular β-glucosidases CEL1a and CEL1b in the induction of cellulase genes by lactose in T. reesei. We demonstrated that while CEL1a and CEL1b were functionally equivalent in mediating the induction, the simultaneous absence of these intracellular β-glucosidases abolished cbh1 gene expression on lactose. d-Galactose restored the efficient cellulase gene induction in the Δcel1a strain independently of its reductive metabolism, but not in the Δcel1a Δcel1b strain. A further comparison of the transcriptional responses of the Δcel1a Δcel1b strain complemented with wild-type CEL1a or a catalytically inactive CEL1a version and the Δcel1a strain constitutively expressing CEL1a or the Kluyveromyces lactis β-galactosidase LAC4 showed that both the CEL1a protein and its glycoside hydrolytic activity were indispensable for cellulase induction by lactose. We also present evidence that intracellular β-glucosidase-mediated lactose induction is further conveyed to XYR1 to ensure the efficiently induced expression of cellulase genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/EC.00100-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135799PMC
August 2014

Two major facilitator superfamily sugar transporters from Trichoderma reesei and their roles in induction of cellulase biosynthesis.

J Biol Chem 2013 Nov 1;288(46):32861-72. Epub 2013 Oct 1.

From the State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Jinan 250100, Shandong, China and.

Proper perception of the extracellular insoluble cellulose is key to initiating the rapid synthesis of cellulases by cellulolytic Trichoderma reesei. Uptake of soluble oligosaccharides derived from cellulose hydrolysis represents a potential point of control in the induced cascade. In this study, we identified a major facilitator superfamily sugar transporter Stp1 capable of transporting cellobiose by reconstructing a cellobiose assimilation system in Saccharomyces cerevisiae. The absence of Stp1 in T. reesei resulted in differential cellulolytic response to Avicel versus cellobiose. Transcriptional profiling revealed a different expression profile in the Δstp1 strain from that of wild-type strain in response to Avicel and demonstrated that Stp1 somehow repressed induction of the bulk of major cellulase and hemicellulose genes. Two other putative major facilitator superfamily sugar transporters were, however, up-regulated in the profiling. Deletion of one of them identified Crt1 that was required for growth and enzymatic activity on cellulose or lactose, but was not required for growth or hemicellulase activity on xylan. The essential role of Crt1 in cellulase induction did not seem to rely on its transporting activity because the overall uptake of cellobiose or sophorose by T. reesei was not compromised in the absence of Crt1. Phylogenetic analysis revealed that orthologs of Crt1 exist in the genomes of many filamentous ascomycete fungi capable of degrading cellulose. These data thus shed new light on the mechanism by which T. reesei senses and transmits the cellulose signal and offers potential strategies for strain improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M113.505826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829138PMC
November 2013

The Chinese Grain for Green Programme: assessing the carbon sequestered via land reform.

J Environ Manage 2013 Sep 25;126:142-6. Epub 2013 May 25.

Physical Resource Theory, Department of Energy and Environment, Chalmers University of Technology, 412 96 Göteborg, Sweden.

The Grain for Green Programme (GGP) was launched in China in 1999 to control erosion and increase vegetation cover. Budgeted at USD 40 billion, GGP has converted over 20 million hectares of cropland and barren land into primarily tree-based plantations. Although GGP includes energy forests, only a negligible part (0.6%) is planted as such, most of the land (78%) being converted for protection. Future use of these plantations is unclear and an energy substitution hypothesis is valid. We estimate the overall carbon sequestration via GGP using official statistics and three approaches, based on i) net primary production, ii) IPCC's greenhouse gas inventory guidelines, and iii) mean annual increment. We highlight uncertainties associated with GGP and the estimates. Results indicate that crop- and barren-land conversion sequestered 222-468 Mt of carbon over GGP's first ten years, the IPCC approach yielding the highest estimate and the other two approaches yielding similar but lower estimates (approximately 250 Mt of carbon). The carbon stock in these plantation systems yields a mean of 12.3 t of carbon per hectare. Assessment uncertainties concern the use of growth curves not designed for particular species and locations, actual plantation survival rates, and discrepancies in GGP figures (e.g., area, type, and survival rate) at different authority levels (from national to local). The carbon sequestered in above- and below-ground biomass from GGP represents 14% (based on the median of the three approaches) of China's yearly (2009) carbon dioxide emissions from fossil fuel use and cement production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jenvman.2013.02.045DOI Listing
September 2013

Differential involvement of β-glucosidases from Hypocrea jecorina in rapid induction of cellulase genes by cellulose and cellobiose.

Eukaryot Cell 2012 Nov 21;11(11):1371-81. Epub 2012 Sep 21.

State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Jinan, Shandong, People's Republic of China.

Appropriate perception of cellulose outside the cell by transforming it into an intracellular signal ensures the rapid production of cellulases by cellulolytic Hypocrea jecorina. The major extracellular β-glucosidase BglI (CEL3a) has been shown to contribute to the efficient induction of cellulase genes. Multiple β-glucosidases belonging to glycosyl hydrolase (GH) family 3 and 1, however, exist in H. jecorina. Here we demonstrated that CEL1b, like CEL1a, was an intracellular β-glucosidase displaying in vitro transglycosylation activity. We then found evidence that these two major intracellular β-glucosidases were involved in the rapid induction of cellulase genes by insoluble cellulose. Deletion of cel1a and cel1b significantly compromised the efficient gene expression of the major cellulase gene, cbh1. Simultaneous absence of BglI, CEL1a, and CEL1b caused the induction of the cellulase gene by cellulose to further deteriorate. The induction defect, however, was not observed with cellobiose. The absence of the three β-glucosidases, rather, facilitated the induced synthesis of cellulase on cellobiose. Furthermore, addition of cellobiose restored the productive induction on cellulose in the deletion strains. The results indicate that the three β-glucosidases may not participate in transforming cellobiose beyond hydrolysis to provoke cellulase formation in H. jecorina. They may otherwise contribute to the accumulation of cellobiose from cellulose as inducing signals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/EC.00170-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486029PMC
November 2012

[Transcriptional regulation of cellulases and hemicellulases gene in Hypocrea jecorina--a review].

Wei Sheng Wu Xue Bao 2010 Nov;50(11):1431-7

State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China.

Hypocrea jecorina (anamorph: Trichoderma reesei) is the main industrial fungi that can produce large amounts of extracellular cellulases and hemicellulases. It also represents a model system to study the mechanism of transcriptional regulation in eukaryotes. The expression of these hydrolases genes in Hypocrea jecorina can be triggered rapidly in the presence of inducers, but differences in the inducing mode of various soluble inducers have been reported. At present, three models have been offered to explain the question of "how an insoluble inducer such as cellulose would initiate the transcription of cellulases?" Moreover, interactions between the identified positive (Xyr1, Ace2, Hap2/3/5) and negative transcriptional regulators (Ace1, Cre1), as well as the interactions between these proteins and the promoters of cellelase and hemicellulase genes have also been primarily characterized. This review focuses on the key factors and the current understanding on the regulation of expression of cellulase and hemicellulase genes in Hypocrea jecorina.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2010

Impacts of urbanization on hydrology in the Yangtze River Delta, China.

Water Sci Technol 2010 ;62(6):1221-9

School of Geographic and Oceanographic Sciences, Nanjing University, Nanjing 210093, China.

The Yangtze River Delta is one of the most developed regions in China and the rapid development of urbanization have greatly influenced regional hydrology and water resources. Taking several typical urbanizing areas in the Yangtze River Delta as examples, this paper probes into the impacts of urbanization on hydrologic cycle and hydrological process with the support of RS, GIS and hydrological model. The research centers on the impacts of urbanization on precipitation, hydrological process, river networks, and water environment in some typical cities. The results show that: (1) Urban rain island effect is not evident when the process of urbanization is slow, while the differences of annual precipitation and flood season precipitation between urban and suburban areas increased to a certain extent in the booming stage of urbanization. (2) The annual runoff depth and the runoff coefficient increased with the development of urbanization, and the effect will be more notable when the urban areas expand to a certain size; (3) River network systems, especially low-grade rivers have been greatly destroyed in the process of urbanization, which increases the risk of flood and water degradation, so it is very important to protect natural river systems. Based on the results, some proposals of sustainable utilization and protection of water resources is also addressed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2166/wst.2010.391DOI Listing
December 2010
-->