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1.  Combining multiple features for error detection and its application in brain–computer interface 
Background
Brain–computer interface (BCI) is an assistive technology that conveys users’ intentions by decoding various brain activities and translating them into control commands, without the need of verbal instructions and/or physical interactions. However, errors existing in BCI systems affect their performance greatly, which in turn confines the development and application of BCI technology. It has been demonstrated viable to extract error potential from electroencephalography recordings.
Methods
This study proposed a new approach of fusing multiple-channel features from temporal, spectral, and spatial domains through two times of dimensionality reduction based on neural network. 26 participants (13 males, mean age = 28.8 ± 5.4, range 20–37) took part in the study, who engaged in a P300 speller task spelling cued words from a 36-character matrix. In order to evaluate the generalization ability across subjects, the data from 16 participants were used for training and the rest for testing.
Results
The total classification accuracy with combination of features is 76.7 %. The receiver operating characteristic (ROC) curve and area under ROC curve (AUC) further indicate the superior performance of the combination of features over any single features in error detection. The average AUC reaches 0.7818 with combined features, while 0.7270, 0.6376, 0.7330 with single temporal, spectral, and spatial features respectively.
Conclusions
The proposed method combining multiple-channel features from temporal, spectral, and spatial domain has better classification performance than any individual feature alone. It has good generalization ability across subject and provides a way of improving error detection, which could serve as promising feedbacks to promote the performance of BCI systems.
doi:10.1186/s12938-016-0134-9
PMCID: PMC4743193  PMID: 26846163
BCI; Error detection; Multi-channel; Combination of features
2.  Effects of CCN3 on rat cartilage endplate chondrocytes cultured under serum deprivation in vitro 
Molecular Medicine Reports  2016;13(3):2017-2022.
The presence of apoptotic cells and loss of extracellular matrix (ECM) are common characteristics of degenerated cartilage endplates (CEPs). In addition, therapeutic efficacy is hampered by an incomplete understanding regarding the mechanisms underlying CEP homeostasis and degeneration. The CCN proteins have recently emerged as important regulators of cell-ECM interactions, and have been identified as key mediators of nucleus pulposus ECM composition and tissue homeostasis. However, whether CCN3 is associated with CEP homeostasis has yet to be elucidated. The present study aimed to investigate the effects of CCN3 on the apoptosis and ECM synthesis of CEP cells cultured under serum deprivation. Rat CEP cells were confirmed to be of the chondrocytic phenotype by toluidine blue staining. The mRNA expression levels of CCN3 were markedly increased, and a dose-dependent increase of apoptotic rate was detected under serum deprivation conditions following treatment with recombinant CCN3, whereas CCN3 did not exert a proapoptotic effect on cells cultured under normal conditions. Furthermore, CCN3-treated cells exhibited a decrease in the expression levels of aggrecan and collagen II in both groups. These results suggested that CCN3 may act as a regulator, rather than an initiator, of serum deprivation-induced cellular apoptosis, and that CCN3 has a catabolic effect on the mediation of ECM synthesis under both normal and serum deprivation conditions. Therefore, CCN3 may represent a novel therapeutic target for the prevention of CEP degeneration.
doi:10.3892/mmr.2016.4803
PMCID: PMC4768995  PMID: 26795879
intervertebral disc degeneration; CCN3; apoptosis; serum deprivation; cartilage endplate; extracellular matrix
3.  Dysregulation of non-coding RNAs in gastric cancer 
World Journal of Gastroenterology : WJG  2015;21(39):10956-10981.
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
doi:10.3748/wjg.v21.i39.10956
PMCID: PMC4607897  PMID: 26494954
Gastric cancer; Dysregulation; Non-coding RNA; Tumorigenesis; Biomarker
4.  Neuronal and Endothelial Nitric Oxide Synthases in the Paraventricular Nucleus Modulate Sympathetic Overdrive in Insulin-Resistant Rats 
PLoS ONE  2015;10(10):e0140762.
A central mechanism participates in sympathetic overdrive during insulin resistance (IR). Nitric oxide synthase (NOS) and nitric oxide (NO) modulate sympathetic nerve activity (SNA) in the paraventricular nucleus (PVN), which influences the autonomic regulation of cardiovascular responses. The aim of this study was to explore whether the NO system in the PVN is involved in the modulation of SNA in fructose-induced IR rats. Control rats received ordinary drinking water, whereas IR rats received 12.5% fructose-containing drinking water for 12 wks to induce IR. Basal SNA was assessed based on the changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to chemicals administered to the PVN. We found an increased plasma norepinephrine level but significantly reduced NO content and neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression levels in the PVN of IR rats compared to Control rats. No difference in inducible NOS (iNOS) protein expression was observed between the two groups. In anesthetized rats, the microinjection of sodium nitroprusside (SNP), an NO donor, or Nω-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NOS, into the PVN significantly decreased and increased basal SNA, respectively, in both normal and IR rats, but these responses to SNP and L-NAME in IR rats were smaller than those in normal rats. The administration of selective inhibitors of nNOS or eNOS, but not iNOS, to the PVN significantly increased basal SNA in both groups, but these responses were also smaller in IR rats. Moreover, IR rats exhibited reduced nNOS and eNOS activity in the PVN. In conclusion, these data indicate that the decreased protein expression and activity levels of nNOS and eNOS in the PVN lead to a reduction in the NO content in the PVN, thereby contributing to a subsequent enhancement in sympathoexcitation during IR.
doi:10.1371/journal.pone.0140762
PMCID: PMC4613827  PMID: 26485682
5.  Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer 
Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in triple-negative breast cancer (TNBC) have not been reported. In this study, we found that BRMS1 was down-regulation in breast cancer cell lines and primary TNBC, while decreased expression of BRMS1 mRNA was significantly associated with lymph node metastasis. And this down-regulation was found to be in accordance with aberrant methylation of the gene. Hypermethylation of the gene was observed in 53.4% (62/116) of the TNBC primary breast carcinomas, while it was found in only 24.1% (28/116) of the corresponding nonmalignant tissues. In addition, BRMS1 expression was restored in MDA-MB-231 after treatment with the demethylating agent, 5-aza-2-deoxycytidine (5-Aza-dC), and demethylation of the highly metastatic cells MDA-MB-231 induced invasion suppression of the cells. Furthermore, the suppression of BRMS1 by siRNA transfection enhanced cancer cells invasion. Collectively, our results suggest that the aberrant methylation of BRMS1 frequently occurs in the down-regulation of BRMS1 in TNBC and that it may play a role in the metastasis of breast cancer.
PMCID: PMC4637641  PMID: 26617826
Triple-negative breast cancer; breast cancer metastasis suppressor 1; methylation; metastasis
6.  GABA in Paraventricular Nucleus Regulates Adipose Afferent Reflex in Rats 
PLoS ONE  2015;10(8):e0136983.
Background
Chemical stimulation of white adipose tissue (WAT) induces adipose afferent reflex (AAR), and thereby causes a general sympathetic activation. Paraventricular nucleus (PVN) is important in control of sympathetic outflow. This study was designed to investigate the role of γ-aminobutyric acid (GABA) in PVN in regulating the AAR.
Methodology/Principal Findings
Experiments were carried out in anesthetized rats. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. AAR was evaluated by the RSNA and MAP responses to electrical stimulation of the right epididymal WAT (eWAT) afferent nerve. Electrical stimulation of eWAT afferent nerve increase RSNA. Bilateral microinjection of the GABAA receptor agonist isoguvacine or the GABAB receptor agonist baclofen attenuated the AAR. The effect of isoguvacine on the AAR was greater than that of baclofen. The GABAA receptor antagonist gabazine enhanced the AAR, while the GABAB receptor antagonist CGP-35348 had no significant effect on the AAR. Bilateral PVN microinjection of vigabatrin, a selective GABA-transaminase inhibitor, to increase endogenous GABA levels in the PVN abolished the AAR. The inhibitory effect of vigabatrin on the AAR was attenuated by the pretreatment with gabazine or CGP-35348. Pretreatment with combined gabazine and CGP-35348 abolished the effects of vigabatrin.
Conclusions
Activation of GABAA or GABAB receptors in the PVN inhibits the AAR. Blockade of GABAA receptors in the PVN enhances the AAR. Endogenous GABA in the PVN plays an important role in regulating the AAR.
doi:10.1371/journal.pone.0136983
PMCID: PMC4552845  PMID: 26317425
7.  Clopidogrel and Aspirin versus Aspirin Alone for Stroke Prevention: A Meta-Analysis 
PLoS ONE  2015;10(8):e0135372.
Background and Purpose
Antiplatelet therapy is widely used for the primary or secondary prevention of stroke. Drugs like clopidogrel have emerged as alternatives for traditional antiplatelet therapy, and dual therapy with clopidogrel and aspirin is of particular interest. We conducted this meta-analysis to systematically review studies about dual therapy comparing monotherapy with aspirin alone.
Methods
Randomized controlled trials were searched in PubMed (1966-May, 2015), EMBASE (1947-May, 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (1948-May, 2015), WHO International Clinical Trial (ICTRP) (2004-May, 2015), China Biology Medicine disc (CBM disc) (1978-May, 2015) and were included into the final analysis according to the definite inclusion criteria mentioned in the study selection section. Risk ratio (RR) was pooled with 95% confidence interval (CI) for dichotomous data. The heterogeneity was considered significant if the χ2 test was significant (P value < 0.10) or the I2 > 50.00%. Subgroup analyses were carried out on the long and short time periods, the race and region.
Results
We included 5 studies involving 24,084 patients. A pooled analysis showed that dual therapy with clopidogrel and aspirin had a lower stroke incidence than monotherapy in both the short term and long term (RR = 0.69, 95% CI: 0.59–0.82, P <0.05; RR = 0.84, 95% CI: 0.72–0.98, P = 0.03, respectively). With regard to safety, dual therapy had a higher risk of bleeding than monotherapy for both periods (RR = 1.51, 95% CI: 1.03–2.23, P = 0.04; RR = 1.54, 95% CI: 1.32–1.79, P<0.05, respectively).
Conclusions
Dual therapy with clopidogrel and aspirin could be a preferable choice to prevent stroke in patients who have had a previous stroke or transient ischemic attack, as well as those who are at high risk for stroke. And the effect of dual therapy seems to be more obvious for short-term. However, it is associated with a higher risk of bleeding.
doi:10.1371/journal.pone.0135372
PMCID: PMC4536208  PMID: 26270530
8.  CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal1 
Central memory (CM) CD8+ T cells “remember” prior encounters because they maintain themselves through cell division in the absence of ongoing challenge (homeostatic self-renewal) as well as reproduce the central memory fate while manufacturing effector cells during secondary antigen encounters (rechallenge self-renewal). We tested the consequence of conditional deletion of the bone marrow (BM) homing receptor CXCR4 on antiviral T cell responses. CXCR4-deficient CD8+ T cells have impaired memory cell maintenance due to defective homeostatic proliferation. Upon rechallenge, however, CXCR4-deficient T cells can re-expand and renew the central memory pool while producing secondary effector cells. The critical BM-derived signals essential for CD8+ T cell homeostatic self-renewal appear to be dispensable to yield self-renewing, functionally asymmetric cell fates during rechallenge.
doi:10.4049/jimmunol.1400488
PMCID: PMC4108510  PMID: 24973450
9.  Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis[S] 
Journal of Lipid Research  2015;56(8):1449-1460.
Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis. Bone marrow transplantation studies in ApoE- and LDLR-deficient mice revealed that hematopoietic scavenger receptor class B type I (SR-BI) deficiency results in severely defective efferocytosis in mouse atherosclerotic lesions, resulting in a 17-fold higher ratio of free to macrophage-associated dead cells in lesions containing SR-BI−/− cells, 5-fold more necrosis, 65.2% less lesional collagen content, nearly 7-fold higher dead cell accumulation, and 2-fold larger lesion area. Hematopoietic SR-BI deletion elicited a maladaptive inflammatory response [higher interleukin (IL)-1β, IL-6, and TNF-α lower IL-10 and transforming growth factor β]. Efferocytosis of apoptotic thymocytes was reduced by 64% in SR-BI−/− versus WT macrophages, both in vitro and in vivo. In response to apoptotic cells, macrophage SR-BI bound with phosphatidylserine and induced Src phosphorylation and cell membrane recruitment, which led to downstream activation of phosphoinositide 3-kinase (PI3K) and Ras-related C3 botulinum toxin substrate 1 (Rac1) for engulfment and clearance of apoptotic cells, as inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis in WT cells. Pharmacological inhibition of Rac1 reduced macrophage efferocytosis in a SR-BI-dependent fashion, and activation of Rac1 corrected the defective efferocytosis in SR-BI−/− macrophages. Thus, deficiency of macrophage SR-BI promotes defective efferocytosis signaling via the Src/PI3K/Rac1 pathway, resulting in increased plaque size, necrosis, and inflammation.
doi:10.1194/jlr.M056689
PMCID: PMC4513986  PMID: 26059978
atherosclerosis; apoptosis; inflammation; scavenger receptor class B type I; Src; phosphoinositide 3-kinase; Ras-related C3 botulinum toxin substrate 1
10.  A non-tight junction function of claudin-7—Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment 
Molecular Cancer  2015;14:120.
Background
Claudins are a family of tight junction (TJ) membrane proteins involved in a broad spectrum of human diseases including cancer. Claudin-7 is a unique TJ membrane protein in that it has a strong basolateral membrane distribution in epithelial cells and in tissues. Therefore, this study aims to investigate the functional significance of this non-TJ localization of claudin-7 in human lung cancer cells.
Methods
Claudin-7 expression was suppressed or deleted by lentivirus shRNA or by targeted-gene deletion. Cell cycle analysis and antibody blocking methods were employed to assay cell proliferation and cell attachment, respectively. Electron microscopy and transepthelial electrical resistance measurement were performed to examine the TJ ultrastructure and barrier function. Co-immunolocalization and co-immunoprecipitation was used to study claudin-7 interaction with integrin β1. Tumor growth in vivo were analyzed using athymic nude mice.
Results
Claudin-7 co-localizes and forms a stable complex with integrin β1. Both suppressing claudin-7 expression by lentivirus shRNA in human lung cancer cells (KD cells) and deletion of claudin-7 in mouse lungs lead to the reduction in integrin β1 and phospho-FAK levels. Suppressing claudin-7 expression increases cell growth and cell cycle progression. More significantly, claudin-7 KD cells have severe defects in cell-matrix interactions and adhere poorly to culture plates with a remarkably reduced integrin β1 expression. When cultured on uncoated glass coverslips, claudin-7 KD cells grow on top of each other and form spheroids while the control cells adhere well and grow as a monolayer. Reintroducing claudin-7 reduces cell proliferation, upregulates integrin β1 expression and increases cell-matrix adhesion. Integrin β1 transfection partially rescues the cell attachment defect. When inoculated into nude mice, claudin-7 KD cells produced significantly larger tumors than control cells.
Conclusion
In this study, we identified a previously unrecognized function of claudin-7 in regulating cell proliferation and maintaining epithelial cell attachment through engaging integrin β1.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0387-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-015-0387-0
PMCID: PMC4470020  PMID: 26081244
Claudin-7; Integrin β1; Cell proliferation; Cell-matrix interactions; Lung cancer cells
11.  Infection Mobilizes Hematopoietic Stem Cells through Cooperative NOD-like Receptor and Toll-like Receptor Signaling 
Cell host & microbe  2014;15(6):779-791.
Summary
Adult hematopoietic stem cells (HSCs) are maintained in specialized niches within the bone marrow under steady-state conditions and mobilized for extramedullary hematopoiesis during periods of stress such as bacterial infections. However, the underlying mechanisms are unclear. We show that systemic infection of mice with Escherichia coli, commonly associated with bacteremia in humans, mobilizes functional HSCs to the spleen. Accumulation of splenic HSCs (CD150+CD48-Lin−/lowScal1+cKit+) was diminished in TLR4-deficient and RIPK2-deficient mice, implicating TLRs and cytosolic NOD1/NOD2 signaling in the process. Accordingly, dual stimulation of NOD1 and TLR4 in radio-resistant cells alone was sufficient to mobilize HSCs, while TLR4 expression on HSCs was dispensable. Mechanistically, TLR4 and NOD1 synergistically induced granulocyte-colony stimulating factor (G-CSF), which was required for extramedullary HSC accumulation. Mobilized HSCs and progenitor cells gave rise to neutrophils and monocytes and contributed to limiting secondary infection.
doi:10.1016/j.chom.2014.05.004
PMCID: PMC4085166  PMID: 24882704
12.  LOW-INTENSITY PULSED ULTRASOUND PROMOTES CHONDROGENIC PROGENITOR CELL MIGRATION VIA FOCAL ADHESION KINASE PATHWAY 
Ultrasound in medicine & biology  2014;40(6):1177-1186.
Low-intensity pulsed ultrasound (LIPUS) has been frequently studied for its beneficial effects on the repair of injured articular cartilage. Here, we hypothesized that these effects are due to stimulation of chondrogenic progenitor cell (CPC) migration toward injured areas in cartilage through focal adhesion kinase (FAK) activation. CPC chemotaxis in bluntly impacted osteochondral explants was examined by confocal microscopy and migratory activity of cultured CPCs was measured in trans-well and monolayer scratch assays. FAK activation by LIPUS was analyzed in cultured CPCs by western blot. LIPUS effects were compared with the effects of two known chemotactic factors; formylated-methionine peptides (fMLF), and high-mobility group box 1 (HMGB1) protein. LIPUS significantly enhanced CPC migration on explants and in cell culture assays. Phosphorylation of FAK at the kinase domain (Tyr 576/577) was maximized by 5 minute exposure to LIPUS at a dose of 27.5 mW/cm2 and at a frequency of 3.5 MHz. Treatment with fMLF, but not HMBG1 enhanced FAK activation to a degree similar to LIPUS, but neither fMLF nor HMGB1 enhanced the LIPUS effect. LIPUS-induced CPC migration was blocked by suppressing FAK phosphorylation with a Src family kinases (SFKs) inhibitor that blocks FAK phosphorylation. Our results imply that LIPUS might be utilized to promote cartilage healing by inducing the migration of CPCs to injured sites, which could delay or prevent the onset of post-traumatic osteoarthritis (PTOA).
doi:10.1016/j.ultrasmedbio.2013.12.007
PMCID: PMC4034572  PMID: 24612644
Low-intensity pulsed ultrasound (LIPUS); Articular Cartilage; Post-traumatic osteoarthritis (PTOA); Focal adhesion kinase (FAK); Cell migration
13.  A SINGLE BLUNT IMPACT ON CARTILAGE PROMOTES FIBRONECTIN FRAGMENTATION AND UPREGULATES CARTILAGE DEGRADING STROMELYSIN-1/MATRIX METALLOPROTEINASE-3 IN A BOVINE EX-VIVO MODEL 
Post-traumatic osteoarthritis (PTOA) is characterized by progressive cartilage degeneration in injured joints. Since fibronectin fragments (Fn-fs) degrade cartilage mainly through up-regulating matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, we hypothesized that Fn-fs play a key role in PTOA by promoting chondrolysis in and around injured cartilage. To test this hypothesis, we profiled the catabolic events focusing on fibronectin fragmentation and proteinase expression in bovine osteochondral explants following a single blunt impact on cartilage with a drop tower device which created partial-thickness tissue damage. Injured and control explants were cultured for up to 14 days. The presence of Fn-fs, MMPs (-1, -3, -13), ADAMTS-5 in culture media and in cartilage was determined with immunoblotting. The daily proteoglycan (PG) depletion of cartilage matrix was assessed with DMMB assay. The effect of explant-conditioned media on chondrocytes was also examined with immunoblotting. Impacted cartilage released significantly higher amount of native Fn, three chondrolytic Fn-fs and PG than non-impacted controls did. Those increases coincided with up-regulation of MMP-3 both in conditioned media and in impacted cartilage. These findings support our hypothesis that PTOA may be propelled by Fn-fs which act as catabolic mediators through up-regulating cartilage-damaging proteinases.
doi:10.1002/jor.22610
PMCID: PMC4034576  PMID: 24610678
cartilage; fibronectin fragments; impact; matrix metalloproteinase-3; proteoglycan
14.  Recognition and Binding of Human Telomeric G-Quadruplex DNA by Unfolding Protein 1 
Biochemistry  2014;53(20):3347-3356.
The specific recognition by proteins of G-quadruplex structures provides evidence of a functional role for in vivo G-quadruplex structures. As previously reported, the ribonucleoprotein, hnRNP Al, and it is proteolytic derivative, unwinding protein 1 (UP1), bind to and destabilize G-quadruplex structures formed by the human telomeric repeat d(TTAGGG)n. UP1 has been proposed to be involved in the recruitment of telomerase to telomeres for chain extension. In this study, a detailed thermodynamic characterization of the binding of UP1 to a human telomeric repeat sequence, the d[AGGG(TTAGGG)3] G-quadruplex, is presented and reveals key insights into the UP1-induced unfolding of the G-quadruplex structure. The UP1–G-quadruplex interactions are shown to be enthalpically driven, exhibiting large negative enthalpy changes for the formation of both the Na+ and K+ G-quadruplex–UP1 complexes (ΔH values of −43 and −19 kcal/mol, respectively). These data reveal three distinct enthalpic contributions from the interactions of UP1 with the Na+ form of G-quadruplex DNA. The initial interaction is characterized by a binding affinity of 8.5 × 108 M–1 (strand), 200 times stronger than the binding of UP1 to a single-stranded DNA with a comparable but non-quadruplex-forming sequence [4.1 × 106 M–1 (strand)]. Circular dichroism spectroscopy reveals the Na+ form of the G-quadruplex to be completely unfolded by UP1 at a binding ratio of 2:1 (UP1:G-quadruplex DNA). The data presented here demonstrate that the favorable energetics of the initial binding event are closely coupled with and drive the unfolding of the G-quadruplex structure.
doi:10.1021/bi500351u
PMCID: PMC4038342  PMID: 24831962
15.  Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1 
eLife  null;4:e05521.
Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery.
DOI: http://dx.doi.org/10.7554/eLife.05521.001
eLife digest
In adults, blood cells develop from a set of stem cells that are found in bone marrow. There are also specialized blood vessels and cells called ‘stromal cells’ within the bone marrow that provide these stem cells with oxygen, nutrients, and other molecules. This local environment, or ‘niche’, plays an important role in regulating the maintenance of these stem cells. But it has not been known whether stem cells can reciprocally regulate their niches.
Unfortunately, radiation used to treat cancer obliterates the stem cells and their niche; both must recover after such a treatment before the patient can produce blood cells normally again. A protein called Angpt1 is thought to play a role in this post-treatment recovery. Angpt1 is known to regulate blood vessels in the bone marrow, and one influential study had previously suggested that bone cells produce Angpt1, which promotes and regulates the maintenance of the stem cells within the niche. However, this previous study did not directly test this. Thus, it was not clear whether Angpt1 promotes the regeneration of the stem cells themselves or if it regulates the rebuilding of the niche.
Now, Zhou, Ding and Morrison have genetically engineered mice to make a ‘reporter’ molecule—which glows green when viewed under a microscope—wherever and whenever the gene for Angpt1 is active. These experiments showed where the protein is produced, and unexpectedly revealed that the bone cells do not make Angpt1. Instead, it is the stem cells and the stromal cells in the niche that made the protein. Further experiments showed that deleting the gene for Angpt1 from mice, or just from their bone cells, did not affect blood cell production; nor did it affect the maintenance or regulation of the stem cells.
Next, Zhou, Ding and Morrison looked at whether Angpt1 might be involved in rebuilding the niche after being exposed to radiation. Some of these irradiated mice had been genetically engineered to lack Angpt1; and, in these mice, blood stem cells and blood cell production recovered more quickly than in mice with Angpt1. The blood vessels in the niche also grew back more quickly in the irradiated mice that lacked Angpt1. However, these regenerated blood vessels were leaky. This suggests that blood stem cells produce Angpt1 to slow the recovery of the niche and reduce leakage from the blood vessels. Thus, blood stem cells can regulate the regeneration of the niches that maintain them.
DOI: http://dx.doi.org/10.7554/eLife.05521.002
doi:10.7554/eLife.05521
PMCID: PMC4411515  PMID: 25821987
Angiopoietin-1; niche; hematopoietic; regeneration; vascular; stem cell; mouse
16.  The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold 
Nature communications  2014;5:4339.
More than 33,000 glycosyltransferases have been identified. Structural studies, however, have only revealed two distinct glycosyltransferase (GT) folds, GT-A and GT-B. Here we report a 1.34 Å resolution X-ray crystallographic structure of a previously uncharacterized “domain of unknown function” 1792 (DUF1792) and show that the domain adopts a new fold and is required for glycosylation of a family of serine-rich repeat streptococcal adhesins. Biochemical studies reveal that the domain is a glucosyltransferase, and it catalyzes the transfer of glucose to the branch point of the hexasaccharide O-linked to the serine-rich repeat of the bacterial adhesin, Fap1 of Streptococcus parasanguinis. DUF1792 homologs from both Gram-positive and Gram-negative bacteria also exhibit the activity. Thus DUF1792 represents a new family of glycosyltransferases, so we designate it as a GT-D glycosyltransferase fold. As the domain is highly conserved in bacteria and not found in eukaryotes, it can be explored as a new antibacterial target.
doi:10.1038/ncomms5339
PMCID: PMC4352575  PMID: 25023666
streptococcal adhesin; glycosyltransferase; DUF1792
17.  EEG resolutions in detecting and decoding finger movements from spectral analysis 
Mu/beta rhythms are well-studied brain activities that originate from sensorimotor cortices. These rhythms reveal spectral changes in alpha and beta bands induced by movements of different body parts, e.g., hands and limbs, in electroencephalography (EEG) signals. However, less can be revealed in them about movements of different fine body parts that activate adjacent brain regions, such as individual fingers from one hand. Several studies have reported spatial and temporal couplings of rhythmic activities at different frequency bands, suggesting the existence of well-defined spectral structures across multiple frequency bands. In the present study, spectral principal component analysis (PCA) was applied on EEG data, obtained from a finger movement task, to identify cross-frequency spectral structures. Features from identified spectral structures were examined in their spatial patterns, cross-condition pattern changes, detection capability of finger movements from resting, and decoding performance of individual finger movements in comparison to classic mu/beta rhythms. These new features reveal some similar, but more different spatial and spectral patterns as compared with classic mu/beta rhythms. Decoding results further indicate that these new features (91%) can detect finger movements much better than classic mu/beta rhythms (75.6%). More importantly, these new features reveal discriminative information about movements of different fingers (fine body-part movements), which is not available in classic mu/beta rhythms. The capability in decoding fingers (and hand gestures in the future) from EEG will contribute significantly to the development of non-invasive BCI and neuroprosthesis with intuitive and flexible controls.
doi:10.3389/fnins.2015.00308
PMCID: PMC4555046  PMID: 26388720
spectral features; fine body-part movement; EEG; PCA; BCI
18.  An autophagosome-based therapeutic vaccine for HBV infection: a preclinical evaluation 
Background
For more than 240 million chronic HBV carriers worldwide, effective therapeutic HBV vaccines are urgently needed. Recently, we demonstrated that autophagosomes were efficient antigens carriers and capable to cross-prime robust T-cell responses and mediate regression of multiple established tumors. Here we tested whether autophagosomes derived from HBV expressing cells could also function as a therapeutic vaccine.
Methods
We generated an autophagosome-based HBV vaccine from HBV-expressing hepatoma cells and examined its ability to induce polyvalent anti-HBV T-cell responses and therapeutic efficacy in mouse models that mimic acute and chronic HBV infection in human.
Results
When compared to the vaccine based on recombinant HBsAg, autophagosome-based HBV vaccine cross-primed multi-specific anti-HBV T-cell responses and significantly reduced HBV replication and HBcAg expression in livers of both acute and chronic mouse models. Therapeutic effect of this HBV vaccine depended on anti-HBV CD8+ effector T cells and associated with increased HBsAg and HBcAg specific IFN-γ producing T cells in the chronic mouse model.
Conclusions
These results indicated that autophagosome-based HBV vaccine could effectively suppress the HBV replication, clear the HBV infected hepatocytes, and break the HBV tolerance in mouse model. The potential clinical application of autophagosome-based HBV vaccine is discussed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0361-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0361-4
PMCID: PMC4301925  PMID: 25526800
Hepatitis B virus; DRibbles; Therapeutic vaccine; Autophagy
19.  Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice[S] 
Journal of Lipid Research  2014;55(11):2296-2308.
Macrophages play crucial roles in the formation of atherosclerotic lesions. Akt, a serine/threonine protein kinase B, is vital for cell proliferation, migration, and survival. Macrophages express three Akt isoforms, Akt1, Akt2, and Akt3, but the roles of Akt1 and Akt2 in atherosclerosis in vivo remain unclear. To dissect the impact of macrophage Akt1 and Akt2 on early atherosclerosis, we generated mice with hematopoietic deficiency of Akt1 or Akt2. After 8 weeks on Western diet, Ldlr−/− mice reconstituted with Akt1−/− fetal liver cells (Akt1−/−→Ldlr−/−) had similar atherosclerotic lesion areas compared with control mice transplanted with WT cells (WT→Ldlr−/−). In contrast, Akt2−/−→Ldlr−/− mice had dramatically reduced atherosclerotic lesions compared with WT→Ldlr−/− mice of both genders. Similarly, in the setting of advanced atherosclerotic lesions, Akt2−/−→Ldlr−/− mice had smaller aortic lesions compared with WT→Ldlr−/− and Akt1−/−→Ldlr−/− mice. Importantly, Akt2−/−→Ldlr−/− mice had reduced numbers of proinflammatory blood monocytes expressing Ly-6Chi and chemokine C-C motif receptor 2. Peritoneal macrophages isolated from Akt2−/− mice were skewed toward an M2 phenotype and showed decreased expression of proinflammatory genes and reduced cell migration. Our data demonstrate that loss of Akt2 suppresses the ability of macrophages to undergo M1 polarization reducing both early and advanced atherosclerosis.
doi:10.1194/jlr.M050633
PMCID: PMC4617132  PMID: 25240046
macrophages/monocytes; cell signaling; apoptosis; foam cells
20.  Combining MK626, a Novel DPP-4 Inhibitor, and Low-Dose Monoclonal CD3 Antibody for Stable Remission of New-Onset Diabetes in Mice 
PLoS ONE  2014;9(9):e107935.
Combining immune intervention with therapies that directly influence the functional state of the β-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support β-cell survival and possibly stimulate β-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of β-cell secretory function with resolution of destructive insulitis and preservation of β-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials.
doi:10.1371/journal.pone.0107935
PMCID: PMC4182446  PMID: 25268801
21.  Neural Manifestations of Implicit Self-Esteem: An ERP Study 
PLoS ONE  2014;9(7):e101837.
Behavioral research has established that humans implicitly tend to hold a positive view toward themselves. In this study, we employed the event-related potential (ERP) technique to explore neural manifestations of positive implicit self-esteem using the Go/Nogo association task (GNAT). Participants generated a response (Go) or withheld a response (Nogo) to self or others words and good or bad attributes. Behavioral data showed that participants responded faster to the self paired with good than the self paired with bad, whereas the opposite proved true for others, reflecting the positive nature of implicit self-esteem. ERP results showed an augmented N200 over the frontal areas in Nogo responses relative to Go responses. Moreover, the positive implicit self-positivity bias delayed the onset time of the N200 wave difference between Nogo and Go trials, suggesting that positive implicit self-esteem is manifested on neural activity about 270 ms after the presentation of self-relevant stimuli. These findings provide neural evidence for the positivity and automaticity of implicit self-esteem.
doi:10.1371/journal.pone.0101837
PMCID: PMC4090159  PMID: 25006966
22.  The antiallodynic action of pregabalin may depend on the suppression of spinal neuronal hyperexcitability in rats with spared nerve injury 
Pregabalin is an anticonvulsant agent that has recently been found to be effective for the treatment of neuropathic pain, although its mechanism of action in this respect has yet to be elucidated. The authors of this article used a rat model of neuropathic pain to examine the potential role of dorsal horn wide dynamic range neurons in the antiallodynic action of pregabalin.
BACKGROUND:
Pregabalin (PGB) is a novel antiepileptic drug and is also used as a first-line medication for the treatment of neuropathic pain. However, the mechanisms of its analgesic effects remain largely unknown.
OBJECTIVES:
To elucidate the mechanisms underlying the antiallodynic action of PGB in rats with neuropathic pain.
METHODS:
In a rat model of neuropathic pain induced by spared nerve injury, mechanical allodynia, as a behavioural sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold with von Frey filaments. Activities of dorsal horn wide dynamic range (WDR) neurons were examined by extracellular electrophysiological recording in vivo.
RESULTS:
Spinal administration of PGB exerted a significant antiallodynic effect and a prominent inhibitory effect on the hypersensitivity of dorsal horn WDR neurons in rats with spared nerve injury.
CONCLUSION:
The antiallodynic action of PGB is likely dependent on the suppression of WDR neuron hyperexcitability in rats with neuropathic pain.
PMCID: PMC4158936  PMID: 24851240
Electrophysiology; Neuropathic pain; Pregabalin; Spinal dorsal horn; WDR neurons
23.  Serum PCSK9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation 
Circulation  2013;127(24):2403-2413.
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
Methods and Results
To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was mainly expressed in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely due to impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apoB-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine (m) PCSK9 levels by 4.3-fold in wild-type (WT) mice and not at all in LDLR−/− ice, where mPCSK9 levels were already 10-fold higher than in WT mice. In addition, LDLR+/− mice had 2.7-fold elevation in mPCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of hLDLR in transgenic mice caused a 70% decrease in serum mPCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in WT (half-life 5.2 min), faster in hLDLR transgenics (2.9 min), and much slower in LDLR−/− recipients (50.5 min). Supportive results were obtained using an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
Conclusions
Our results support a scenario where LDLR represents the main route of elimination of PCSK9, and a reciprocal regulation between these two proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
doi:10.1161/CIRCULATIONAHA.113.001592
PMCID: PMC3806304  PMID: 23690465
cholesterol; lipoproteins; PCSK9; turnover studies; LDL receptor
24.  Preliminary X-ray crystallographic studies of an N-terminal domain of unknown function from a putative glycosyltransferase from Streptococcus parasanguinis  
A streptococcal domain of unknown function 1792 has been crystallized.
Serine-rich repeat glycoproteins (SRRPs) belong to a growing family of bacterial adhesins; they play important roles in bacterial virulence. Fap1, the first SRRP protein to be identified, is glycosylated; while the first two steps of its glycosylation have been determined, the remaining glycosylation steps are unknown. In a search for proteins that might be relevant to the glycosylation of Fap1, a putative glycosyltransferase (GalT1) from Streptococcus parasanguinis was identified. GalT1 possesses a domain of unknown function at the N-terminus. This domain is highly conserved in bacteria and is a member of a broad superfamily. However, the structure of this domain has not been determined. Here, the conditions used to produce a recombinant version of this protein domain and to grow protein crystals are reported. The crystals obtained belonged to space group C2, with unit-cell parameters a = 71.0, b = 45.1, c = 78.6 Å, β = 109.6°, and diffracted to 1.55 Å resolution at a synchrotron X-ray source. This domain does not share sequence identity with proteins of known structures above a level of 12%.
doi:10.1107/S1744309113007161
PMCID: PMC3660891  PMID: 23695567
DUF1792; glycosyltransferase; Streptococcus parasanguinis
25.  Improved Stabilization Method for Lurie Networked Control Systems 
The Scientific World Journal  2014;2014:789398.
The problem of stabilization of Lurie networked control systems (NCSs) is investigated in this paper. The network-induced delays in NCSs are assumed to be time-varying and bounded. By utilizing a reciprocally convex technique to consider the relationship between the network-induced delay and its varying interval, a new absolute stability condition is derived in terms of linear matrix inequalities (LMIs). Based on the obtained condition, an improved cone complementary linearisation (CCL) iteration algorithm is presented to design a state feedback controller. The effectiveness of the proposed method is verified by a numerical example.
doi:10.1155/2014/789398
PMCID: PMC4032754  PMID: 24892090

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