Insights into APC/C: From cellular function to diseases and therapeutics

Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that targets different substrates for ubiquitylation and therefore regulates a variety of cellular processes such as cell division, differentiation, genome stability, energy metabolism, cell death, autophagy as well as carcinogenesis. Activity of APC/C is principally governed by two WD-40 domain proteins, Cdc20 and Cdh1, in and beyond cell cycle. In the past decade, the results based on numerous biochemical, 3D structural, mouse genetic and small molecule inhibitor studies have largely attracted our attention into the emerging role of APC/C and its regulation in biological function, human diseases and potential therapeutics. This review will aim to summarize some recently reported insights into APC/C in regulating cellular function, connection of its dysfunction with human diseases and its implication of therapeutics

Prevalence of Hypertension and Association of Obesity with Hypertension in School Ggoing Children of Surat City, Western India.

Purpose: The association of obesity with hypertension has been recognized for the decades which are the important risk factors for the cardiovascular disease. So the purpose of the present study was to determine association of obesity with hypertension in school going children of Surat. Methodology: School going children aged between 12-18 years, of five schools in Surat were selected for the study. Height and weight were measured and BMI was calculated. Blood pressure measurements were taken as per recommendation of American heart society and family history of hypertension has also been assessed. Hypertension was considered if blood pressure is more than 95th percentile according to the update of task force report and Obesity was diagnosed by BMI for age. Results: Of 682 children, 8.94% were obese and 20.09% were hypertensive. Conclusion: Obesity is strongly associated with hypertension in children and both together may risk factors for later coronary disease

Mortality associated with avian reovirus infection in a free-living magpie (Pica pica) in Great Britain

Avian reoviruses (ARVs) cause a range of disease presentations in domestic, captive and free-living bird species. ARVs have been reported as a cause of significant disease and mortality in free-living corvid species in North America and continental Europe. Until this report, there have been no confirmed cases of ARV-associated disease in British wild birds

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field

The state of ambient air quality in Pakistan—a review

Background and purpose: Pakistan, during the last decade, has seen an extensive escalation in population growth, urbanization, and industrialization, together with a great increase in motorization and energy use. As a result, a substantial rise has taken place in the types and number of emission sources of various air pollutants. However, due to the lack of air quality management capabilities, the country is suffering from deterioration of air quality. Evidence from various governmental organizations and international bodies has indicated that air pollution is a significant risk to the environment, quality of life, and health of the population. The Government has taken positive steps toward air quality management in the form of the Pakistan Clean Air Program and has recently established a small number of continuous monitoring stations. However, ambient air quality standards have not yet been established. This paper reviews the data being available on the criteria air pollutants: particulate matter (PM), sulfur dioxide, ozone, carbon monoxide, nitrogen dioxide, and lead. Methods: Air pollution studies in Pakistan published in both scientific journals and by the Government have been reviewed and the reported concentrations of PM, SO2, O3, CO, NO2, and Pb collated. A comparison of the levels of these air pollutants with the World Health Organization air quality guidelines was carried out. Results: Particulate matter was the most serious air pollutant in the country. NO2 has emerged as the second high-risk pollutant. The reported levels of PM, SO2, CO, NO2, and Pb were many times higher than the World Health Organization air quality guidelines. Only O3 concentrations were below the guidelines. Conclusions: The current state of air quality calls for immediate action to tackle the poor air quality. The establishment of ambient air quality standards, an extension of the continuous monitoring sites, and the development of emission control strategies are essential. © Springer-Verlag 2009

Hidden Orbital Order in URu2Si2URu_{2}Si_{2}

When matter is cooled from high temperatures, collective instabilities develop amongst its constituent particles that lead to new kinds of order. An anomaly in the specific heat is a classic signature of this phenomenon. Usually the associated order is easily identified, but sometimes its nature remains elusive. The heavy fermion metal $URu_2Si_2$ is one such example, where the order responsible for the sharp specific heat anomaly at $T_0=17 K$ has remained unidentified despite more than seventeen years of effort. In $URu_{2}Si_{2}$, the coexistence of large electron-electron repulsion and antiferromagnetic fluctuations in $URu_2Si_2$ leads to an almost incompressible heavy electron fluid, where anisotropically paired quasiparticle states are energetically favored. In this paper we use these insights to develop a detailed proposal for the hidden order in $URu_2Si_2$. We show that incommensurate orbital antiferromagnetism, associated with circulating currents between the uranium ions, can account for the local fields and entropy loss observed at the $17 K$ transition; furthermore we make detailed predictions for neutron scattering measurements

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed

An investigation into anterior segment anatomy and genetics of pigment dispersion syndrome

Pigment dispersion syndrome (PDS) is an ocular condition predisposing to glaucomatous optic neuropathy in patients at a relatively young age. Concavity of the iris is considered to be important in the pathogenesis of PDS, however, it is also appears to be a feature of non-PDS eyes, particularly in young myopes. Much of the current understanding of anterior segment anatomy is derived from studies using ultrasound biomicroscopy, a relatively invasive imaging modality that involves direct ocular contact. Anterior-segment optical coherence tomography (AS-OCT) allows imaging of the anterior segment with the patient in the upright position without the need for contact with the ocular surface. AS-OCT may allow a more physiological assessment of anterior segment anatomy as well as being better suited to paediatric subjects. AS-OCT was used to conduct a case-control study of anterior segment anatomy in PDS subjects and age-, sex- and refraction- matched controls to determine which features of anterior segment anatomy best discriminated between the 2 groups. In addition AS-OCT was used to assess anterior segment anatomy, with particular emphasis on iris curvature, in a cohort of 10-12 year old school children and explore correlations with ocular biometry and parameters reflecting corneal biomechanical properties. Longitudinal data was collected through re-visiting the cohort 2 years later. Chromosomal susceptibility loci for PDS have been described, although no causative gene has been identified. Two approaches were used to identify novel disease susceptibility loci: 1) linkage analysis was used in a 3-generation family segregating for PDS/pigmentary glaucoma, and, 2) DNA from a large cohort of unrelated PDS probands was collected and sent for genotyping with a view to conducting a pilot genome-wide association study. Finally a candidate gene, GPNMB, the human homologue of a causative gene in a mouse model of pigmentary glaucoma was sequenced in a panel of 96 unrelated PDS/pigmentary glaucoma subjects