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"Zhong, M"
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Dynamic light absorption of biomass-burning organic carbon photochemically aged under natural sunlight
Wood-burning aerosol produced under smoldering conditions was photochemically aged with different relative humidity (RH) and NOx conditions using a 104 m3 dual outdoor chamber under natural sunlight. Light absorption of organic carbon (OC) was measured over the course of photooxidation using a UV–visible spectrometer connected to an integrating sphere. At high RH, the color decayed rapidly. NOx slightly prolonged the color of wood smoke, suggesting that NOx promotes the formation of chromophores via secondary processes. Overall, the mass absorption cross section (integrated between 280 and 600 nm) of OC increased by 11–54% (except high RH) in the morning and then gradually decreased by 19–68% in the afternoon. This dynamic change in light absorption of wood-burning OC can be explained by two mechanisms: chromophore formation and sunlight bleaching. To investigate the effect of chemical transformation on light absorption, wood smoke particles were characterized using various spectrometers. The intensity of fluorescence, which is mainly related to polycyclic aromatic hydrocarbons (PAHs), rapidly decreased with time, indicating the potential bleaching of PAHs. A decline of levoglucosan concentrations evinced the change of primary organic aerosol with time. The aerosol water content measured by Fourier transform infrared spectroscopy showed that wood-burning aerosol became less hygroscopic as photooxidation proceeded. A similar trend in light absorption changes has been observed in ambient smoke aerosol originating from the 2012 County Line wildfire in Florida. We conclude that the biomass-burning OC becomes less light absorbing after 8–9 h sunlight exposure compared to fresh wood-burning OC.
Journal Article
CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED
50
<200 n
M
), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
Journal Article
Topologically convergent and divergent functional connectivity patterns in unmedicated unipolar depression and bipolar disorder
Bipolar disorder (BD), particularly BD II, is frequently misdiagnosed as unipolar depression (UD), leading to inappropriate treatment and poor clinical outcomes. Although depressive symptoms may be expressed similarly in UD and BD, the similarities and differences in the architecture of brain functional networks between the two disorders are still unknown. In this study, we hypothesized that UD and BD II patients would show convergent and divergent patterns of disrupted topological organization of the functional connectome, especially in the default mode network (DMN) and the limbic network. Brain resting-state functional magnetic resonance imaging (fMRI) data were acquired from 32 UD-unmedicated patients, 31 unmedicated BD II patients (current episode depressed) and 43 healthy subjects. Using graph theory, we systematically studied the topological organization of their whole-brain functional networks at the following three levels: whole brain, modularity and node. First, both the UD and BD II patients showed increased characteristic path length and decreased global efficiency compared with the controls. Second, both the UD and BD II patients showed disrupted intramodular connectivity within the DMN and limbic system network. Third, decreased nodal characteristics (nodal strength and nodal efficiency) were found predominantly in brain regions in the DMN, limbic network and cerebellum of both the UD and BD II patients, whereas differences between the UD and BD II patients in the nodal characteristics were also observed in the precuneus and temporal pole. Convergent deficits in the topological organization of the whole brain, DMN and limbic networks may reflect overlapping pathophysiological processes in unipolar and bipolar depression. Our discovery of divergent regional connectivity that supports emotion processing could help to identify biomarkers that will aid in differentiating these disorders.
Journal Article
Gut microbiota, a potential cause of higher insulin sensitivity in children with Prader–Willi syndrome
Purpose
Obesity is the main driving factor for comorbidities in Prader–Willi syndrome (PWS) patients due to overeating behaviors. The gut microbiota has been implicated in the etiology of obesity and associated comorbidities. The purpose of the present study was to characterize the fecal microbiota in Chinese patients with PWS and compare it to that of patients with obesity as well as healthy controls.
Methods
We conducted a cross-sectional study with 35 PWS patients (PWS), 35 patients with obesity (OB), and 35 healthy controls (HC). Metagenomic sequencing was performed in stool samples.
Results
The composition of the fecal microbiota in PWS patients differed from that of participants in the OB and HC groups. It was characterized by increased
Akkermansia Eubacterium, Eubacterium rectale
, and
Roseburia intestinalis
and decreased
Parabacteroides
and
Phascolarctobacterium
. Additionally, the homeostatic model assessment of insulin resistance (HOMA-IR) was lower in PWS patients than in patients with obesity. Spearman rank correlation analysis showed that
Achromobacter
,
Acidiphilium
,
Xylophilus
, and
Frisingicoccus
were significantly negatively correlated with HOMA-IR.
Conclusion
The composition of the gut microbiota in Chinese PWS patients differed from that in patients with obesity, which might contribute to higher insulin sensitivity in PWS patients.
Journal Article
Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder
A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of
HOX
genes may lead us to investigate the role of
HOX
genes involved in the development of ASD. Discovery of the lncRNAs of
SHANK2-AS
and
BDNF-AS
, the natural antisense of genes
SHANK2
and
BDNF
, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD.
Journal Article
Numerical simulation of landslide dam breaching due to overtopping
The breach of landslide dam often causes significant disaster in the inundated area; the prediction of breach hydrograph is in high demand for the dam breach risk evaluation. In this study, according to the model tests and Tangjiashan landslide dam breach case, the surface erosion accompanied by intermittent mass failure is known as the key breaching mechanism for landslide dam due to overtopping failure. The downstream slope angle would gradually decrease during the dam-breaching process, whereas a planar wedge failure occurs when the breach slopes at the dam crest and downstream breach channel fail. Based on the breach mechanism, a numerical model for landslide dam breach due to overtopping is developed to simulate the coupling process of water and soil. The model focuses on the breach morphology evolution during the breaching for the sake of the improvement of breach hydrograph prediction. Furthermore, the model can handle one- and two-sided breach, as well as incomplete and base erosion at the vertical direction. The case study of Tangjiashan landslide dam-breaching feedback analysis testifies the rationality of the present model with the relative errors less than 10% for peak discharge, final breach widths, and time to peak. The sensitivity analysis indicates that the final breach depth and soil erodibility affect the breach flow prediction of the landslide dam significantly, whereas the one- or two-sided breach mode is less sensitive.
Journal Article
Laser surface cladding: The state of the art and challenges
Abstract
Laser cladding is a process whereby a new layer of material is deposited on a substrate by laser fusion of blown powders or pre-placed powder coatings. Multiple layers can be deposited to form shapes with complex geometry. This manufacturing process has been used for material surface property modification and for the repair and manufacture of three-dimensional components. Laser cladding has attracted extensive research over the past 30 years. Over 2000 research papers have been published in journals and international conferences. Research in laser cladding covers many scientific issues, including processing techniques, physical and chemical properties of deposited materials and clad—substrate interfaces, microstructure and phases, rapid solidification phenomena, modelling and simulation, and systems engineering and applications. This article, focusing on the rapid heating/cooling processes and material response, summarizes the state of the art on two fundamental scientific aspects: rapid solidification and the material characteristics. The article includes a review of the microstructural refinement, extended solid solution, metastable phases, amorphous structure, and directional solidification. In addition, the article discusses the progress and state of the art in laser cladding of commercial alloy powders, carbides and intermetallics, in-situ synthesized particulate reinforced metal matrix composite coatings, compositional gradient materials, and alloy development. Laser cladding is capable of producing materials with designed macro/microstructures and properties.
Journal Article
Regulation of LL-37 in Bone and Periodontium Regeneration
The goal of regenerative therapy is to restore the structure and function of the lost tissues in the fields of medicine and dentistry. However, there are some challenges in regeneration therapy such as the delivery of oxygen and nutrition, and the risk of infection in conditions such as periodontitis, osteomyelitis, etc. Leucine leucine-37 (LL-37) is a 37-residue, amphipathic, and helical peptide found only in humans and is expressed throughout the body. It has been shown to induce neovascularization and vascular endothelial growth factor (VEGF) expression. LL-37 also stimulates the migration and differentiation of mesenchymal stem cells (MSCs). Recent studies have shown that LL-37 plays an important role in the innate defense system through the elimination of pathogenic microbes and the modulation of the host immune response. LL-37 also manifests other functions such as promoting wound healing, angiogenesis, cell differentiation, and modulating apoptosis. This review summarizes the current studies on the structure, expression, and function of LL-37 and highlights the contributions of LL-37 to oral cavity, periodontium, and bone regeneration.
Journal Article
SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide
The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, we here define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). Without Fc-cross-linking agents or effector cells, SAR specifically induces homotypic aggregation (HA)-associated cell death in MM cells dependent on the level of cell surface CD38 expression, actin cytoskeleton and membrane lipid raft. SAR and its F(ab)'2 fragments trigger caspase 3/7-dependent apoptosis in MM cells highly expressing CD38, even with p53 mutation. Importantly, SAR specifically induces lysosome-dependent cell death (LCD) by enlarging lysosomes and increasing lysosomal membrane permeabilization associated with leakage of cathepsin B and LAMP-1, regardless of the presence of interleukin-6 or bone marrow stromal cells. Conversely, the lysosomal vacuolar H+-ATPase inhibitor blocks SAR-induced LCD. SAR further upregulates reactive oxygen species. Pom enhances SAR-induced direct and indirect killing even in MM cells resistant to Pom/Len. Taken together, SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. Our data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.
Journal Article