Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown

Patterning of light-emitting conjugated polymer nanofibres.

Organic materials have revolutionized optoelectronics by their processability, flexibility and low cost, with application to light-emitting devices for full-colour screens, solar cells and lasers. Some low-dimensional organic semiconductor structures exhibit properties resembling those of inorganics, such as polarized emission and enhanced electroluminescence. One-dimensional metallic, III-V and II-VI nanostructures have also been the subject of intense investigation as building blocks for nanoelectronics and photonics. Given that one-dimensional polymer nanostructures, such as polymer nanofibres, are compatible with sub-micrometre patterning capability and electromagnetic confinement within subwavelength volumes, they can offer the benefits of organic light sources to nanoscale optics. Here we report on the optical properties of fully conjugated, electrospun polymer nanofibres. We assess their waveguiding performance and emission tuneability in the whole visible range. We demonstrate the enhancement of the fibre forward emission through imprinting periodic nanostructures using room-temperature nanoimprint lithography, and investigate the angular dispersion of differently polarized emitted light

Invasion and MMP expression profile in desmoid tumours

Desmoid tumours are locally invasive soft tissue tumours in which beta-catenin mediated TCF-dependent transcription is activated. The role of soluble factors secreted by the myofibroblastic desmoid tumour, which could stimulate tumour invasiveness, was investigated. Using collagen gel invasion assays, the presence of factors stimulating invasion in desmoid conditioned media (CM) could be established. Since matrix metalloproteinases (MMPs) have been implicated in the process of tumoral invasion, the expression levels of the MMP family members were evaluated. Quantitative reverse transcription-PCR was used to determine the expression levels of MMP1, MMP2, MMP3, MMP7, MMP11, MMP12, MMP13, MMP14 and the inhibitors TIMP1, TIMP2 and TIMP3. Besides overexpression of MMP7, a known TCF-dependent target gene, a striking upregulation of the expression levels of MMP1, MMP3, MMP11, MMP12 and MMP13 in desmoid tumours, compared to unaffected fibroblasts from the same patients, was found. Treating the CM of desmoids with a synthetic and a physiologic MMP inhibitor reduced the invasion-stimulating capacity of the desmoid CM by approximately 50%. These results suggest the involvement of soluble factors, released by the desmoid cells, in stimulating invasion and implicate the MMPs as facilitators of invasion

Differential Expression of Alpha 4 Integrins on Effector Memory T Helper Cells during Bordetella Infections. Delayed Responses in Bordetella pertussis

Bordetella pertussis (B. pertussis) is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX) to test the hypothesis that effector memory T-helper cells (emTh) display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i.) with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4β7 and α4β1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs) from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7+ DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4+ cells expressing α4β1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease

Human Endometrial CD98 Is Essential for Blastocyst Adhesion

BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window

Space Telescope and Optical Reverberation Mapping Project. V. Optical Spectroscopic Campaign and Emission-line Analysis for NGC 5548

We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 +-optical continuum by 4.17+0.36-0.36 and 0.79+0.35-0.34 days, respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Lyα, He ii(+O iii]), and Si iv(+O iv]) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the R BLR-L AGN relation based on the past behavior of NGC 5548

Assessment of Yellow Fever Epidemic Risk: An Original Multi-criteria Modeling Approach

This article describes the use of an original modeling approach to assess the risk of yellow fever (YF) epidemics. YF is a viral hemorrhagic fever responsible in past centuries for devastating outbreaks. Since the 1930s, a vaccine has been available that protects the individual for at least 10 years, if not for life. However, immunization of populations in African countries was gradually discontinued after the 1960s. With the decrease in immunity against YF in African populations the disease reemerged in the 1980s. In 2005, WHO, UNICEF, and the GAVI Alliance decided to support preventive vaccination of at-risk populations in West African endemic countries in order to tackle the reemergence of YF and reduce the risk of urban YF outbreaks. Financial resources were made available to scale up a global YF vaccine stockpile and to support countries with limited resources in the management of preventive vaccination campaigns. This article describes the process we used to determine the most at-risk populations using a mathematical model to prioritize targeted immunization campaigns. We believe that this approach could be useful for other diseases for which decision making process is difficult because of limited data availability, complex risk variables, and a need for rapid decisions and implementation

The synthetic bacterial lipopeptide Pam3CSK4 modulates respiratory syncytial virus infection independent of TLR activation

Respiratory syncytial virus (RSV) is an important cause of acute respiratory disease in infants, immunocompromised subjects and the elderly. However, it is unclear why most primary RSV infections are associated with relatively mild symptoms, whereas some result in severe lower respiratory tract infections and bronchiolitis. Since RSV hospitalization has been associated with respiratory bacterial co-infections, we have tested if bacterial Toll-like receptor (TLR) agonists influence RSVA2- GFP infection in human primary cells or cell lines. The synthetic bacterial lipopeptide Pam3-Cys-Ser-Lys4 (Pam3CSK4), the prototype ligand for the heterodimeric TLR1/TLR2 complex, enhanced RSV infection in primary epithelial, myeloid and lymphoid cells. Surprisingly, enhancement was optimal when lipopeptides and virus were added simultaneously, whereas addition of Pam3CSK4 immediately after infection had no effect. We have identified two structurally related lipopeptides without TLR-signaling capacity that also modulate RSV infection, whereas Pam3CSK4-reminiscent TLR1/2 agonists did not, and conclude that modulation of infection is independent of TLR activation. A similar TLR-independent enhancement of infection could also be demonstrated for wild-type RSV strains, and for HIV-1, measles virus and human metapneumovirus. We show that the effect of Pam3CSK4 is primarily mediated by enhanced binding of RSV to its target cells. The Npalmitoylated cystein

Tremor in multiple sclerosis

Tremor is estimated to occur in about 25 to 60 percent of patients with multiple sclerosis (MS). This symptom, which can be severely disabling and embarrassing for patients, is difficult to manage. Isoniazid in high doses, carbamazepine, propranolol and gluthetimide have been reported to provide some relief, but published evidence of effectiveness is very limited. Most trials were of small size and of short duration. Cannabinoids appear ineffective. Tremor reduction can be obtained with stereotactic thalamotomy or thalamic stimulation. However, the studies were small and information on long-term functional outcome is scarce. Physiotherapy, tremor reducing orthoses, and limb cooling can achieve some functional improvement. Tremor in MS remains a significant challenge and unmet need, requiring further basic and clinical research

Space Telescope and Optical Reverberation Mapping Project. IX. Velocity–Delay Maps for Broad Emission Lines in NGC 5548

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity–delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity–delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5–10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s−1 in the 10–20 lt-day delay range. An incomplete ellipse in the velocity–delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay $\tau =(R/c)(1-\sin i)\approx 5$ days gives the inclination i ≈ 45°. The inferred black hole mass is MBH ≈ 7 × 107 M⊙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday" identified in previous work. Moreover, a helical "Barber-Pole" pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out