243 research outputs found
Length heterogeneity at conserved sequence block 2 in human mitochondrial DNA acts as a rheostat for RNA polymerase POLRMT activity
The guanine (G)-tract of conserved sequence block 2 (CSB 2) in human mitochondrial DNA can result in transcription termination due to formation of a hybrid G-quadruplex between the nascent RNA and the nontemplate DNA strand. This structure can then influence genome replication, stability and localization. Here we surveyed the frequency of variation in sequence identity and length at CSB 2 amongst human mitochondrial genomes and used in vitro transcription to assess the effects of this length heterogeneity on the activity of the mitochondrial RNA polymerase, POLRMT. In general, increased G-tract length correlated with increased termination levels. However, variation in the population favoured CSB 2 sequences which produced efficient termination while particularly weak or strong signals were avoided. For all variants examined, the 3Ⲡend of the transcripts mapped to the same downstream sequences and were prevented from terminating by addition of the transcription factor TEFM. We propose that CSB 2 length heterogeneity allows variation in the efficiency of transcription termination without affecting the position of the products or the capacity for regulation by TEFM
Geographic variation and localised clustering of congenital anomalies in Great Britain
Background: Environmental pollution as a cause of congenital anomalies is sometimes suspected because of clustering of anomalies in areas of higher exposure. This highlights questions around spatial heterogeneity (clustering) in congenital anomaly rates. If spatial variation is endemic, then any one specific cluster is less remarkable, though the presence of uncontrolled geographically clustered risk factors is suggested. If rates are relatively homogeneous across space other than around specific hazards, then evidence for these hazards causing the clusters is strengthened. We sought to estimate the extent of spatial heterogeneity in congenital anomaly rates in the United Kingdom. Methods: The study population covered about one million births from five registers in Britain from 1991â1999. We estimated heterogeneity across four geographical levels: register area, hospital catchment, electoral ward, and enumeration district, using a negative binomial regression model. We also sought clusters using a circular scan statistic. Results: Congenital anomaly rates clearly varied across register areas and hospital catchments (p 0.2). Adjusting for socioeconomic deprivation and maternal age made little difference to the extent of geographical variation for most congenital anomaly subtypes. The two most significant circular clusters (of four ano-rectal atresias and six congenital heart diseases) contained two or more siblings. Conclusion: The variation in rates between registers and hospital catchment area may have resulted in part from differences in case ascertainment, and this should be taken into account in geographical epidemiological studies of environmental exposures. The absence of evidence for variation below this level should be interpreted cautiously in view of the low power of general heterogeneity tests. Nevertheless, the data suggest that strong localised clusters in congenital anomalies are uncommon, so clusters around specific putative environmental hazards are remarkable when observed. Negative binomial models applied at successive hierarchical levels provide an approach of intermediate complexity to characterising geographical heterogeneity
Living bioethics, clinical ethics committees and children's consent to heart surgery
This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theoryâpractice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee membersâ reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and childrenâs interests and rights. Different approaches to framing ethical questions are also considered. Being aware of the four theoriesâ influence can help when seeking to understand and possibly change clinical ethics committee routines. The paper is not a research report but is informed by a recent study in two London paediatric cardiac units. Forty-five practitioners and related experts were interviewed, including eight members of ethics committees, about the work of informing, preparing and supporting families during the extended process of consent to childrenâs elective heart surgery. The mosaic of multidisciplinary teamwork is reported in a series of papers about each profession, including this one on bioethics and law and clinical ethics committeesâ influence on clinical practice. The qualitative social research was funded by the British Heart Foundation, in order that more may be known about the perioperative views and needs of all concerned. Questions included how disputes can be avoided, how high ethical standards and respectful cooperation between staff and families can be encouraged, and how minorsâ consent or refusal may be respected, with the support of clinical ethics committees
Letter from Robert D. Andrews, Boston, Massachusetts, to Hugh S. Fullerton, New York, New York : typed manuscript signed, 1925 August 19
Recommends Nancy Webster for title of Most Interesting Woman. Letterhead: Andrew, Jones, Biscoe & Whitmore Architects.https://repository.wellesley.edu/autographletters/1093/thumbnail.jp
PAPSS2ârelated brachyolmia : clinical and radiological phenotype in 18 new cases
Brachyolmia is a skeletal dysplasia characterized by short spineâshort stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19âyears, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their shortâspine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short overâfaced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Biâparental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be underârecognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester
Surveillance of multiple congenital anomalies; searching for new associations
\ua9 2023, The Author(s).Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies occurring together more frequently than expected may improve the detection of teratogens. Thirty-two EUROCAT congenital anomaly registries covering 6,599,765 births provided 123,566 cases with one or more major congenital anomalies (excluding chromosomal and genetic syndromes) for the birth years 2008â2016. The EUROCAT multiple congenital anomaly algorithm identified 8804 cases with two or more major congenital anomalies in different organ systems, that were not recognized as part of a syndrome or sequence. For each pair of anomalies, the odds of a case having both anomalies relative to having only one anomaly was calculated and the p value was estimated using a two-sided Fisherâs exact test. The BenjaminiâHochberg procedure adjusted p values to control the false discovery rate and pairs of anomalies with adjusted p values < 0.05 were identified. A total of 1386 combinations of two anomalies were analyzed. Out of the 31 statistically significant positive associations identified, 20 were found to be known associations or sequences already described in the literature and 11 were considered âpotential new associationsâ by the EUROCAT Coding and Classification Committee. After a review of the literature and a detailed examination of the individual cases with the anomaly pairs, six pairs remained classified as new associations. In summary, systematically searching for congenital anomalies occurring together more frequently than expected using the EUROCAT database is worthwhile and has identified six new associations that merit further investigation
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Outlooks in GEO-6
As understanding of the interdependence between a healthy
planet and healthy people becomes more developed, complex
issues that thread through systems and societies gain new
importance. Beyond the traditional Global Environment
Outlook (GEO) themes addressing air, biodiversity, oceans,
land and fresh water, this GEO-6 assessment addresses
cross-cutting issues worthy of further examination. Using
a systems approach, these cross-cutting issues offer
entry points allowing another dimension for analysing
GEO-6 themes as well as understanding the network of
interconnections throughout earth and human systems.
These cross-cutting issues are grouped according to shared
characteristics: health, environmental disasters, gender,
education and urbanization are grouped as âpeople and
livelihoodsâ; climate change, polar and mountain regions,
chemicals and waste and wastewater are grouped as
âchanging environmentsâ; and resource use, energy and food
systems are considered as âresources and materialsâ. While
each issue provides useful entry points into GEO-6 themes,
it is important to discuss the state of the environment and
policy context for each one
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