Functional measurement is important for retinal study and disease diagnosis. Transient intrinsic optical signal (IOS) response, tightly correlated with functional stimulation, has been previously detected in normal retinas. In this paper, comparative IOS imaging of wild-type (WT) and rod-degenerated mutant mouse retinas is reported. Both 2-month and 1-year-old mice were measured. In 2-month-old mutant mice, time course and peak value of the stimulus-evoked IOS were significantly delayed (relative to stimulus onset) and reduced, respectively, compared to age matched WT mice. In 1-year-old mutant mice, stimulus-evoked IOS was totally absent. However, enhanced spontaneous IOS responses, which might reflect inner neural remodeling in diseased retina, were observed in both 2-month and 1-year-old mutant retinas. Our experiments demonstrate the potential of using IOS imaging for noninvasive and high resolution identification of disease-associated retinal dysfunctions. Moreover, high spatiotemporal resolution IOS imaging may also lead to advanced understanding of disease-associated neural remodeling in the retina.

Background

The objective of this study was to develop a modified retroperitoneal laparoscopic nephrectomy and compare its results with the previous technique.

Methods

One hundred retroperitoneal laparoscopic nephrectomies were performed from February 2007 to October 2011. The previous technique was performed in 60 cases (Group 1). The modified technique (n = 40) included fast access to the renal pedicle according to several anatomic landmarks and early ligation of renal vessels (Group 2). The mean operation time, mean blood loss, duration of hospital stay conversion rate and complication rate were compared between the groups.

Results

No significant differences were detected regarding mean patient age, mean body mass index, and tumor size between the two groups (P >0.05). The mean operation time was 59.5 ± 20.0 and 39.5 ± 17.5 minutes, respectively, in Groups 1 and 2 (P <0.001). The mean intraoperative blood loss was 147 ± 35 and 100 ± 25 ml, respectively, in Groups 1 and 2 (P <0.001). No significant differences were detected regarding the conversion rate and the complication rate between the two groups (P >0.05).

Conclusions

Early ligature using fast access to the renal vessels during retroperitoneal laparoscopic radical nephrectomy contributed to less operation time and intraoperative blood loss compared with the previous technique. In addition, the modified technique permits the procedure to be performed following the principles of open radical nephrectomy.

Background

Recent studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and risk of prostate cancer showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies.

Methods

Data were collected from the following electronic databases: Pubmed, Embase, and Chinese Biomedical Database (CBM). The odds ratio (OR) and its 95% confidence interval (95%CI) was used to assess the strength of the association. We summarized the data on the association between GSTT1 null genotype and risk of prostate cancer in the overall population, and performed subgroup analyses by ethnicity, adjusted ORs, and types of controls.

Results

Ultimately, a total of 43 studies with a total of 26,393 subjects (9,934 cases and 16,459 controls) were eligible for meta-analysis. Overall, there was a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.14, 95%CI 1.01–1.29, P = 0.034). Meta-analysis of adjusted ORs also showed a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.34, 95%CI 1.09–1.64, P = 0.006). Similar results were found in the subgroup analyses by ethnicity and types of controls.

Conclusion

This meta-analysis demonstrates that GSTT1 null genotype is associated with prostate cancer susceptibility, and GSTT1 null genotype contributes to increased risk of prostate cancer.

Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including APC and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, plays a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is GSK3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA-binding and transactivation and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.

Background

Statins are lipid-lowering agents that also exhibit pleiotropic effects in decreasing oxidative stress and inflammation. There have been several published studies reporting the use of statins in the treatment of asthma patients, but their results are not consistent. The aim of this study is to determine whether statins are beneficial for asthma administration, and explore the potential covariables that may affect their clinical effectiveness.

Methods

A systematic literature search was performed in PubMed, Embase and Cochrane Center Register of Controlled Trials from inception to September 2012. Randomized controlled trials (RCT), retrospective studies and controlled clinical trials which reported the use of statins in the treatment of asthma patients were eligible. Quality evaluation was conducted for RCT using Jadad criteria.

Results

A total of 18 articles were included. In our study, we found no conclusive evidence to demonstrate that statins could enhance the lung function in asthmatics, although, they may reduce airway inflammation. Additionally, the results were not consistent across studies with respect to symptoms, quality of life, maintenance medication, asthma hospitalization/emergency department (ED) visits.

Conclusions

Statins may reduce airway inflammation in asthmatics, without having a significant effect on lung function. Further large sample and multicenter clinical trials are needed to confirm this and to see if there are more responsive phenotypes of asthma.

To evaluate vaccine efficacy in protecting against coxsackievirus A16 (CA16), which causes human hand, foot, and mouth disease (HFMD), we established the first neonatal mouse model. In this article, we report data concerning CA16-induced pathological changes, and we demonstrate that anti-CA16 antibody can protect mice against lethal challenge and that the neonatal mouse model could be used to evaluate vaccine efficacy. To establish a mouse model, a BJCA08/CA16 strain (at 260 50% lethal doses [LD50]) was isolated from a patient and used to intracerebrally (i.c.) inoculate neonatal mice. The infection resulted in wasting, hind-limb paralysis, and even death. Pathological examination and immunohistochemistry (IHC) staining indicated that BJCA08 had a strong tropism to muscle and caused severe necrosis in skeletal and cardiac muscles. We then found that BJCA08 pretreated with goat anti-G10/CA16 serum could significantly lose its lethal effect in neonatal mice. When the anti-G10 serum was intraperitoneally (i.p.) injected into the neonatal mice and, within 1 h, the same mice were intracerebrally inoculated with BJCA08, there was significant passive immunization protection. In a separate experiment, female mice were immunized with formaldehyde-inactivated G10/CA16 and BJCA08/CA16 and then allowed to mate 1 h after the first immunization. We found that there was significant protection against BJCA08 for neonatal mice born to the immunized dams. These data demonstrated that anti-CA16 antibody may block virus invasion and protect mice against lethal challenge, and that the neonatal mouse model was a viable tool for evaluating vaccine efficacy.

Sarcandra glabra, as a type of “antipyretic-detoxicate drugs”, has always been widely used in traditional Chinese medicine (TCM). The Sarcandra glabra extract (SGE) is applied frequently as anti-inflammatory and anti-infectious drug in folk medicine. However, relative experiment data supporting this effective clinical consequence was limited. In order to mimic the physiological conditions of the susceptible population, we employed restraint stress mouse model to investigate the effect of SGE against influenza. Mice were infected with influenza virus three days after restraint, while SGE was orally administrated for 10 consecutive days. Body weight, morbidity, and mortality were recorded daily. Histopathologic changes, susceptibility genes expressions and inflammatory markers in lungs were determined. Our results showed that restraint stress significantly increased susceptibility and severity of influenza virus. However, oral administration of SGE could reduce morbidity, mortality and significantly prolonged survival time. The results further showed that SGE had a crucial effect on improving susceptibility markers levels to recover the balance of host defense system and inhibiting inflammatory cytokines levels through down-regulation of NF-κB protein expression to ameliorate the lung injury. These data showed that SGE reduced the susceptibility and severity of influenza.

Background

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China.

Methods and Findings

This comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD50 of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14–21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90–100% survival), while the ED50 of NAb responses and protective effects varied among three FCP-As.

Conclusions

These studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results.

The Rex repressor has been implicated in regulation of central carbon and energy metabolism in Gram-positive bacteria. We have previously shown that Streptococcus mutans, the primary causative agent of dental caries, alters its transcriptome upon Rex-deficiency and renders S. mutans to have increased susceptibility to oxidative stress, aberrations in glucan production, and poor biofilm formation. In this study, we showed that rex in S. mutans is co-transcribed as an operon with downstream guaA, encoding a putative glutamine amidotransferase. Electrophoretic mobility shift assays showed that recombinant Rex bound promoters of target genes avidly and specifically, including those down-regulated in response to Rex-deficiency, and that the ability of recombinant Rex to bind to selected promoters was modulated by NADH and NAD+. Results suggest that Rex in S. mutans can function as an activator in response to intracellular NADH/NAD+ level, although the exact binding site for activator Rex remains unclear. Consistent with a role in oxidative stress tolerance, hydrogen peroxide challenge assays showed that the Rex-deficient mutant, TW239, and the Rex/GuaA double mutant, JB314, were more susceptible to hydrogen peroxide killing than the wildtype, UA159. Relative to UA159, JB314 displayed major defects in biofilm formation, with a decrease of more than 50-fold in biomass after 48-hours. Collectively, these results further suggest that Rex in S. mutans regulates fermentation pathways, oxidative stress tolerance, and biofilm formation in response to intracellular NADH/NAD+ level. Current effort is being directed to further investigation of the role of GuaA in S. mutans cellular physiology.

Functional measurement is important for retinal study and disease diagnosis. Transient intrinsic optical signal (IOS) response, tightly correlated with functional stimulation, has been previously detected in normal retinas. In this paper, comparative IOS imaging of wild-type (WT) and rod-degenerated mutant mouse retinas is reported. Both 2-month and 1-year-old mice were measured. In 2-month-old mutant mice, time course and peak value of the stimulus-evoked IOS were significantly delayed (relative to stimulus onset) and reduced, respectively, compared to age matched WT mice. In 1-year-old mutant mice, stimulus-evoked IOS was totally absent. However, enhanced spontaneous IOS responses, which might reflect inner neural remodeling in diseased retina, were observed in both 2-month and 1-year-old mutant retinas. Our experiments demonstrate the potential of using IOS imaging for noninvasive and high resolution identification of disease-associated retinal dysfunctions. Moreover, high spatiotemporal resolution IOS imaging may also lead to advanced understanding of disease-associated neural remodeling in the retina.

Background

Hand, foot, and mouth disease (HFMD) has been emerging as an important public problem over the past few decades, especially in Asian and Pacific regions. A national program on EV71 vaccine development against HFMD was initiated in China, in 2008, which called for a need for seroepidemiological study for the target population.

Methodology/Principal Findings

This was a retrospective study conducted in Jiangsu Province, in October, 2010. We measured the neutralizing antibodies against EV71 and CoxA16 in a cohort of infants aged of 2, 7, 12, and 27–38 months and their mothers just before delivery. Series sera samples from 975 infants and 555 mothers were collected and analyzed. Questionnaires on the history of HFMD were completed in the survey. A total of 143 HFMD cases were collected, but only 11.2% were reported to the National Infectious Disease Information Management System. The level of maternal antibody titers decreased dramatically during the first 7 month and remained at a relatively low level thereafter. But it increased significantly from month 12 to months 27–38. The accumulate incidence density of HFMD demonstrated a significant increase after 14 months of age, resulting in a accumulate incidence density of 50.8/1000 person-years in survey period. Seropositivity of EV71 antibody in infants at the age of 2 months seems to demonstrate a protective effect against HFMD.

Conclusions and Significance

High seropositive rate of EV71 and CoxA16 antibody was found in prenatal women in mainland China, and there is a need to enhance the HFMD case management and the current surveillance system. We suggest that infants aged between 6 to 14 months should have the first priority to receive EV71 vaccine.

Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor α (RXRα), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.

Background

To characterize the human humoral immune response against enterovirus 71 (EV71) infection and map human epitopes on the viral capsid proteins.

Methods

A series of 256 peptides spanning the capsid proteins (VP1, VP2, VP3) of BJ08 strain (genomic C4) were synthesized. An indirect enzyme-linked immunosorbent assay (ELISA) was carried out to detect anti-EV71 IgM and IgG in sera of infected children in acute or recovery phase. The partially overlapped peptides contained 12 amino acids and were coated in the plate as antigen (0.1 μg/μl). Sera from rabbits immunized with inactivated BJ08 virus were also used to screen the peptide panel.

Results

A total of 10 human anti-EV71 IgM epitopes (vp1-14 in VP1; vp2-6, 21, 40 and 50 in VP2 and vp3-10, 12, 15, 24 and 75 in VP3) were identified in acute phase sera. In contrast, only one anti-EV71 IgG epitope in VP1 (vp1-15) was identified in sera of recovery stage. Four rabbit anti-EV71 IgG epitopes (vp1-14, 31, 54 and 71) were identified and mapped to VP1.

Conclusion

These data suggested that human IgM epitopes were mainly mapped to VP2 and VP3 with multi-epitope responses occurred at acute infection, while the only IgG epitope located on protein VP1 was activated in recovery phase sera. The dynamic changes of humoral immune response at different stages of infection may have public health significance in evaluation of EV71 vaccine immunogenicity and the clinical application of diagnostic reagents.

Using freshly isolated animal retinas, we have conducted a series of experiments to test fast intrinsic optical signals (IOSs) that have time courses comparable to electrophysiological kinetics. In this Letter, we demonstrate the feasibility of in vivo imaging of fast IOSs in intact frogs. A rapid line-scan confocal ophthalmoscope was constructed to achieve high-speed IOS recording. By rejecting out-of-focus background light, the line-scan confocal imager provided the resolution to differentiate individual photoreceptors in vivo. Rapid confocal imaging disclosed robust IOSs with time courses comparable to retinal electroretinogram kinetics. High-resolution IOS images revealed both positive (increasing) and negative (decreasing) light responses, with subcellular complexity.

Background: Neoadjuvant chemotherapy with concurrent docetaxel, doxorubicin and cyclophosphamide is commonly used for patients with locally advanced breast cancer. Epirubicin is another anthracycline used in breast cancer but the concurrent use of epirubicin and taxane is not well-established. We conducted a single institution, phase II study to assess the efficacy and safety of concurrent docetaxel, epirubicin and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen in breast cancer. Methods: Patients with newly diagnosed locally advanced breast cancer defined as T2 >3 cm, T3, T4 with any N, or any T with N1-3 were eligible. A chemotherapy regimen of docetaxel 75mg/m2, epirubicin 75mg/m2 and cyclophosphamide 600mg/m2 was given with filgrastim support every 3 weeks for 6 cycles. The primary end-point was pathologic complete response rate. Results: Twenty patients were enrolled from 2003 to 2006. The median age was 51 (29-70) year-old. Eight patients were premenopausal. Ten patients had positive hormone receptors. Four patients had HER2 positive receptor. Nineteen patients completed six cycles of TEC chemotherapy. The pathologic complete response rate was 25%. Eight of sixteen patients with N1-3 disease had pathological negative lymph nodes. With a median follow up of 57.5 (16-71) months, four patients relapsed including one death from recurrence. The estimated 5 year relapse-free survival was 79.3% and the 5-year overall survival was 94.7%. No patient had cardiac failure or death during treatment. The most common grade 3-4 toxicity was neutropenia (35%). Conclusion: TEC regimen is a well- tolerated and effective neoadjuvant chemotherapy regimen for locally advanced breast cancer that results in a pathologic complete response rate of 25%.

The extract from Ginkgo biloba leaves has become a very popular plant medicine and herbal supplement for its potential benefit in alleviating symptoms associated with peripheral vascular disease, dementia, asthma and tinnitus. Most research on G. biloba leaves focus on the leaves collected in July and August from four to seven year-old trees, however a large number of leaves from fruit cultivars (trees older than 10 years) are ignored and become obsolete after fruit harvest season (November). In this paper, we expand the tree age range (from one to 300 years) and first comparatively analyze the total flavonol glycosides and terpene lactones at different ages, from different cultivation sources and genders of G. biloba leaves collected in November by using the validated HPLC-ELSD and HPLC-PDA methods. The results show that the contents of total terpene lactones and flavonol glycosides in the leaves of young ginkgo trees are higher than those in old trees, and they are higher in male trees than in female trees. Geographical factors appear to have a significant influence on the contents as well. These results will provide a good basis for the comprehensive utilization of G. biloba leaves, especially the leaves from fruit cultivars.

Simultaneous monitoring of many functioning β-cells is essential for understanding β-cell dysfunction as an early event in the progression to diabetes. Intrinsic optical signal (IOS) imaging has been shown to allow high resolution detection of stimulus-evoked physiological responses in the retina and other neural tissues. In this paper, we demonstrate the feasibility of using IOS imaging for functional examination of insulin secreting INS-1 cells, a popular model for investigating diabetes associated β-cell dysfunction. Our experiments indicate that IOS imaging permits simultaneous monitoring of glucose-stimulated physiological responses in multiple cells with high spatial (sub-cellular) and temporal (sub-second) resolution. Rapid IOS image sequences revealed transient optical responses that had time courses tightly correlated with the glucose stimulation.

Engineered systems are designed to deftly operate under predetermined conditions yet are notoriously fragile when unexpected perturbations arise. In contrast, biological systems operate in a highly flexible manner; learn quickly adequate responses to novel conditions, and evolve new routines and traits to remain competitive under persistent environmental change. A recent theory on the origins of biological flexibility has proposed that degeneracy—the existence of multi-functional components with partially overlapping functions—is a primary determinant of the robustness and adaptability found in evolved systems. While degeneracy’s contribution to biological flexibility is well documented, there has been little investigation of degeneracy design principles for achieving flexibility in systems engineering. Actually, the conditions that can lead to degeneracy are routinely eliminated in engineering design. With the planning of transportation vehicle fleets taken as a case study, this article reports evidence that degeneracy improves the robustness and adaptability of a simulated fleet towards unpredicted changes in task requirements without incurring costs to fleet efficiency. We find that degeneracy supports faster rates of design adaptation and ultimately leads to better fleet designs. In investigating the limitations of degeneracy as a design principle, we consider decision-making difficulties that arise from degeneracy’s influence on fleet complexity. While global decision-making becomes more challenging, we also find degeneracy accommodates rapid distributed decision-making leading to (near-optimal) robust system performance. Given the range of conditions where favorable short-term and long-term performance outcomes are observed, we propose that degeneracy may fundamentally alter the propensity for adaptation and is useful within different engineering and planning contexts.

Previous transgenic-reporter and targeted-deletion studies indicate that the subset-specific expression of CD8αβ heterodimers is controlled by multiple enhancer activities, since no silencer elements had been found within the locus. We have identified such a silencer as L2a, a previously characterized ~220 bp nuclear matrix associating region (MAR) located ~4.5 kb upstream of CD8α. L2a transgenes driven by the E8I enhancer showed no reporter expression in thymic subsets or T cells in splenic, inguinal and mesenteric lymph node peripheral T cells. Deletion of L2a resulted in significant reporter de-repression, even in the CD4+CD8+ double positive (DP) thymocyte population. L2a contains binding sites for two MAR-interacting proteins, SATB1 and CDP. We found that that binding of these factors was markedly influenced by the content and spacing of L2a sub-motifs (L and S) and that SATB1 binds preferentially to the L motif both in vitro and in vivo. A small fraction of the transgenic CD8+ single positive (SP) thymocytes and peripheral CD8+ T cells bypassed L2a-silencing to give rise to variegated expression of the transgenic reporter. Crossing the L2a-containing transgene onto a SATB1 knockdown background enhanced variegated expression, suggesting that SATB1 is critical in overcoming L2a-silenced transcription.

Background

Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS)-induced uveitis in mice.

Methods

Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse) into the footpad in the model and lutein groups on day 5 after the last drug administration. Eyes of the mice were collected 24 hours after the LPS injection for the detection of indicators using commercial kits and reverse transcription-polymerase chain reaction.

Results

LPS-induced uveitis was confirmed by significant pathological damage and increased the nitric oxide level in eye tissue of BALB/C mice 24 hours after the footpad injection. The elevated nitric oxide level was significantly reduced by oral administration of lutein (125 and 500 mg/kg/d for five days) before LPS injection. Moreover, lutein decreased the malondialdehyde content, increased the oxygen radical absorbance capacity level, glutathione, the vitamin C contents and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Lutein further increased expressions of copper-zinc SOD, manganese SOD and GPx mRNA. Conclusion The antioxidant properties of lutein contribute to the protection against LPS-induced uveitis, partially through the intervention of inflammation process.

Linear polarization intrinsic optical signal (LP-IOS) measurement can provide sensitive detection of neural activities in stimulus-activated neural tissues. However, the LP-IOS magnitude and signal-to-noise ratio (SNR) are highly correlated with the nerve orientation relative to the polarization plane of the incident light. Because of the complexity of orientation dependency, LP-IOS optimization and outcome interpretation are time consuming and complicated. In this study, we demonstrate the feasibility of circular polarization intrinsic optical signal (CP-IOS) measurement. Our theoretical modeling and experimental investigation indicate that CP-IOS magnitude and SNR are independent from the nerve orientation. Therefore, CP-IOS promises a practical method for polarization IOS imaging of complex neural systems.

Background

CD8+ cytotoxic T lymphocytes (CTLs) are crucial for eliminating hepatitis B virus (HBV) infected cells. DNA vaccination, a novel therapeutic strategy for chronic virus infection, has been shown to induce CTL responses. However, accumulated data have shown that CTLs could not be effectively induced by HBV DNA vaccination.

Methodology/Principal Findings

Here, we report that praziquantel (PZQ), an anti-schistoma drug, could act as an adjuvant to overcome the lack of potent CTL responses by HBV DNA vaccination in mice. PZQ in combination with HBV DNA vaccination augmented the induction of CD8+ T cell-dependent and HBV-specific delayed hypersensitivity responses (DTH) in C57BL/6 mice. Furthermore, the induced CD8+ T cells consisted of both Tc1 and Tc17 subtypes. By using IFN-γ knockout (KO) mice and IL-17 KO mice, both cytokines were found to be involved in the DTH. The relevance of these findings to HBV immunization was established in HBsAg transgenic mice, in which PZQ also augmented the induction of HBV-specific Tc1 and Tc17 cells and resulted in reduction of HBsAg positive hepatocytes. Adoptive transfer experiments further showed that PZQ-primed CD8+ T cells from wild type mice, but not the counterpart from IFN-γ KO or IL-17 KO mice, resulted in elimination of HBsAg positive hepatocytes.

Conclusions/Significance

Our results suggest that PZQ is an effective adjuvant to facilitate Tc1 and Tc17 responses to HBV DNA vaccination, inducing broad CD8+ T cell-based immunotherapy that breaks tolerance to HBsAg.

The effects of organic loading rates (OLRs) on fermentative productions of hydrogen and ethanol were investigated in a continuous stirred tank reactor (CSTR) with attached sludge using molasses as substrate. The CSTR reactor with attached sludge was operated under different OLRs, ranging from 8 to 24 kg/m3·d. The H2 and ethanol production rate essentially increased with increasing OLR. The highest H2 production rate (10.74 mmol/h·L) and ethanol production rate (11.72 mmol/h·L) were obtained both operating at OLR = 24 kg/m3·d. Linear regression results show that ethanol production rate (y) and H2 production rate (x) were proportionately correlated and can be expressed as y = 1.5365x − 5.054 (r2 = 0.9751). The best energy generation rate was 19.08 kJ/h·L, which occurred at OLR = 24 kg/m3·d. In addition, the hydrogen yield was affected by the presence of ethanol and acetic acid in the liquid phase, and the maximum hydrogen production rate occurred while the ratio of ethanol to acetic acid was close to 1.

Background

Protein-protein interaction networks and phenotype similarity information have been synthesized together to discover novel disease-causing genes. Genetic or phenotypic similarities are manifested as certain modularity properties in a phenotype-gene heterogeneous network consisting of the phenotype-phenotype similarity network, protein-protein interaction network and gene-disease association network. However, the quantitative analysis of modularity in the heterogeneous network and its influence on disease-gene discovery are still unaddressed. Furthermore, the genetic correspondence of the disease subtypes can be identified by marking the genes and phenotypes in the phenotype-gene network. We present a novel network inference method to measure the network modularity, and in particular to suggest the subtypes of diseases based on the heterogeneous network.

Results

Based on a measure which is introduced to evaluate the closeness between two nodes in the phenotype-gene heterogeneous network, we developed a Hitting-Time-based method, CIPHER-HIT, for assessing the modularity of disease gene predictions and credibly prioritizing disease-causing genes, and then identifying the genetic modules corresponding to potential subtypes of the queried phenotype. The CIPHER-HIT is free to rely on any preset parameters. We found that when taking into account the modularity levels, the CIPHER-HIT method can significantly improve the performance of disease gene predictions, which demonstrates modularity is one of the key features for credible inference of disease genes on the phenotype-gene heterogeneous network. By applying the CIPHER-HIT to the subtype analysis of Breast cancer, we found that the prioritized genes can be divided into two sub-modules, one contains the members of the Fanconi anemia gene family, and the other contains a reported protein complex MRE11/RAD50/NBN.

Conclusions

The phenotype-gene heterogeneous network contains abundant information for not only disease genes discovery but also disease subtypes detection. The CIPHER-HIT method presented here is effective for network inference, particularly on credible prediction of disease genes and the subtype analysis of diseases, for example Breast cancer. This method provides a promising way to analyze heterogeneous biological networks, both globally and locally.

The purpose of this study was to investigate cellular sources of autofluorescence signals in freshly isolated frog (Rana pipiens) retinas. Equipped with an ultrafast laser, a laser scanning two-photon excitation fluorescence microscope was employed for sub-cellular resolution examination of both sliced and flat-mounted retinas. Two-photon imaging of retinal slices revealed autofluorescence signals over multiple functional layers, including the photoreceptor layer (PRL), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Using flat-mounted retinas, depth-resolved imaging of individual retinal layers further confirmed multiple sources of autofluorescence signals. Cellular structures were clearly observed at the PRL, ONL, INL, and GCL. At the PRL, the autofluorescence was dominantly recorded from the intracellular compartment of the photoreceptors; while mixed intracellular and extracellular autofluorescence signals were observed at the ONL, INL, and GCL. High resolution autofluorescence imaging clearly revealed mosaic organization of rod and cone photoreceptors; and sub-cellular bright autofluorescence spots, which might relate to connecting cilium, was observed in the cone photoreceptors only. Moreover, single-cone and double-cone outer segments could be directly differentiated.