Hasil untuk "physics.atm-clus"

Celeste M. Karch, A. Goate

D. Harold, R. Abraham, P. Hollingworth et al.

Nat. Genet. 41, 1088–1093 (2009); published online 6 September 2009; corrected after print 9 May 2013 In the version of this article initially published, Reinhard Heun was not included in the author list. This has been corrected in the HTML and PDF versions of the article.

Felix L. Yeh, Yuanyuan Wang, I. Tom et al.

S. Morabito, Emily Miyoshi, Neethu Michael et al.

F. Waldhauser, W. Ellsworth

Yaping Cai, K. Guan, Jian Peng et al.

Abstract Accurate and timely spatial classification of crop types based on remote sensing data is important for both scientific and practical purposes. Spatially explicit crop-type information can be used to estimate crop areas for a variety of monitoring and decision-making applications such as crop insurance, land rental, supply-chain logistics, and financial market forecasting. However, there is no publically available spatially explicit in-season crop-type classification information for the U.S. Corn Belt (a landscape predominated by corn and soybean). Instead, researchers and decision-makers have to wait until four to six months after harvest to have such information from the previous year. The state-of-the-art research on crop-type classification has been shifted from relying on only spectral features of single static images to combining together spectral and time-series information. While Landsat data have a desirable spatial resolution for field-level crop-type classification, the ability to extract temporal phenology information based on Landsat data remains a challenge due to low temporal revisiting frequency and inevitable cloud contamination. To address this challenge and generate accurate, cost-effective, and in-season crop-type classification, this research uses the USDA's Common Land Units (CLUs) to aggregate spectral information for each field based on a time-series Landsat image data stack to largely overcome the cloud contamination issue while exploiting a machine learning model based on Deep Neural Network (DNN) and high-performance computing for intelligent and scalable computation of classification processes. Experiments were designed to evaluate what information is most useful for training the machine learning model for crop-type classification, and how various spatial and temporal factors affect the crop-type classification performance in order to derive timely crop type information. All experiments were conducted over Champaign County located in central Illinois, and a total of 1322 Landsat multi-temporal scenes including all the six optical spectral bands spanning from 2000 to 2015 were used. Computational experiments show the inclusion of temporal phenology information and evenly distributed spatial training samples in the study domain improves classification performance. The shortwave infrared bands show notably better performance than the widely used visible and near-infrared bands for classifying corn and soybean. In comparison with USDA's Crop Data Layer (CDL), this study found a relatively high Overall Accuracy (i.e. the number of the corrected classified fields divided by the number of the total fields) of 96% for classifying corn and soybean across all CLU fields in the Champaign County from 2000 to 2015. Furthermore, our approach achieved 95% Overall Accuracy by late July of the concurrent year for classifying corn and soybean. The findings suggest the methodology presented in this paper is promising for accurate, cost-effective, and in-season classification of field-level crop types, which may be scaled up to large geographic extents such as the U.S. Corn Belt.

Zurine De Miguel, Nathalie Khoury, Michael J. Betley et al.

H. Hampel, F. Caraci, A. Cuello et al.

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

Evangeline M. Foster, Adrià Dangla-Valls, S. Lovestone et al.

Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer’s disease (AD). With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Although clusterin is normally a secreted protein, it has also been found intracellularly under certain stress conditions. Multiple hypotheses have been proposed regarding the origin of intracellular clusterin, including specific biogenic processes leading to alternative transcripts and protein isoforms, but these lines of research are incomplete and contradictory. Current consensus is that intracellular clusterin is most likely to have exited the secretory pathway at some point or to have re-entered the cell after secretion. Clusterin’s relationship with amyloid beta (Aβ) has been of great interest to the AD field, including clusterin’s apparent role in altering Aβ aggregation and/or clearance. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. CLU is also the third most significant genetic risk factor for late onset AD and several variants have been identified in CLU. Although the exact contribution of these variants to altered AD risk is unclear, some have been linked to altered CLU expression at both mRNA and protein levels, altered cognitive and memory function, and altered brain structure. The apparent complexity of clusterin’s biogenesis, the lack of clarity over the origin of the intracellular clusterin species, and the number of pathophysiological functions attributed to clusterin have all contributed to the challenge of understanding the role of clusterin in AD pathophysiology. Here, we highlight clusterin’s relevance to AD by discussing the evidence linking clusterin to AD, as well as drawing parallels on how the role of clusterin in other diseases and pathways may help us understand its biological function(s) in association with AD.

X. Qin, F. Cardoso Rodriguez, J. Sufi et al.

Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.

Christodoulos Keskinis, Eleni Moysidou, S. Stai et al.

Background & Objectives: Targeted-release budesonide (TRB) is the first approved agent aimed at targeting the early pathogenetic cascade in IgA nephropathy (IgAN). Materials and Methods: This prospective study included Caucasian IgAN patients diagnosed within the last 5 years, who had started a 10-month TRB treatment and were followed in the outpatient clinic. All participants had been on the maximal supportive care dose for at least the previous 6 months. Kidney function and proteinuria levels were recorded at the start of TRB treatment (T0) and at 3, 6, and 10 months (T3, T6, and T10, respectively), while urinary monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and clusterin (CLU) levels were measured at T0 and T3. Results: In the cohort of all patients (mean age 53.24 ± 12.76 years, estimated glomerular filtration rate (eGFR 52.84 ± 25.93 mL/min/1.73 m2, proteinuria 2.84 ± 1.26 g/24 h), significant correlations were observed at T0 between MMP-9 and MCP-1 (r = 0.74, p = 0.004), MMP-9 and uCLU (r = 0.77, p = 0.002), and MCP-1 and uCLU (r = 0.65, p = 0.01). At T3, a significant correlation between MMP-9 and urinary CLU (uCLU) persisted (r = 0.71, p = 0.03). Higher MCP-1 (r = −0.560, p = 0.046) and MMP-9 (r = −0.330, p = 0.012) levels at T0 were associated with reduced proteinuria. Conversely, increased clusterin at T3 (r = 0.599, p = 0.031) was associated with worsening proteinuria. Conclusions: The treatment response to TRB was heterogeneous, with recent diagnosis (RD) patients showing improved kidney function and proteinuria, while older diagnosis (OD) patients exhibited worsening biomarkers and declining kidney function. Therefore, early interventions are crucial in IgAN patients. Finally, the biomarkers studied can be used prognostically to monitor disease progression.

Roger B. Dodd, Masahiro Enomoto, Ye Zhou et al.

Lingling Xuan, Lulu Ren, Xiaoxu Kang et al.

Background It has been demonstrated that clusterin (CLU) is a protective protein involved in a variety of diseases and disorders. However, the role of CLU in diabetic atherosclerosis is not elucidative. The objective of this study is to investigate the role of CLU in diabetic atherosclerosis and the molecular mechanisms. Method In in vivo experiments, Clu knockout and overexpressed murine models were used to investigate the role of Clu in diabetic atherosclerosis. Atherosclerotic plaque formation was determined by hematoxylin-eosin (H&E) staining and Oil Red O staining. F4/80 and CD68 levels were determined by immunohistochemical staining. Transmission electron microscopy was used to observe changes in cell pyroptosis morphology. NLRP3 and IL-1β levels were determined by Western blot and immunofluorescence staining. In in vitro experiments, TNF-α, IL-6, and IL-1β levels in THP-1 derived macrophages were determined by real-time qPCR and ELISA. Results We found that Clu-overexpression reduced while Clu knockout promoted atherosclerotic plaque formation, macrophage infiltration and inflammatory factor expression in mouse aortic plaques. Consistently, CLU overexpression inhibits the production of TNF-α, IL-6, and IL-1β in THP-1 derived macrophages. Moreover, Clu inhibited the release of inflammatory factors and macrophage pyroptosis in diabetic atherosclerosis murine models. Conclusion Our study revealed that CLU could ameliorate diabetic atherosclerosis via suppressing inflammatory factors release and pyroptosis of macrophage. CLU may be a promising therapeutic target for diabetic atherosclerosis.

Qingqing Xu, Xin Liu, Yibo Zhang et al.

Background Clusterin (CLU) is a multifunctional protein involved in various pathophysiological processes and diseases. Glioma, the most common aggressive primary brain tumor, is characterized by high morbidity, mortality, and extremely poor prognosis. Our research has found that CLU is upregulated in glioma and contributes to increased tumor malignancy. However, the specific regulatory mechanisms of CLU in the context of glioma are not fully understood. Methods We used glioma public databases, immunohistochemistry (IHC), and immunoblotting techniques to evaluate the expression levels and prognostic value of CLU in glioma. Cell migration and proliferation assays, including the scratch wound healing and MTT assays, were conducted to assess the functional impact of CLU. In addition, immunoblotting and flow cytometry were used to analyze apoptosis-related proteins and CLU-BCL2L1 interactions. An in situ tumor model using nude mice was established to investigate the effects of CLU in vivo. Results Bioinformatics analyses showed that CLU was highly expressed in glioma, associated with poor clinical outcomes. Functional assays revealed that CLU and BCL2L1 promoted glioma cell migration and proliferation. Silencing CLU reduced the migration and proliferation of glioma cells, while overexpression of CLU enhanced these aggressive phenotypes. Mechanistic studies showed CLU regulated BCL2L1 expression, inhibiting apoptosis pathways and promoting malignancy. In vivo experiments confirmed the inhibitory effects of CLU downregulation on glioma growth. Conclusion This study clarifies the role of the CLU-BCL2L1 axis in promoting glioma migration and proliferation both in vitro and in vivo. It suggests that targeting this pathway may be a promising therapeutic strategy for glioma.

Jing He, Chunchun Ao, Mao Li et al.

Emerging evidence has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cells (UC-MSCs) in chemotherapy-induced premature ovarian failure (POF). This study was designed to investigate the appropriate timing and molecular mechanism of UC-MSCs treatment for chemotherapy-induced POF. Ovarian structure and function of mice were assessed every 3 days after injections with cyclophosphamide (CTX) and busulfan (BUS). UC-MSCs and UC-MSCs-derived extracellular vesicles (EVs) were infused into mice via the tail vein, respectively. Ovarian function was analyzed by follicle counts, the serum levels of hormones and ovarian morphology. The apoptosis and proliferation of ovarian granulosa cells were analyzed in vitro and in vivo. Label-free quantitative proteomics was used to detect the differentially expressed proteins in UC-MSC-derived EVs. After CTX/BUS injection, we observed that the ovarian function of POF mice was significantly deteriorated on day 9 after CTX/BUS infusion. TUNEL assay indicated that the number of apoptotic cells in the ovaries of POF mice was significantly higher than that in normal mice on day 3 after CTX/BUS injection. Transplantation of UC-MSCs on day 6 after CTX/BUS injection significantly improved ovarian function, enhanced proliferation and inhibited apoptosis of ovarian granulosa cells, whereas the therapeutic effect of UC-MSCs transplantation decreased on day 9, or day 12 after CTX/BUS injection. Moreover, EVs derived from UC-MSCs exerted similar therapeutic effects on POF. UC-MSCs-derived EVs could activate the PI3K/AKT signaling pathway and reduce ovarian granulosa cell apoptosis. Quantitative proteomics analysis revealed that clusterin (CLU) was highly expressed in the EVs of UC-MSCs. The supplementation of CLU proteins prevented ovarian granulosa cells from chemotherapy-induced apoptosis. Further mechanistic analysis showed that CLU-knockdown blocked the PI3K/AKT signaling and reversed the protective effects of UC-MSCs-derived EVs. Administration of UC-MSCs and UC-MSCs-derived EVs on day 6 of CTX/BUS injection could effectively improve the ovarian function of POF mice. UC-MSCs-derived EVs carrying CLU promoted proliferation and inhibited apoptosis of ovarian granulosa cells through activating the PI3K/AKT pathway. This study identifies a previously unrecognized molecular mechanism of UC-MSCs-mediated protective effects on POF, which pave the way for the use of cell-free therapeutic approach for POF.

P. Praharaj, S. Patra, Amruta Singh et al.

ABSTRACT Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.

Eunbi Yu, S. Oh, See-Hyoung Park et al.

Blue light, a high-energy radiation in the visible light spectrum, was recently reported to induce skin pigmentation. In this study, we investigated the involvement of TRPV1-mediated signaling along with OPN3 in blue light-induced melanogenesis, as well as its signaling pathway. Operating downstream target of OPN3 in blue light-induced melanogenesis, blue light activated TRPV1 and upregulated its expression, resulting in calcium influx. [Ca2+] induced activation of CaMKII and MAPK. It also downregulated clusterin expression, leading to the nuclear translocation of PAX3, ultimately affecting melanin synthesis. In addition, blue light interfered with autophagy-mediated regulation of melanosomes by decreasing not only the interaction between CLU and LC3B but the expression of ATF family. These findings demonstrate that the pigmenting effects of blue light are mediated by CaMKII- and MAPK-mediated signaling, as well as CLU-dependent inhibition of autophagy through OPN3-TRPV1-calcium influx, suggesting a new signaling pathway by which blue light regulates melanocyte biology. Furthermore, these results suggest that TRPV1 and CLU could be potential therapeutic targets for blue light-induced pigmentation due to prolonged exposure to blue light.

Sara Hlavca, Wing Hei Chan, Rebekah M. Engel et al.

Intra-tumoural heterogeneity and cancer cell plasticity in colorectal cancer (CRC) have been key challenges to effective treatment for patients. It has been suggested that a subpopulation of LGR5-expressing cancer stem cells (CSCs) is responsible for driving tumour relapse and therapy resistance in CRC. However, studies have revealed that the LGR5^+ve CSC population is highly sensitive to chemotherapy. It has been hypothesised that another subset of tumour cells can phenotypically revert to a stem-like state in response to chemotherapy treatment which replenishes the LGR5^+ve CSC population and maintains tumour growth. Recently, a unique stem cell population marked by enriched clusterin (CLU) expression and termed the revival stem cell (RevSC) was identified in the regenerating murine intestine. This CLU-expressing cell population is quiescent during homeostasis but has the ability to survive and regenerate other stem cells upon injury. More recently, the CLU^+ve signature has been implicated in several adverse outcomes in CRC, including chemotherapy resistance and poor patient survival; however, the mechanism behind this remains undetermined. In this review, we discuss recent insights on CLU in CRC and its roles in enhancing the plasticity of cells and further consider the implications of CLU as a prospective target for therapeutic intervention.

Ming Ma, Zhiyi Sun, Ziwei Deng et al.

Chen Chen, Y. Shu, Chengkai Yan et al.

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models. Glia abnormalities drive the progression of demyelinating diseases. Here, the authors show that reactivated astrocytes secrete clusterin to impede remyelination by blocking astrocytic removal of myelin debris and oligodendrocyte precursor cell differentiation in mouse models of demyelination.