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81.
Donna S. Mackay Genevieve A. Wright Naushin H. Waseem Michel Michaelides Graham E. Holder Anthony G. Robson Anthony T. Moore Vincent Plagnol Andrew R. Webster 《Human mutation》2013,34(3):506-514
In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1‐like1, a photoreceptor‐specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease. 相似文献
82.
George E. A. Swann Virginia N. Panizzo Sebastiano Piccolroaz Vanessa Pashley Matthew S. A. Horstwood Sarah Roberts Elena Vologina Natalia Piotrowska Michael Sturm Andre Zhdanov Nikolay Granin Charlotte Norman Suzanne McGowan Anson W. Mackay 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(44):27211
Lake Baikal, lying in a rift zone in southeastern Siberia, is the world''s oldest, deepest, and most voluminous lake that began to form over 30 million years ago. Cited as the “most outstanding example of a freshwater ecosystem” and designated a World Heritage Site in 1996 due to its high level of endemicity, the lake and its ecosystem have become increasingly threatened by both climate change and anthropogenic disturbance. Here, we present a record of nutrient cycling in the lake, derived from the silicon isotope composition of diatoms, which dominate aquatic primary productivity. Using historical records from the region, we assess the extent to which natural and anthropogenic factors have altered biogeochemical cycling in the lake over the last 2,000 y. We show that rates of nutrient supply from deep waters to the photic zone have dramatically increased since the mid-19th century in response to changing wind dynamics, reduced ice cover, and their associated impact on limnological processes in the lake. With stressors linked to untreated sewage and catchment development also now impacting the near-shore region of Lake Baikal, the resilience of the lake’s highly endemic ecosystem to ongoing and future disturbance is increasingly uncertain.Ancient lakes have long been associated with both high levels of biodiversity and endemicity. However, they are also being threatened by anthropogenic forcings that have led to impacts ranging from the warming of lake waters (1), hydrological modifications (2), increases in aquatic toxicity (3), and declining endemic populations due to introductions of nonnative species (4). With global populations increasingly reliant on large and ancient lakes for ecosystem services, the biodiversity (5) and value of aquatic systems to society (6), particularly in ancient lake systems (7), are at risk. Lake Baikal (Russia) is an exceptional example of an ancient lake (Fig. 1). In addition to containing ∼20% of global surface freshwater, the lake is characterized by its high degree of biodiversity with over 2,500 flora and fauna, the majority of which are endemic (8). This has been attributed to the lake’s age and fully oxygenated water column, driven by seasonal overturning and deep water renewal (9, 10) that sustains an almost completely endemic deep water fauna (8).Open in a separate windowFig. 1.Location of Lake Baikal and its catchment (gray) together with the location of World Meteorological Organization station in Irkutsk, major catchment rivers (brown), coring sites (BAIK13-1, BAIK13-4), and sites providing additional data used in this study (BAIK13-7).Concerns exist over the future health of this unique ecosystem, amid evidence of extensive shoreline eutrophication (11, 12) and climate-induced shifts in primary productivity (13, 14). Together, these changes have impacted organisms ranging from sponges and gastropods to ciliates, flagellates, and algal communities (15). Given the likelihood of future anthropogenic disturbance on Lake Baikal, further disrupting productivity exchanges through the lake’s food web, there is a need to place these contemporary observations into their historical setting. In Lake Baikal, we have evidence that algal communities have undergone rapid multidecadal to multicentennial timescale changes over the last 2,000 y (16). However, there is a need to also gain a clearer insight into how biogeochemical and nutrient cycling has altered over the same timescale, both to contextualize natural and anthropogenic drivers of change and to understand the susceptibility of the lake’s ecosystem to further alteration under different climate states (17). Annual primary productivity in Lake Baikal is ultimately regulated by photic zone nutrient availability, in addition to ice/snow cover, which regulates light availability for photosynthesis (10, 18). Here, by analyzing the silicon isotope composition of diatom silica (δ30Sidiatom), we show that nutrient supply to the surface waters of Lake Baikal has rapidly increased through the 20th and 21st centuries coincident with increased wind-driven Ekman transport and reduced ice cover. These changes in photic zone nutrient availability have the potential to alter resource competition and prey–predator interactions across the lake (15, 19). 相似文献
83.
Kuang-Chun Hu Horng-Yuan Wang Sung-Chen Liu Chuan-Chuan Liu Chung-Lieh Hung Ming-Jong Bair Chun-Jen Liu Ming-Shiang Wu Shou-Chuan Shih 《World journal of gastroenterology : WJG》2014,20(24):7718-7729
Nonalcoholic fatty liver disease(NAFLD)refers to the accumulation of fat(mainly triglycerides)within hepatocytes.Approximately 20%-30%of adults in the general population in developed countries have NAFLD;this trend is increasing because of the pandemicity of obesity and diabetes,and is becoming a serious public health burden.Twenty percent of individuals with NAFLD develop chronic hepatic inflammation[nonalcoholic steatohepatitis(NASH)],which can be associated with the development of cirrhosis,portal hypertension,and hepatocellular carcinoma in a minority of patients.And thus,the detection and diagnosis of NAFLD is important for general practitioners.Liver biopsy is the gold standard for diagnosing NAFLD and confirming the presence of NASH.However,the invasiveness of this procedure limits its application to screening the general population or patients with contraindications for liver biopsy.The development of noninvasive diagnostic methods for NAFLD is of paramount importance.This review focuses on the updates of noninvasive diagnosis of NAFLD.Besides,we review clinical evidence supporting a strong association between NAFLD and the risk of cardiovascular disease because of the cross link between these two disorders. 相似文献
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85.
W. G. Mackay K. Smith C. Williams C. Chalmers R. Masterton 《European journal of clinical microbiology & infectious diseases》2014,33(12):2121-2130
The demographics of the healthcare population are changing, with an ever-greater proportion of people being treated outside the traditional hospital setting through community healthcare. This shift in the way that healthcare is delivered raises new concerns over community healthcare-associated infections (HCAIs). A literature search between 2000 and December 2013 was conducted in databases including PubMed, SciVerse ScienceDirect and Google Scholar. National and international guideline and policy documents were searched using Google. Many terms were used in the literature searches, including ‘nosocomial’, ‘healthcare infection’, ‘community’ and ‘nursing home’. The rates of HCAI in community healthcare are similar to the rates found in the acute hospital setting, but the types of infection differ, with a greater focus on urinary tract infections (UTIs) in the community and ventilator-associated pneumonias in the hospital setting. Patients who acquire a community HCAI are more likely to exhibit reduced physical condition, have increased levels of morbidity and have higher mortality rates than individuals without infection. Infection control programmes have been developed worldwide to reduce the rates of hospital HCAIs. Such interventions are equally as valid in the community, but how best to implement them and their subsequent impact are much less well understood. The future is clear: HCAIs in the community are going to become an ever-increasing burden and it is critical that our approach to these infections is brought quickly in line with present hospital sector standards. 相似文献
86.
C. Andersson C. S. Wenander P. A. Usher J. B. Hebsgaard B.‐C. Sondergaard B. Rønø C. Mackay B. Friedrichsen C. Chang R. Tang L. Hornum 《Clinical and experimental immunology》2014,177(1):219-233
Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti‐C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti‐murine C5aR (anti‐mC5aR) surrogate antibody in mouse collagen‐induced arthritis (CIA). First, efficacy was demonstrated in a multiple‐dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti‐mC5aR‐treated mice. Then, the mechanism of action was examined by looking for early effects of anti‐mC5aR treatment in single‐dose treatment studies. We found that 48 h after single‐dose treatment with anti‐mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and IL‐17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose‐setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti‐C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR. 相似文献
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90.
Sean C. Grondin Colin Schieman Elizabeth Kelly Gail Darling Donna Maziak Moné Palacios Mackay Gary Gelfand 《Canadian journal of surgery》2013,56(4):E75-E81