Function of psoriasis susceptibility gene CCHCR1

Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, neoangiogenesis and inflammation. Its etiology is multifactorial, as both the environmental and genetic factors have an important role in the pathogenesis of psoriasis. The exact disease mechanism behind psoriasis still remains unknown. The most important genetic susceptibility region for psoriasis has been located to PSORS1 locus in chromosome 6. The area includes multiply good candidate genes but the strong linkage disequilibrium between them has made genetic studies difficult. One of the candidate genes in PSORS1 is CCHCR1, which has a psoriasis-associated gene form CCHCR1*WWCC. The aim of the study was to elucidate the function of CCHCR1 and its potential role in the pathogenesis of psoriasis. In this study, transgenic mice expressing either the healthy or psoriasis-associated gene form of CCHCR1 were engineered and characterized. Mice were phenotypically normal but their gene expression profiles revealed many similarities to that observed in human psoriatic skin. In addition, the psoriasis-associated gene form had specific impacts on the expression of many genes relevant to the pathogenesis of psoriasis. We also challenged the skin of CCHCR1 transgenic mice with wounding or 12-O-tetradecanoylphorbol-13-acetate (TPA). The experiments revealed that CCHCR1 impacts on keratinocyte proliferation by limiting it. In addition, we demonstrated that CCHCR1 has a role in steroidogenesis and showed that both CCHCR1 forms promote synthesis of steroids. Also many agents relevant either for steroidogenesis or cell proliferation were shown to regulate the expression level of CCHCR1. The present study showed that CCHCR1 has functional properties relevant in the context of psoriasis. Firstly, CCHCR1 affects proliferation of keratinocytes as it may function as a negative regulator of keratinocyte proliferation. Secondly, CCHCR1 also has a role in steroidogenesis, a function relevant both in the pathogenesis of psoriasis and regulation of cell proliferation. This study suggests that aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis.

Immunodeficiencies, pathogens and sex in upper respiratory diseases

In the first part of this thesis the association of different forms of sinonasal diseases and plasma concentrations of C3, C4, immunoglobulins, immunoglobulin G subclasses, C4A and C4B gene numbers were studied in 287 adult patients and 150 sex-matched adult controls. Patients were well characterized and stratified into groups using strict clinical criteria and females and males were also studied as separate groups. Severe primary antibody antibody deficiencies were rare in patients coming to sinonasal operations. Female patients had more recurrent sinusitis and other mucosal infections and males had more nasal polyposis. Upregulation of complement activity was seen in acute rhinosinusitis patients (high levels of plasma C3, C4, and complement classical pathway activity CH50) and male patients coming to sinonasal operations (high levels of plasma C3 and C4). In females, total and partial C4B deficiencies and lower levels of IgG1 and IgG3 were associated with rhinosinusitis leading to sinonasal operations. C4A deficiencies were found to predispose to severe chronic rhinosinusitis in females and males. In female patients with chronic or recurrent rhinosinusitis with nasal polyposis C4B deficiencies seem to predispose to the disease, but in males with a similar disease C4B deficiencies seem to be protective. This suggests a different pathophysiology between sexes in this form of sinonasal disease. In the second part of this thesis work 213 children coming to elective tonsillectomy were studied and compared with 155 randomly selected school children. An association with recurrent upper respiratory tract infections and hypersensitivity disorders was seen especially in children under 7 years of age. However, this association was not seen in levels of specific IgE to respiratory allergens in the same age group. Both symptomatic respiratory allergy and specific IgE to respiratory allergens became more common in boys than girls over 7 years of age. We were able to show that although both rhinoviruses and bacterial pathogens were found in the tonsils, no association between their presence and clinical forms of tonsillar disease was seen. The ability of GAS to bind complement regulators FH and C4BP did not differ between strains causing tonsillar diseases or septicemia, suggesting that other virulence mechanisms of the bacteria are more important.

Dynamic structure factor across the liquid-solid interface: appearance of a delta-function elastic peak

We present a theoretical calculation of the dynamic structure factor, S(k, ω), at the liquid-solid interface for large values of the wavevector k. An analytic expression is derived which shows the evolution of the elastic peak as the solid surface is approached from the liquid side.

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Brownian particles in stationary and moving traps: The mean and variance of the heat distribution function

A recent theoretical model developed by Imparato et al. Phys of the experimentally measured heat and work effects produced by the thermal fluctuations of single micron-sized polystyrene beads in stationary and moving optical traps has proved to be quite successful in rationalizing the observed experimental data. The model, based on the overdamped Brownian dynamics of a particle in a harmonic potential that moves at a constant speed under a time-dependent force, is used to obtain an approximate expression for the distribution of the heat dissipated by the particle at long times. In this paper, we generalize the above model to consider particle dynamics in the presence of colored noise, without passing to the overdamped limit, as a way of modeling experimental situations in which the fluctuations of the medium exhibit long-lived temporal correlations, of the kind characteristic of polymeric solutions, for instance, or of similar viscoelastic fluids. Although we have not been able to find an expression for the heat distribution itself, we do obtain exact expressions for its mean and variance, both for the static and for the moving trap cases. These moments are valid for arbitrary times and they also hold in the inertial regime, but they reduce exactly to the results of Imparato et al. in appropriate limits. DOI: 10.1103/PhysRevE.80.011118 PACS.

The Myopathic Protein Myotilin in Developing Mouse and in Muscle Function

Skeletal muscle cells are highly specialised in order to accomplish their function. During development, the fusion of hundreds of immature myoblasts creates large syncytial myofibres with a highly ordered cytoplasm filled with packed myofibrils. The assembly and organisation of contractile myofibrils must be tightly controlled. Indeed, the number of proteins involved in sarcomere building is impressive, and the role of many of them has only recently begun to be elucidated. Myotilin was originally identified as a high affinity a-actinin binding protein in yeast twohybrid screen. It was then found to interact also with filamin C, actin, ZASP and FATZ-1. Human myotilin is mainly expressed in striated muscle and induces efficient actin bundling in vitro and in cells. Moreover, mutations in myotilin cause different forms of muscle disease, now collectively known as myotilinopathies. In this thesis, consisting of three publications, the work on the mouse orthologue is presented. First, the cloning and molecular characterisation of the mouse myotilin gene showed that human and mouse myotilin share high sequence homology and a similar expression pattern and gene regulation. Functional analysis of the mouse promoter revealed the myogenic factor-binding elements that are required for myotilin gene transcription. Secondly, expression of myotilin was studied during mouse embryogenesis. Surprisingly, myotilin was expressed in a wide array of tissues at some stages of development; its expression pattern became more restricted at perinatal stages and in adult life. Immunostaining of human embryos confirmed broader myotilin expression compared to the sarcomeric marker titin. Finally, in the third article, targeted deletion of myotilin gene in mice revealed that it is not essential for muscle development and function. These data altogether indicate that the mouse can be used as a model for human myotilinopathy and that loss of myotilin does not alter significantly muscle structure and function. Therefore, disease-associated mutant myotilin may act as a dominant myopathic factor.

Metallo crown porphyrins as ionophores-metal dependent uncoupling of mitochondrial energy potential

Porphyrins appended with crown ether moieties function as efficient uncouplesrs of oxidative phorphorylation in rat liver mitochondria. Permeation of these highly organized porphyrins decrease the respiratory coefficient index (RCI) values. Lowering of the RCI values parallels the number of K+ chelating crown ether groups attached to the porphyrins. The inhibitory effect upon the oxidative phorphorylation reaction depends on the nature of divalent metal ions, VO, Co, Cu and Zn in the porphyrin cavity and related to their relative tendency to complex intracellular K+ ions.

A Branch and Bound Algorithm for a Transportation Type Problem with Piecewise Linear Convex Objective Function

A branch and bound type algorithm is presented in this paper to the problem of finding a transportation schedule which minimises the total transportation cost, where the transportation cost over each route is assumed to be a piecewice linear continuous convex function with increasing slopes. The algorithm is an extension of the work done by Balachandran and Perry, in which the transportation cost over each route is assumed to beapiecewise linear discontinuous function with decreasing slopes. A numerical example is solved illustrating the algorithm.

Time evolution of graphene growth on SiC as a function of annealing temperature

We followed by X-ray Photoelectron Spectroscopy (XPS) the time evolution of graphene layers obtained by annealing 3C SiC(111)/Si(111) crystals at different temperatures. The intensity of the carbon signal provides a quantification of the graphene thickness as a function of the annealing time, which follows a power law with exponent 0.5. We show that a kinetic model, based on a bottom-up growth mechanism, provides a full explanation to the evolution of the graphene thickness as a function of time, allowing to calculate the effective activation energy of the process and the energy barriers, in excellent agreement with previous theoretical results. Our study provides a complete and exhaustive picture of Si diffusion into the SiC matrix, establishing the conditions for a perfect control of the graphene growth by Si sublimation.

Study of the structure and function of the sheath of tropically adapted bulls and risk factors for preputial eversion and preputial prolapse

Preputial prolapse is an obvious condition affecting bulls from many breeds. Unfortunately, the losses in production and welfare concerns associated with preputial prolapse can remain undetected for long periods of time in the extensive beef areas of northern Australia where the bulls are not inspected regularly. Thus, there is a critical need to identify the structural factors predisposing to preputial prolapse in young bulls so that they can be culled early. Despite there being no firm scientific evidence of an association between preputial eversion and preputial prolapse, it seems logical that the increased exposure of the sensitive prepuce as a consequence of preputial eversion may increase the risk of bulls developing preputial pathology, in particular preputial prolapse. This may be particularly relevant in Bos indicus bulls as they have a more pendulous sheath and thus eversion of the prepuce may be associated with a greater risk of injury to the prepuce compared to that in Bos taurus bulls. Further, studies of preputial eversion in Bos taurus bulls have concluded that there is an association between polledness and increased prevalence and severity (length of everted prepuce and duration of eversion) of preputial eversion due primarily to the absence or poor development of the caudal preputial muscles. No similar definitive work in Bos indicus bulls has been conducted and thus anatomical studies reported in this thesis were conducted to determine if a similar association occurred in Bos indicus bulls. A survey of a sample of large beef breeding herds in northern Australia found that preputial prolapse is a significant problem in Bos indicus and Bos indicus derived bulls and affected both young and older bulls. The importance of preputial prolapse confirmed the value of further research into the causes of this problem. A series of anatomical studies confirmed that preputial eversion in Bos indicus derived bulls was not more prevalent in polled bulls than horned bulls and was not associated with deficiency of the caudal preputial muscles as was established in Bos taurus bulls. An anatomical study of Bos indicus derived bulls with preputial prolapse found that preputial prolapse occurred in horned bulls of varying ages and these bulls did not have any evidence of deficiency in the caudal preputial muscles. However, preputial prolapse was observed in young polled bulls that had poorly developed or absent caudal preputial muscles. It was concluded that deficiency of the caudal preputial muscles in polled Bos indicus derived bulls may predispose to preputial prolapse at an early age, but no predisposing anatomical factors were found for horned Bos indicus derived bulls. In these studies, preputial eversion and preputial prolapse were found in horned Bos indicus derived bulls that did not have any preputial muscle deficiency and it was noted that preputial eversion was not related to the length of the prepuce. Further studies confirmed that preputial eversion was linearly and consistently associated with position of the glans penis within the sheath in Bos indicus derived bulls, and movement of the glans penis towards the preputial orifice consistently resulted in preputial eversion in these bulls. A method to objectively measure the relationship between movement of the glans penis within the sheath and preputial eversion was developed. Studies in humans have linked function of some abdominal muscles to function of the pelvic organs. This relationship was investigated in Bos indicus derived bulls to determine whether the function of specific abdominal muscles affected position of the penis in the sheath. Using the method developed to objectively measure the relationship between penis movement and preputial eversion, the abdominal muscles that potentially were associated with movement of the glans penis or preputial eversion were examined but no significant relationships were observed. In the anatomical study of Bos indicus derived bulls not affected with preputial prolapse a more pendulous sheath was associated with increased prevalence of preputial eversion. This relationship was confirmed for horned and polled bulls in the penis movement studies. Bos indicus derived bulls with more pendulous sheaths evert their prepuces more than bulls with less pendulous sheaths thus increasing the risk of damage to the prepuce either from the environment, other bulls, or from them inadvertently stepping on the everted prepuce when they get to their feet. Culling Bos indicus derived bulls with more pendulous sheaths should reduce the incidence of preputial eversion and possibly preputial prolapse. The anatomical study of Bos indicus derived bulls that did not have preputial prolapse demonstrates that there are herds of bulls where the polled bulls do not have any evidence of deficiency of the caudal preputial iv muscles. There is a need to develop a practical and cost effective test to identify polled Bos indicus bulls that have a deficiency in their caudal preputial muscles.

Animal-Level Factors Affecting Ovarian Function in Bos indicus Heifers Treated to Synchronize Ovulation with Intravaginal Progesterone-Releasing Devices and Oestradiol Benzoate

The primary objective of this study was to investigate the impact of animal-level factors including energy balance and environmental/management stress, on the ovarian function of Bos indicus heifers treated to synchronize ovulation. Two-year-old Brahman (BN) (n = 30) and BN-cross (n = 34) heifers were randomly allocated to three intravaginal progesterone-releasing device (IPRD) treatment groups: (i) standard-dose IPRD [Cue-Mate (R) (CM) 1.56 g; n = 17]; (ii) half-dose IPRD [0.78 g progesterone (P4); CM 0.78 g; n = 15]; (iii) half-dose IPRD + 300 IU equine chorionic gonadotrophin at IPRD removal (CM 0.78 g + G; n = 14); (iv) and a control group, 2x PGF2a [500 mu g prostaglandin F2a (PGF2a)] on Day -16 and -2 (n = 18). Intravaginal progesterone-releasing device-treated heifers received 250 mu g PGF2a at IPRD insertion (Day -10) and IPRD removal (Day -2) and 1 mg oestradiol benzoate on Day -10 and -1. Heifers were managed in a small feedlot and fed a defined ration. Ovarian function was evaluated by ultrasonography and plasma P4 throughout the synchronized and return cycles. Energy balance was evaluated using plasma insulin-like growth factor 1 (IGF-I) and glucose concentrations. The impact of environmental stressors was evaluated using plasma cortisol concentration. Heifers that had normal ovarian function had significantly higher IGF-I concentrations at commencement of the experiment (p = 0.008) and significantly higher plasma glucose concentrations at Day -2 (p = 0.040) and Day 4 (p = 0.043), than heifers with abnormal ovarian function. There was no difference between the mean pre-ovulatory cortisol concentrations of heifers that ovulated or did not ovulate. However, heifers that ovulated had higher cortisol concentrations at Day 4 (p = 0.056) and 6 (p = 0.026) after ovulation than heifers that did not ovulate.

Approximate analysis of coupled non-linear non-conservative systems subjected to step-function excitation

The paper deals with the approximate analysis of non-linear non-conservative systems oftwo degrees of freedom subjected to step-function excitation. The method of averaging of Krylov and Bogoliubov is used to arrive at the approximate equations for amplitude and phase. An example of a spring-mass-damper system is presented to illustrate the method and a comparison with numerical results brings out the validity of the approach.

Is Mycoplasma bovis a missing component of the bovine respiratory disease complex in Australia?

Background: Bovine respiratory disease complex (BRDC) is a multi-factorial disease in which numerous factors, such as animal management, pathogen exposure and environmental conditions, contribute to the development of acute respiratory illness in feedlot cattle. The role of specific pathogens in the development of BRDC has been difficult to define because of the complex nature of the disease and the presence of implicated bacterial pathogens in the upper respiratory tract of healthy animals. Mycoplasma bovis is an important pathogen of cattle and recognised as a major contributor to cases of mastitis, caseonecrotic bronchopneumonia, arthritis and otitis media. To date, the role of M.bovis in the development of BRDC of Australian feeder cattle has not been investigated. Methods: In this review, the current literature pertaining to the role of M.bovis in BRDC is evaluated. In addition, preliminary data are presented that identify M.bovis as a potential contributor to BRDC in Australian feedlots, which has not been considered previously. Results and Conclusion: The preliminary results demonstrate detection of M.bovis in samples from all feedlots studied. When considered in the context of the reviewed literature, they support the inclusion of M.bovis on the list of pathogens to be considered during investigations into BRDC in Australia. © 2014 Australian Veterinary Association.

Exercise and vascular function in child obesity: A meta-analysis

CONTEXT: Conduit artery flow-mediated dilation (FMD) is a noninvasive index of preclinical atherosclerosis in humans. Exercise interventions can improve FMD in both healthy and clinical populations. OBJECTIVE: This systematic review and meta-analysis aimed to summarize the effect of exercise training on FMD in overweight and obese children and adolescents as well as investigate the role of cardiorespiratory fitness (peak oxygen consumption [Vo2peak]) on effects observed. DATA SOURCES: PubMed, Medline, Embase, and Cinahl databases were searched from the earliest available date to February 2015. STUDY SELECTION: Studies of children and/or adolescents who were overweight or obese were included. DATA EXTRACTION: Standardized data extraction forms were used for patient and intervention characteristics, control/comparator groups, and key outcomes. Procedural quality of the studies was assessed using a modified version of the Physiotherapy Evidence Base Database scale. RESULTS: A meta-analysis involving 219 participants compared the mean difference of pre- versus postintervention vascular function (FMD) and Vo2peak between an exercise training intervention and a control condition. There was a significantly greater improvement in FMD (mean difference 1.54%, P < .05) and Vo2peak (mean difference 3.64 mL/kg/min, P < .05) after exercise training compared with controls. LIMITATIONS: Given the diversity of exercise prescriptions, participant characteristics, and FMD measurement protocols, varying FMD effect size was noted between trials. CONCLUSIONS: Exercise training improves vascular function in overweight and obese children, as indicated by enhanced FMD. Further research is required to establish the optimum exercise program for maintenance of healthy vascular function in this at-risk pediatric population.