Evidence for a role of the Drosophila melanogaster suppressor of sable gene in the pre-mRNA splicing pathway.

Recessive mutations of the Drosophila melanogaster suppressor of sable [su(s)] gene result in elevated accumulation of RNA from vermilion (v) mutant alleles that have an insertion of the 7.5-kb retrotransposon 412 in the first exon of the v gene. During transcription of such a v mutant gene, the 412 sequences are incorporated into the primary transcripts and are subsequently removed by splicing at cryptic sites within 412 sequences. In a su(s)+ background, the level of these unusually spliced transcripts is exceedingly low, and su(s) mutations increase their accumulation. We previously proposed that v RNA levels are elevated in su(s) mutants because of increased recognition of the cryptic splice sites, and the aim of this study was to test this hypothesis. We generated a v mutant derivative with a smaller 412 insertion, introduced alterations into the 412-associated splice sites, and examined the effect of su(s) mutations on expression of these derivatives after germ line transformation. To increase overall expression levels, the v promoter was replaced with the stronger Metallothionein (Mtn) gene promoter. We found that transformants bearing a v derivative with 480 bp of 412 sequences accumulate both transcripts, with 412 sequences spliced out and transcripts that retain 412 sequences. Mutations of su(s) increase the levels of both transcript classes without affecting the relative amounts of the two forms. Strikingly, replacement of the cryptic 5' splice sites with a 5' consensus produces the same effect as, and eliminates the response to, a su(s) mutation. In addition, we demonstrated that mutations of su(s) lead to increased accumulation of v transcripts even when the previously identified cryptic 412 5' and 3' splice sites were destroyed and that other cryptic splice sites reside within Mtn and 412 sequences. These results indicate that the v mutant transcripts are stabilized by assembly of the 412 sequences into splicing complexes and support the hypothesis that splicing complexes more readily assemble on cryptic splice sites in su(s) mutants

Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly

SummaryThe oxidative stress hypothesis of aging predicts that a reduction in the generation of mitochondrial reactive oxygen species (ROS) will decrease oxidative damage and extend life span. Increasing mitochondrial proton leak-dependent state 4 respiration by increasing mitochondrial uncoupling is an intervention postulated to decrease mitochondrial ROS production. When human UCP2 (hUCP2) is targeted to the mitochondria of adult fly neurons, we find an increase in state 4 respiration, a decrease in ROS production, a decrease in oxidative damage, heightened resistance to the free radical generator paraquat, and an extension in life span without compromising fertility or physical activity. Our results demonstrate that neuronal-specific expression of hUCP2 in adult flies decreases cellular oxidative damage and is sufficient to extend life span

Conversion From Tacrolimus to Belatacept to Prevent the Progression of Chronic Kidney Disease in Pancreas Transplantation: Case Report of Two Patients

Belatacept is a novel immunosuppressive agent that may be used as an alternative to calcineurin inhibitors (CNI) in immunosuppression (IS) regimens. We report two cases of pancreas transplant that were switched from tacrolimus (TAC) to belatacept. Case 1: 38‐year‐old female with pancreas transplant alone maintained on TAC‐based IS regimen whose serum creatinine (SCr) slowly deteriorated from 0.6 mg/dL at baseline to 2.2 mg/dL, 16 months posttransplant. A native kidney biopsy performed showed CNI toxicity. The patient was started on belatacept and TAC was eliminated. Case 2: 49‐year‐old female with simultaneous pancreas–kidney transplant, maintained on TAC‐based regimen where the SCr worsened over an initial 3‐month period from a baseline of 1.0 to 3.0 mg/dL. Belatacept was started and TAC was lowered. Due to persistent graft dysfunction and kidney transplant biopsy still showing changes consistent with CNI toxicity, the TAC was then discontinued. At >1 year postbelatacept and off TAC follow‐up, kidney function as measured by SCr remains stable at 1.0 ± 0.2 mg/dL in both recipients. Neither patient developed rejection following the switch, and pancreas allograft function remains stable in both recipients

How Do NYPD Officers Respond to Terror Threats?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155976/1/ecca12328.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155976/2/ecca12328_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155976/3/ecca12328-sup-0001-Appendix.pd

A retrotransposon 412 insertion within an exon of the Drosophila melanogaster vermilion gene is spliced from the precursor RNA.

Three alleles of the Drosophila melanogaster vermilion (v) gene are suppressed by recessive mutations at the suppressor of sable [su(s)], gene. Previous work has established that these alleles have identical insertions of the 412 retrotransposon in the 5'-untranslated region of the gene. Despite the transposon insertion in an exon, v mutants accumulate trace amounts of apparently wild-type-sized transcripts in a su(s)+ background, and the level of v transcript accumulation is increased by su(s) mutations. Here, we have characterized transcripts from a suppressible v mutant in both su(s)+ and su(s)- backgrounds by S1 nuclease protection experiments and sequence analysis of polymerase chain reaction (PCR) generated cDNA clones. We find that transposon sequences are imprecisely eliminated from v mutant transcripts by splicing at donor and acceptor sites located near the ends of the 412 retrotransposon. Four different 5' donor sites are alternatively spliced to a single 3' acceptor site. The implications of this finding are discussed in relation to possible functions of the su(s)+ gene product

Structure and transcription of the Drosophila melanogaster vermilion gene and several mutant alleles.

The nucleotide sequence and intron-exon structure of the Drosophila melanogaster vermilion (v) gene have been determined. In addition, the sites of several mutations and the effects of these mutations on transcription have been examined. The major v mRNA is generated upon splicing six exons of lengths (5' to 3') 83, 161, 134, 607, 94, and 227 nucleotides (nt). A minor species of v mRNA is initiated at an upstream site and has a 5' exon of at least 152 nt which overlaps the region included in the 83-nt exon of the major v RNA. The three v mutations, v1, v2, and vk, which can be suppressed by mutations at suppressor of sable, su(s), are insertions of transposon 412 at the same position in exon 1, 36 nt downstream of the major transcription initiation site. Despite the 7.5-kilobase insertion in these v alleles, a reduced level of wild-type-sized mRNA accumulates in suppressed mutant strains. The structure and transcription of several unsuppressible v alleles have also been examined. The v36f mutation is a B104/roo insertion in intron 4 near the splice donor site. A mutant carrying this alteration accumulates a very low level of mRNA that is apparently polyadenylated at a site within the B104/roo transposon. The v48a mutation, which deletes approximately 200 nt of DNA, fuses portions of exons 3 and 4 without disruption of the translational reading frame. A smaller transcript accumulates at a wild-type level, and thus an altered, nonfunctional polypeptide is likely to be synthesized in strains carrying this mutation.(ABSTRACT TRUNCATED AT 250 WORDS

Pancreas transplantation for Cystic Fibrosis: A Frequently Missed Opportunity

Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant

Substance abuse and psychiatric co-morbidity as predictors of premature mortality in Swedish drug abusers a prospective longitudinal study 1970 - 2006

<p>Abstract</p> <p>Background</p> <p>Few longitudinal cohort studies have focused on the impact of substances abused and psychiatric disorders on premature mortality. The aim of the present study was to identify predictors of increased risk of drug related death and non drug related death in substance abusers of opiates, stimulants, cannabis, sedatives/hypnotics, hallucinogens and alcohol over several decades.</p> <p>Methods</p> <p>Follow-up study of a consecutive cohort of 561 substance abusers, admitted to a detoxification unit January 1970 to February 1978 in southern Sweden, and followed up in 2006. Demographic and clinical data, substance diagnoses and three groups of psychiatric diagnoses were identified at first admission. Causes of death were coded according to ICD-10 and classified as drug related deaths or non drug related deaths. To identify the incidence of some probable risk factors of drug related premature death, the data were subjected to a competing risks Cox regression analysis.</p> <p>Results</p> <p>Of 561 patients in the cohort, 11 individuals had either emigrated or could not be located, and 204/561 patients (36.4%) were deceased by 2006. The cumulative risk of drug related death increased more in the first 15 years and leveled out later on when non drug related causes of death had a similar incidence. In the final model, male gender, regular use of opiates or barbiturates at first admission, and neurosis were associated with an increased risk of drug related premature death, while cannabis use and psychosis were associated with a decreased risk. Neurosis, mainly depression and/or anxiety disorders, predicted drug related premature death while chronic psychosis and personality disorders did not. Chronic alcohol addiction was associated with increased risk of non drug related death.</p> <p>Conclusions</p> <p>The cohort of drug abusers had an increased risk of premature death to the age of 69. Drug related premature death was predicted by male gender, the use of opiates or barbiturates and depression and anxiety disorders at first admission. The predicted cumulative incidence of drug related death was significantly higher in opiate and barbiturate abusers over the observed period of 37 years, while stimulant abuse did not have any impact. Alcohol contributed to non drug related death.</p

Moral economies of consumption

The aim of this article is twofold: first, to bring together debates about enduring normative concerns surrounding the morality of consumption with more recent concerns about the ways specific moralities are constituted in and through markets. The second aim is to develop the concept of ‘moral economy’ and call for an approach to its study, attentive to how moralities of consumption develop through interactions between instituted systems of provision, forms of state regulation, customs within communities and the everyday reflections of consumers about the things that matter to them. As consumers are increasingly asked to factor environmental and fair labour concerns into their purchase and post-purchase habits, there is a real need to understand how moralities of consumption are both formatted through institutional frameworks and shaped everyday by actors from within. After developing a framework for the study of moral economies, this article explores in depth the experiences of one couple in relation to the cessation of a cardboard recycling collection in Shropshire (England) to show why a multilevel perspective is needed to appreciate the place of morality within the market