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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  Human Phosphatidylethanolamine-Binding Protein 4 Promoted the Radioresistance of Human Rectal Cancer by Activating Akt in an ROS-Dependent Way 
PLoS ONE  2014;9(3):e90062.
Human phosphatidylethanolamine-binding protein 4(hPEBP4) is a novel anti-apoptosis molecule associated with the resistance of tumors to apoptotic agents. Here we sought to investigate the role of hPEBP4 in the radioresistance of rectal cancer. Immunohistochemistry analysis showed hPEBP4 was expressed in 27/33 of rectal cancer specimens, but only in 2/33 of neighboring normal mucosa. Silencing the expression of hPEBP4 with siRNA significantly reduced the clonogenic survival and enhanced the apoptosis of rectal cancer cells on irradiation. Instead, forced overexpression of hPEBP4 promoted its survival and decreased the apoptosis. Western blot showed hPEBP4 could increase the radiation-induced Akt activation, for which reactive oxygen specimen(ROS) was required. The radioresistance effect of hPEBP4 was reversed after given LY-294002 to inhibit Akt activation or antioxidant to abolish the ROS production. We also confirmed that effect of hPEBP4 in vivo with nude mice. Thus we concluded that hPEBP4, specifically expressed in rectal cancer cells, is associated with radioresistance of rectal cancer, implying that modulation of hPEBP4 may have important therapeutic implications in radiotherapy of rectal cancer.
doi:10.1371/journal.pone.0090062
PMCID: PMC3940727  PMID: 24594691
9.  Mixed Scrub Typhus Genotype, Shandong, China, 2011 
Emerging Infectious Diseases  2014;20(3):484-485.
doi:10.3201/eid2003.121349
PMCID: PMC3944857  PMID: 24565414
scrub typhus; Orientia tsutsugamushi; coinfection; genotype; Apodemus agrarius; striped field mouse; HXS; sdu-2; bacteria; typhoid; scrub typhus; zoonoses; mite; vector; Leptotrombidium arenicola
10.  Improved Stability Criteria of Static Recurrent Neural Networks with a Time-Varying Delay 
The Scientific World Journal  2014;2014:391282.
This paper investigates the stability of static recurrent neural networks (SRNNs) with a time-varying delay. Based on the complete delay-decomposing approach and quadratic separation framework, a novel Lyapunov-Krasovskii functional is constructed. By employing a reciprocally convex technique to consider the relationship between the time-varying delay and its varying interval, some improved delay-dependent stability conditions are presented in terms of linear matrix inequalities (LMIs). Finally, a numerical example is provided to show the merits and the effectiveness of the proposed methods.
doi:10.1155/2014/391282
PMCID: PMC3988971  PMID: 25143974
11.  The Study of Cooperative Obstacle Avoidance Method for MWSN Based on Flocking Control 
The Scientific World Journal  2014;2014:614346.
Compared with the space fixed feature of traditional wireless sensor network (WSN), mobile WSN has better robustness and adaptability in unknown environment, so that it is always applied in the research of target tracking. In order to reach the target, the nodes group should find a self-adaptive method to avoid the obstacles together in their moving directions. Previous methods, which were based on flocking control model, realized the strategy of obstacle avoidance by means of potential field. However, these may sometimes lead the nodes group to fall into a restricted area like a trap and never get out of it. Based on traditional flocking control model, this paper introduced a new cooperative obstacle avoidance model combined with improved SA obstacle avoidance algorithm. It defined the tangent line of the intersection of node's velocity line and the edge of obstacle as the steering direction. Furthermore, the cooperative obstacle avoidance model was also improved in avoiding complex obstacles. When nodes group encounters mobile obstacles, nodes will predict movement path based on the spatial location and velocity of obstacle. And when nodes group enters concave obstacles, nodes will temporarily ignore the gravity of the target and search path along the edge of the concave obstacles. Simulation results showed that cooperative obstacle avoidance model has significant improvement on average speed and time efficiency in avoiding obstacle compared with the traditional flocking control model. It is more suitable for obstacle avoidance in complex environment.
doi:10.1155/2014/614346
PMCID: PMC3934532  PMID: 24683348
12.  Application of Butterfly Clos-Network in Network-on-Chip 
The Scientific World Journal  2014;2014:102651.
This paper studied the topology of NoC (Network-on-Chip). By combining the characteristics of the Clos network and butterfly network, a new topology named BFC (Butterfly Clos-network) network was proposed. This topology integrates several modules, which belongs to the same layer but different dimensions, into a new module. In the BFC network, a bidirectional link is used to complete information exchange, instead of information exchange between different layers in the original network. During the routing period, other nondestination nodes can be used as middle stages to transfer data packets to complete the routing mission. Therefore, this topology has the characteristic of multistage. Simulation analyses show that BFC inherits the rich path diversity of Clos network, and it has a better performance than butterfly network in throughput and delay in a quite congested traffic pattern.
doi:10.1155/2014/102651
PMCID: PMC3926393  PMID: 24688357
13.  Claudins in intestines: distribution and functional significance in health and diseases 
Tissue barriers  2013;1(3):e24978.
Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases, and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases.
doi:10.4161/tisb.24978
PMCID: PMC3879173  PMID: 24478939
Tight junctions; claudins; intestinal barrier; epithelial cells; paracellular permeability; endotoxin; gastrointestinal tract; inflammatory bowel disease
14.  Decoding Individual Finger Movements from One Hand Using Human EEG Signals 
PLoS ONE  2014;9(1):e85192.
Brain computer interface (BCI) is an assistive technology, which decodes neurophysiological signals generated by the human brain and translates them into control signals to control external devices, e.g., wheelchairs. One problem challenging noninvasive BCI technologies is the limited control dimensions from decoding movements of, mainly, large body parts, e.g., upper and lower limbs. It has been reported that complicated dexterous functions, i.e., finger movements, can be decoded in electrocorticography (ECoG) signals, while it remains unclear whether noninvasive electroencephalography (EEG) signals also have sufficient information to decode the same type of movements. Phenomena of broadband power increase and low-frequency-band power decrease were observed in EEG in the present study, when EEG power spectra were decomposed by a principal component analysis (PCA). These movement-related spectral structures and their changes caused by finger movements in EEG are consistent with observations in previous ECoG study, as well as the results from ECoG data in the present study. The average decoding accuracy of 77.11% over all subjects was obtained in classifying each pair of fingers from one hand using movement-related spectral changes as features to be decoded using a support vector machine (SVM) classifier. The average decoding accuracy in three epilepsy patients using ECoG data was 91.28% with the similarly obtained features and same classifier. Both decoding accuracies of EEG and ECoG are significantly higher than the empirical guessing level (51.26%) in all subjects (p<0.05). The present study suggests the similar movement-related spectral changes in EEG as in ECoG, and demonstrates the feasibility of discriminating finger movements from one hand using EEG. These findings are promising to facilitate the development of BCIs with rich control signals using noninvasive technologies.
doi:10.1371/journal.pone.0085192
PMCID: PMC3885680  PMID: 24416360
15.  SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors 
Cell stem cell  2013;13(1):102-116.
SUMMARY
Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitors (MPPs) are routinely isolated using various markers but remain heterogeneous. Here we show that four SLAM family markers, CD150, CD48, CD229, and CD244, can distinguish HSCs and MPPs from restricted progenitors and subdivide them into a hierarchy of functionally distinct subpopulations with stepwise changes in cell-cycle status, self-renewal, and reconstituting potential. CD229 expression largely distinguished lymphoid-biased HSCs from rarely-dividing myeloid-biased HSCs, enabling prospective enrichment of these HSC subsets. Differences in CD229 and CD244 expression resolved CD150−CD48−/lowLineage−/lowSca-1+c-Kit+ cells into a hierarchy of highly-purified MPPs that retained erythroid and platelet potential but exhibited progressive changes in mitotic activity and reconstituting potential. Use of these markers, and reconstitution assays, showed that conditional deletion of Scf from endothelial cells and perivascular stromal cells eliminated the vast majority of bone marrow HSCs, including nearly all CD229−/low HSCs, demonstrating that quiescent HSCs are maintained by a perivascular niche.
doi:10.1016/j.stem.2013.05.014
PMCID: PMC3736853  PMID: 23827712
16.  Superoxide Anions in Paraventricular Nucleus Modulate Adipose Afferent Reflex and Sympathetic Activity in Rats 
PLoS ONE  2013;8(12):e83771.
Background
Adipose afferent reflex (AAR) is a sympatho-excitatory reflex induced by chemical stimulation of white adipose tissue (WAT). Ionotropic glutamate receptors including NMDA receptors (NMDAR) and non-NMDA receptors (non-NMDAR) in paraventricular nucleus (PVN) mediate the AAR. Enhanced AAR contributes to sympathetic activation and hypertension in obesity rats. This study was designed to investigate the role and mechanism of superoxide anions in PVN in modulating the AAR.
Methodology/Principal Findings
Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anesthetized rats. AAR was evaluated by the RSNA and MAP responses to injections of capsaicin into four sites of right inguinal WAT (8.0 nmol in 8.0 µl for each site). Microinjection of polyethylene glycol-superoxide dismutase (PEG-SOD), the superoxide anion scavenger tempol or the NAD(P)H oxidase inhibitor apocynin into the PVN decreased the baseline RSNA and MAP, and attenuated the AAR. Unilateral WAT injection of capsaicin increased superoxide anions in bilateral PVN, which was prevented by the WAT denervation. WAT injection of capsaicin increased superoxide anion level and NAD(P)H oxidase activity in the PVN, which was abolished by the PVN pretreatment with the combined NMDAR antagonist AP5 and non-NMDAR antagonist CNQX. Microinjection of the NMDAR agonist NMDA or the non-NMDAR agonist AMPA increased superoxide anion level and NAD(P)H oxidase activity in the PVN.
Conclusions
NAD(P)H oxidase-derived superoxide anions in the PVN contributes to the tonic modulation of AAR. Activation of ionotropic glutamate receptors in the PVN is involved in the AAR-induced production of superoxide anions in the PVN.
doi:10.1371/journal.pone.0083771
PMCID: PMC3871588  PMID: 24376743
17.  Scrub Typhus: Surveillance, Clinical Profile and Diagnostic Issues in Shandong, China 
To elucidate the epidemic status, clinical profile, and current diagnostic issues of scrub typhus in Shandong Province, we analyzed the surveillance data of scrub typhus from 2006 to 2011 and conducted a hospital-based disease survey in 2010. Scrub typhus was clustered in mountainous and coastal areas in Shandong Province, with an epidemic period from September to November. The most common manifestations were fever (100%), eschar or skin ulcer (86.3%), fatigue (71.6%), anorexia (71.6%), and rash (68.6%). Predominant complications included bronchopneumonia, toxic hepatitis, and acute cholecystitis in 21.6%, 3.9%, and 2.9% of the cases, respectively. Severe complications including toxic myocarditis, heart failure, pneumonedema, pleural effusion, and emphysema were first reported in Shandong. Missed and delayed diagnosis of scrub typhus was common in local medical institutions. Alarm should be raised for changes of clinical features and current diagnostic issues of scrub typhus in newly developed endemic areas.
doi:10.4269/ajtmh.2012.12-0306
PMCID: PMC3516082  PMID: 23091193
18.  Melanocortin 4 Receptors in the Paraventricular Nucleus Modulate the Adipose Afferent Reflex in Rat 
PLoS ONE  2013;8(11):e80295.
Background and Aim
Paraventricular nucleus (PVN) of hypothalamus is an important central component in modulating adipose afferent reflex (AAR). Melanocortin receptors (MC3/4Rs) expressions are found in the hypothalamic PVN. This study was designed to determine the roles of MC3/4Rs in the PVN in modulating the AAR and its downstream signaling pathway in normal rats.
Methodology/Principal Findings
Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anaesthetized rats. AAR was evaluated using RSNA and MAP responses to capsaicin injection into the inguinal white adipose tissue (iWAT). Microinjection of the MC3/4R agonist melanotan II (MTII) into the PVN enhanced the AAR. The MC3/4R antagonist SHU9119 or MC4R antagonist HS024 attenuated the AAR and abolished MTII-induced AAR response. The adenylate cyclase (AC) inhibitor SQ22536 or the protein kinase A (PKA) inhibitor Rp-cAMP attenuated the AAR and the effect of MTII on the AAR was abolished by pretreatment with SQ22536 or Rp-cAMP in the PVN. Furthermore, both PVN microinjection of MTII and iWAT injection of capsaicin increased the cAMP level in the PVN. SHU9119 in the PVN abolished the increase in cAMP level which induced by iWAT injection of capsaicin.
Conclusion
The activation of MC4Rs rather than MC3Rs enhances the AAR, and a cAMP-PKA pathway is involved in the effects of MC4Rs in the PVN.
doi:10.1371/journal.pone.0080295
PMCID: PMC3823614  PMID: 24244673
19.  The claudin family of proteins in human malignancy: a clinical perspective 
Tight junctions, or zonula occludens, are the most apical component of the junctional complex and provide one form of cell–cell adhesion in epithelial and endothelial cells. Nearly 90% of malignant tumors are derived from the epithelium. Loss of cell–cell adhesion is one of the steps in the progression of cancer to metastasis. At least three main tight junction family proteins have been discovered: occludin, claudin, and junctional adhesion molecule (JAM). Claudins are the most important structural and functional components of tight junction integral membrane proteins, with at least 24 members in mammals. They are crucial for the paracellular flux of ions and small molecules. Overexpression or downregulation of claudins is frequently observed in epithelial-derived cancers. However, molecular mechanisms by which claudins affect tumorigenesis remain largely unknown. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies, including pancreatic, colonic, lung, ovarian, thyroid, prostate, esophageal, and breast cancers. In this review, we will give the readers an overall picture of the changes in claudin expression observed in various cancers and their mechanisms of regulation. Downregulation of claudins contributes to epithelial transformation by increasing the paracellular permeability of nutrients and growth factors to cancerous cells. In the cases of upregulation of claudin expression, the barrier function of the cancerous epithelia changes, as they often display a disorganized arrangement of tight junction strands with increased permeability to paracellular markers. Finally, we will summarize the literature suggesting that claudins may become useful biomarkers for cancer detection and diagnosis as well as possible therapeutic targets for cancer treatment.
doi:10.2147/CMAR.S38294
PMCID: PMC3825674  PMID: 24232410
tight junctions; claudins; human cancers
20.  Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches 
Nature  2013;495(7440):231-235.
While haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche1, most published experimental manipulations of the HSC niche have also impacted the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs1 and restricted progenitors2,3 reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine, CXCL12, for HSC and restricted progenitor maintenance. Cxcl12DsRed knock-in mice showed that Cxcl12 was primarily expressed by perivascular stromal cells and at lower levels by endothelial cells, osteoblasts, and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or Nestin-cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors, but not HSCs or myeloerythroid progenitors and did not mobilize these cells into circulation. Different stem/progenitor cells thus occupy distinct cellular niches in bone marrow: HSCs in a perivascular niche and early lymphoid progenitors in an endosteal niche.
doi:10.1038/nature11885
PMCID: PMC3600153  PMID: 23434755
21.  Genetic Variants of Orientia tsutsugamushi in Domestic Rodents, Northern China 
Emerging Infectious Diseases  2013;19(7):1135-1137.
We screened Orientia tsutsugamushi from 385 domestic rodents and 19 humans with scrub typhus in rural Tai’an District, Shandong Province, a new scrub typhus epidemic area in northern China. Sequence analysis identified 7 genotypes in the rodents, of which 2 were also identified in the humans.
doi:10.3201/eid1907.120984
PMCID: PMC3713967  PMID: 23764295
scrub typhus; Orientia tsutsugamushi; genotype; phylogeny; parasites; China; rodents; humans
22.  Computational Methods in Neuroengineering 
doi:10.1155/2013/617347
PMCID: PMC3713316  PMID: 23935703
23.  Claudins in intestines 
Tissue Barriers  2013;1(3):e24978.
Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases.
doi:10.4161/tisb.24978
PMCID: PMC3879173  PMID: 24478939
tight junctions; claudins; intestinal barrier; epithelial cells; paracellular permeability; endotoxin; gastrointestinal tract; inflammatory bowel disease
24.  Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinoma 
Diagnostic Pathology  2013;8:89.
Background
Epithelial-mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metastasis of various cancers. The aim was to evaluate that whether EMT-related proteins' alterations are associated with clinicopathological features and prognosis in lung adenocarcinoma.
Methods
The expression of EMT-related proteins including cytokeratin, E-cadherin, TTF-1, β-catenin, vimentin, Snail, Twist, CD44 was evaluated by immunohistochemistry using a tissue array method in the lung adenocarcinoma tissues of 95 patients. In addition, clinicopathological characteristics and survival were compared with the expression of EMT-related proteins.
Results
Loss of epithelial proteins and/or acquisition of the expression of mesenchymal proteins were observed in lung adenocarcinoma. These proteins’ alteration was associated with poor cell differentiation and poor patients’ outcome, respectively. Subjects were divided into two groups according to the number of EMT-related proteins’ alteration. A higher number of EMT-related proteins’ alteration was found to be significantly associated with unfavorable outcome. Multivariate analysis showed that a higher number of EMT-related proteins’ alteration was independently associated with poor prognosis.
Conclusions
The number of EMT-related proteins’ alteration is a significant prognostic marker to predict overall survival in patients with lung adenocarcinoma. The information generated will be valuable for the prognosis of patients with lung adenocarcinoma.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1007838329872974
doi:10.1186/1746-1596-8-89
PMCID: PMC3671218  PMID: 23706092
Epithelial–mesenchymal transition; Lung adenocarcinoma; Survival analysis; Tissue array analysis
25.  Evaluation of EEG Features in Decoding Individual Finger Movements from One Hand 
With the advancements in modern signal processing techniques, the field of brain-computer interface (BCI) is progressing fast towards noninvasiveness. One challenge still impeding these developments is the limited number of features, especially movement-related features, available to generate control signals for noninvasive BCIs. A few recent studies investigated several movement-related features, such as spectral features in electrocorticography (ECoG) data obtained through a spectral principal component analysis (PCA) and direct use of EEG temporal data, and demonstrated the decoding of individual fingers. The present paper evaluated multiple movement-related features under the same task, that is, discriminating individual fingers from one hand using noninvasive EEG. The present results demonstrate the existence of a broadband feature in EEG to discriminate individual fingers, which has only been identified previously in ECoG. It further shows that multiple spectral features obtained from the spectral PCA yield an average decoding accuracy of 45.2%, which is significantly higher than the guess level (P < 0.05) and other features investigated (P < 0.05), including EEG spectral power changes in alpha and beta bands and EEG temporal data. The decoding of individual fingers using noninvasive EEG is promising to improve number of features for control, which can facilitate the development of noninvasive BCI applications with rich complexity.
doi:10.1155/2013/243257
PMCID: PMC3655488  PMID: 23710250

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