Compositionality, stochasticity and cooperativity in dynamic models of gene regulation

We present an approach for constructing dynamic models for the simulation of gene regulatory networks from simple computational elements. Each element is called a ``gene gate'' and defines an input/output-relationship corresponding to the binding and production of transcription factors. The proposed reaction kinetics of the gene gates can be mapped onto stochastic processes and the standard ode-description. While the ode-approach requires fixing the system's topology before its correct implementation, expressing them in stochastic pi-calculus leads to a fully compositional scheme: network elements become autonomous and only the input/output relationships fix their wiring. The modularity of our approach allows to pass easily from a basic first-level description to refined models which capture more details of the biological system. As an illustrative application we present the stochastic repressilator, an artificial cellular clock, which oscillates readily without any cooperative effects.Comment: 15 pages, 8 figures. Accepted by the HFSP journal (13/09/07

A Case of Familial Cutaneous Collagenoma

Familial cutaneous collagenoma is a rare hereditary disease that is inherited in an autosomal dominant pattern. It is characterized by early onset of multiple, skin-colored, sometimes hypopigmented cutaneous nodules, which initially show a symmetrical arrangement on the trunk, and later on the neck and upper limbs. We report on a case of a 45-year-old female who presented with multiple oval to round hypopigmented papules measuring 5~15 mm on her trunk. Histopathologically, the lesions showed an increased amount of collagen fibers and decreased, fragmented elastic fibers in the dermis. The skin lesions were diagnosed as familial cutaneous collagenoma and no treatment was administered. To the best of our knowledge, our case is the first reported case of familial cutaneous collagenoma (FCC) in the Korean literature

Shape-induced force fields in optical trapping

Advances in optical tweezers, coupled with the proliferation of two-photon polymerization systems, mean that it is now becoming routine to fabricate and trap non-spherical particles. The shaping of both light beams and particles allows fine control over the flow of momentum from the optical to mechanical regimes. However, understanding and predicting the behaviour of such systems is highly complex in comparison with the traditional optically trapped microsphere. In this Article, we present a conceptually new and simple approach based on the nature of the optical force density. We illustrate the method through the design and fabrication of a shaped particle capable of acting as a passive force clamp, and we demonstrate its use as an optically trapped probe for imaging surface topography. Further applications of the design rules highlighted here may lead to new sensors for probing biomolecule mechanics, as well as to the development of optically actuated micromachines

Efficacy, pharmacokinetic and pharmacodynamic evaluation of Apaziquone in the treatment of non- muscle invasive bladder cancer

Introduction: Apaziquone (also known as EO9 and Qapzola) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 minutes or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers

Initial development and validation of a mitochondrial disease quality of life scale.

Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach's α≥0.83) and construct validity

Should we perform systematic electrophysiological study in Steinert's disease?

Myotonic dystrophy type 1 (Steinert's disease) is a multisystem disorder with autosomal dominant inheritance. This disease is associated with the presence of an abnormal expansion of a cytosine thymine-guanine (CTG) trinucleotide repeat on chromosome 19q13.3. Because of rhythmic complications, the place for systematic electrophysiological study (EPS) has to be discussed

Effects of Infrared Radiation on Skin Photo-Aging and Pigmentation

Infrared radiation is increasingly and uncritically used for cosmetic and wellness purposes, despite the poorly understood biologic effects of such treatments on humans. In the present study, we investigated the effects of infrared radiation on collagen and elastin production in dermal fibroblasts, as well as the clinical and histopathologic effects of infrared radiation on photo-aged facial skin lesions. In order to determine the effects of infrared radiation on collagen and elastin production, dermal fibroblasts were exposed to infrared radiation for varying lengths of time and collagen and elastin contents were subsequently determined. Additionally, 20 patients with mild to moderate facial wrinkles and hyperpigmented lesions received daily treatments of far infrared radiation (900 to 1000 µm) for six-months. During the treatment, patients and a medical observer conducted independent photographic and clinical evaluations every 4 weeks, and skin biopsies were obtained for histological analysis at baseline and one month post-treatment. We found that the content of collagen and elastin produced by the fibroblasts increased after infrared radiation, and that this increase was proportional to the duration of irradiation exposure. Following 6 months of treatment, all patients reported good (51-75%) improvements in skin texture and roughness. Additionally, patients noted fair (25-50%) improvement in color tone of the skin; however, improvements in hyperpigmented lesions were not observed. Objective medical evaluation of the patients indicated that roughness and laxity were fairly improved, but there was no significant improvement in hyperpigmented lesions. Histological examination failed to reveal any differences as well. These results suggest that infrared radiation may have beneficial effects on skin texture and wrinkles by increasing collagen and elastin contents from the stimulated fibroblasts. Therefore, skin treatment with infrared radiation may be an effective and safe non-ablative remodeling method, and may also be useful in the treatment of photo-aged skin

Hyperhomocysteinemia and Low Folate and Vitamin B12 Are Associated with Vascular Dysfunction and Impaired Nitric Oxide Sensitivity in Morbidly Obese Patients.

There is a high prevalence of hyperhomocysteinemia that has been linked to high cardiovascular risk in obese individuals and could be attributed to poor nutritional status of folate and vitamin B12. We sought to examine the association between blood homocysteine (Hcy) folate, and vitamin B12 levels and vascular dysfunction in morbidly obese adults using novel ex vivo flow-induced dilation (FID) measurements of isolated adipose tissue arterioles. Brachial artery flow-mediated dilation (FMD) was also measured. Subcutaneous and visceral adipose tissue biopsies were obtained from morbidly obese individuals and non-obese controls. Resistance arterioles were isolated in which FID, acetylcholine-induced dilation (AChID), and nitric oxide (NO) production were measured in the absence or presence of the NO synthase inhibitor, L-NAME, Hcy, or the superoxide dismutase mimetic, TEMPOL. Our results demonstrated that plasma Hcy concentrations were significantly higher, while folate, vitamin B12, and NO were significantly lower in obese subjects compared to controls. Hcy concentrations correlated positively with BMI, fat %, and insulin levels but not with folate or vitamin B12. Brachial and arteriolar vasodilation were lower in obese subjects, positively correlated with folate and vitamin B12, and inversely correlated with Hcy. Arteriolar NO measurements and sensitivity to L-NAME were lower in obese subjects compared to controls. Finally, Hcy incubation reduced arteriolar FID and NO sensitivity, an effect that was abolished by TEMPOL. In conclusion, these data suggest that high concentrations of plasma Hcy and low concentrations of folate and vitamin B12 could be independent predictors of vascular dysfunction in morbidly obese individuals