219 research outputs found
The Life and Death of Newcastle Gaol 1822-2022
An exhibition about Newcastle’s borough gaol at Carliol Square- the prison, the prisoners and its legacy in the city. Newcastle City Library
Delineation of phenotypes and genotypes related to cohesin structural protein RAD21
RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype–phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype–phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.Spanish Ministry of Science, Innovation and Universities/State Research Agency RTC-2017-6494-1 and RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) as well as funds from the European JPIAMR-VRI network “CONNECT” to PG-
Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans
It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized
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ADVANCED RECIPROCATING COMPRESSION TECHNOLOGY (ARCT)
The U.S. natural gas pipeline industry is facing the twin challenges of increased flexibility and capacity expansion. To meet these challenges, the industry requires improved choices in gas compression to address new construction and enhancement of the currently installed infrastructure. The current fleet of installed reciprocating compression is primarily slow-speed integral machines. Most new reciprocating compression is and will be large, high-speed separable units. The major challenges with the fleet of slow-speed integral machines are: limited flexibility and a large range in performance. In an attempt to increase flexibility, many operators are choosing to single-act cylinders, which are causing reduced reliability and integrity. While the best performing units in the fleet exhibit thermal efficiencies between 90% and 92%, the low performers are running down to 50% with the mean at about 80%. The major cause for this large disparity is due to installation losses in the pulsation control system. In the better performers, the losses are about evenly split between installation losses and valve losses. The major challenges for high-speed machines are: cylinder nozzle pulsations, mechanical vibrations due to cylinder stretch, short valve life, and low thermal performance. To shift nozzle pulsation to higher orders, nozzles are shortened, and to dampen the amplitudes, orifices are added. The shortened nozzles result in mechanical coupling with the cylinder, thereby, causing increased vibration due to the cylinder stretch mode. Valve life is even shorter than for slow speeds and can be on the order of a few months. The thermal efficiency is 10% to 15% lower than slow-speed equipment with the best performance in the 75% to 80% range. The goal of this advanced reciprocating compression program is to develop the technology for both high speed and low speed compression that will expand unit flexibility, increase thermal efficiency, and increase reliability and integrity. Retrofit technologies that address the challenges of slow-speed integral compression are: (1) optimum turndown using a combination of speed and clearance with single-acting operation as a last resort; (2) if single-acting is required, implement infinite length nozzles to address nozzle pulsation and tunable side branch absorbers for 1x lateral pulsations; and (3) advanced valves, either the semi-active plate valve or the passive rotary valve, to extend valve life to three years with half the pressure drop. This next generation of slow-speed compression should attain 95% efficiency, a three-year valve life, and expanded turndown. New equipment technologies that address the challenges of large-horsepower, high-speed compression are: (1) optimum turndown with unit speed; (2) tapered nozzles to effectively reduce nozzle pulsation with half the pressure drop and minimization of mechanical cylinder stretch induced vibrations; (3) tunable side branch absorber or higher-order filter bottle to address lateral piping pulsations over the entire extended speed range with minimal pressure drop; and (4) semi-active plate valves or passive rotary valves to extend valve life with half the pressure drop. This next generation of large-horsepower, high-speed compression should attain 90% efficiency, a two-year valve life, 50% turndown, and less than 0.75 IPS vibration. This program has generated proof-of-concept technologies with the potential to meet these ambitious goals. Full development of these identified technologies is underway. The GMRC has committed to pursue the most promising enabling technologies for their industry
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