Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis

OBJECTIVE: To analyze the expression, regulation, and biologic relevance of Toll-like receptors (TLRs) 1-10 in synovial and skin fibroblasts and to determine the expression levels of TLRs 2, 3, and 4 in synovial tissues from patients with early rheumatoid arthritis (RA), longstanding RA, and osteoarthritis (OA). METHODS: Expression of TLRs 1-10 in RA synovial fibroblasts (RASFs), OASFs, and skin fibroblasts was analyzed by real-time polymerase chain reaction (PCR). Fibroblasts were stimulated with tumor necrosis factor alpha, interleukin-1beta (IL-1beta), bacterial lipopeptide, poly(I-C), lipopolysaccharide, and flagellin. Production of IL-6 was determined by enzyme-linked immunosorbent assay and induction of TLRs 2-5, matrix metalloproteinases (MMPs) 3 and 13 messenger RNA by real-time PCR. Expression of TLRs 2-4 in synovial tissues was analyzed by immunohistochemistry. RESULTS: Synovial fibroblasts expressed TLRs 1-6, but not TLRs 7-10. Among the expressed TLRs, TLR-3 and TLR-4 were the most abundant in synovial fibroblasts, and stimulation of synovial fibroblasts with the TLR-3 ligand poly(I-C) led to the most pronounced increase in IL-6, MMP-3, and MMP-13. In contrast, skin fibroblasts did not up-regulate MMP-3 or MMP-13 after stimulation with any of the tested stimuli. In synovial tissues from patients with early RA, TLR-3 and TLR-4 were highly expressed and were comparable to the levels of patients with longstanding RA. These expression levels were elevated as compared with those in OA. CONCLUSION: Our findings of high expression of TLRs, particularly TLRs 3 and 4, at an early stage of RA and the reactivity of synovial fibroblasts in vitro to TLR ligands suggest that TLR signaling pathways resulting in persistent inflammation and joint destruction are activated early in the disease process

Antimüllerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking

To evaluate exposure to tobacco, marijuana and indoor heating/cooking sources in relation to anti-Müllerian hormone (AMH) levels

Distributed feedback InGaN/GaN laser diodes

We have realised InGaN/GaN distributed feedback laser diodes emitting at a single wavelength in the 42X nm wavelength range. Laser diodes based on Gallium Nitride (GaN) are useful devices in a wide range of applications including atomic spectroscopy, data storage and optical communications. To fully exploit some of these application areas there is a need for a GaN laser diode with high spectral purity, e.g. in atomic clocks, where a narrow line width blue laser source can be used to target the atomic cooling transition. Previously, GaN DFB lasers have been realised using buried or surface gratings. Buried gratings require complex overgrowth steps which can introduce epi-defects. Surface gratings designs, can compromise the quality of the p-type contact due to dry etch damage and are prone to increased optical losses in the grating regions. In our approach the grating is etched into the sidewall of the ridge. Advantages include a simpler fabrication route and design freedom over the grating coupling strength.Our intended application for these devices is cooling of the Sr+ ion and for this objective the laser characteristics of SMSR, linewidth, and power are critical. We investigate how these characteristics are affected by adjusting laser design parameters such as grating coupling coefficient and cavity length

Recent progress in distributed feedback InGaN/GaN laser diodes

Laser diodes based on Gallium Nitride (GaN) are useful devices in a wide range of applications including atomic spectroscopy, data storage and optical communications. To fully exploit some of these application areas there is a need for a GaN laser diode with high spectral purity, e.g. in atomic clocks, where a narrow linewidth blue laser source can be used to target the atomic cooling transition. We report on the continuous wave, room temperature operation of a distributed feedback laser diode (DFB-LD) with high-order notched gratings. The design, fabrication and characterization of DFB devices based on the (Al,In) GaN material system is described. A single peak emission at 408.6 nm with an optical power of 20 mW at 225 mA and a side mode suppression ratio (SMSR) of 35 dB was achieved. Additionally, we demonstrate the use of a GaN DFB-LD as a transmitter in visible optical communications system. We also present results from a DFB-LD optimized for laser cooling of Sr+

GaN-based distributed feedback laser diodes for optical communications

Over the past 20 years, research into Gallium Nitride (GaN) has evolved from LED lighting to Laser Diodes (LDs), with applications ranging from quantum to medical and into communications. Previously, off-the-shelf GaN LDs have been reported with a view on free space and underwater communications. However, there are applications where the ability to select a single emitted wavelength is highly desirable, namely in atomic clocks or in filtered free-space communications systems. To accomplish this, Distributed Feedback (DFB) geometries are utilised. Due to the complexity of overgrowth steps for buried gratings in III-Nitride material systems, GaN DFBs have a grating etched into the sidewall to ensure single mode operation, with wavelengths ranging from 405nm to 435nm achieved. The main motivation in developing these devices is for the cooling of strontium ions (Sr+) in atomic clock applications, but their feasibility for optical communications have also been investigated. Data transmission rates exceeding 1 Gbit/s have been observed in unfiltered systems, and work is currently ongoing to examine their viability for filtered communications. Ultimately, transmission through Wavelength Division Multiplexing (WDM) or Orthogonal Frequency Division Multiplexing (OFDM) is desired, to ensure that data is communicated more coherently and efficiently. We present results on the characterisation of GaN DFBs, and demonstrate their capability for use in filtered optical communications systems

Applications of Single Frequency Blue Lasers

Gallium nitride (GaN) sources are becoming a regular part of today's world and are now key devices for lighting infrastructures, communications systems and quantum applications, amongst others. In particular, many applications have seen the shift from LEDs to laser diodes to make use of higher powers, higher bandwidths and increased transmission distances. Laser communication systems are well established, however there are applications where the ability to select a single emitted wavelength is highly desirable, such as quantum atomic clocks or in filtered communication systems. Distributed feedback (DFB) lasers have been realised emitting at a single wavelength where the grating structure is etched into the sidewall of the ridge. The main motivation in developing these lasers is for the cooling of ions in atomic clocks; however their feasibility for optical communications is also explored. Narrow linewidth lasers are desirable and this paper will explore how this is achieved. Data rates in excess of 1 Gbit/s have also been achieved in a directly modulated, unfiltered system. These devices lend themselves towards wavelength division multiplexing and filtered optical communications systems and this will be analysed further in the work presented here

Long Sun-Exposures Influencing High Sub-Cutaneous Synthesis of Vitamin-D3 may be Associated with Exacerbation of Symptoms in Allergic-Asthma.

Does excessive sun-exposure, non-use of sunscreen and/or high doses of vitamin-D3 supplements provoke exacerbation of asthma? Clinical examinations, retrospective records-access and questionnaire surveys were distributed to a convenience sample of allergic-asthma patient (n=183). Patients (19-89 years) attending the outpatient respiratory clinics at Maidstone Hospital were enrolled. 90.3% of patients (total IgE levels ≥75 kU/L ; n=103) exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days presented with wheeze (χ2(1) = 7.46; p< 0.05) compared to only 9.7% patients of similar atopy-status, presenting with wheeze if exposed to sunlight of < 15 minutes per day for 6-7 days. 68.9% patients (with IgE levels ≥ 75 kU/L ; n=103), non-users of sunscreen (SPF 30 and above), exposed to direct sunlight of ≥ 15 minutes per day continuously for 6-7 days developed a wheeze, compared to fewer users of sunscreen (9.7%, n=103), exposed to the same duration of sunlight who developed asthma symptoms (p< 0.05). Vitamin-D3 supplementation in asthma-patients with clinical signs of hypovitaminosis-D (n=21), produced symptoms of morning chest-tightness (76.2%), allergic rhinitis (61.9%) and wheeze (100%), 2 weeks after initiation of treatment. Our results advocate direct sunlight exposure < 15 minutes per day and use of sunscreen as a novel approach to preventing atopic-asthma symptoms in allergic-asthma patients.. Activated vitamin-D3 is well-recognised to shift the immune-balance towards Th2 predominance, favouring allergic asthma. These results suggest that limiting subcutaneous synthesis of vitamin-D3 in asthma patients and re-addressing dosage of vitamin-D3 supplementation is necessary may contribute to prevent exacerbation of symptoms

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte– endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro- thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers

Background: Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. Methods:We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (\u3c7 vs ≥7) and race (European American vs. African American). Results: We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. Conclusions: This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak-to-null associations between balding status and intraprostatic sex hormones reaffirm differences in organ-specific sex hormone metabolism, implying that other sex steroid hormone-related factors (eg, androgen receptor) play important roles in organ-specific androgenic actions, and that other overlapping pathways may be involved in associations between the two complex conditions

Generic Insect Repellent Detector from the Fruit Fly Drosophila melanogaster

Background: Insect repellents are prophylactic tools against a number of vector-borne diseases. There is growing demand for repellents outperforming DEET in cost and safety, but with the current technologies R&amp;D of a new product takes almost 10 years, with a prohibitive cost of $30 million dollar in part due to the demand for large-scale synthesis of thousands of test compounds of which only 1 may reach the market. R&amp;D could be expedited and cost dramatically reduced with a molecular/physiological target to streamline putative repellents for final efficacy and toxicological tests. Methodology: Using olfactory-based choice assay we show here that the fruit fly is repelled by not only DEET, but also IR3535 and picaridin thus suggesting they might have ‘‘generic repellent detector(s),’ ’ which may be of practical applications in new repellent screenings. We performed single unit recordings from all olfactory sensilla in the antennae and maxillary palps. Although the ab3A neuron in the wild type flies responded to picaridin, it was unresponsive to DEET and IR3535. By contrast, a neuron housed in the palp basiconic sensilla pb1 responded to DEET, IR3535, and picaridin, with apparent sensitivity higher than that of the DEET detectors in the mosquitoes Culex quinquefasciatus and Aedes aegypti. DmOr42a was transplanted from pb1 to the ‘‘empty neuron’ ’ and showed to be sensitive to the three insect repellents. Conclusions: For the first time we have demonstrated that the fruit fly avoids not only DEET but also IR3535 and picaridin, and identified an olfactory receptor neuron (ORN), which is sensitive to these three major insect repellents. We have als