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Genome Biology and Evolution Dec 2017Vertebrate (cellular retinaldehyde-binding protein) and Drosophila (prolonged depolarization afterpotential is not apparent [PINTA]) proteins with a CRAL-TRIO domain...
Vertebrate (cellular retinaldehyde-binding protein) and Drosophila (prolonged depolarization afterpotential is not apparent [PINTA]) proteins with a CRAL-TRIO domain transport retinal-based chromophores that bind to opsin proteins and are necessary for phototransduction. The CRAL-TRIO domain gene family is composed of genes that encode proteins with a common N-terminal structural domain. Although there is an expansion of this gene family in Lepidoptera, there is no lepidopteran ortholog of pinta. Further, the function of these genes in lepidopterans has not yet been established. Here, we explored the molecular evolution and expression of CRAL-TRIO domain genes in the butterfly Heliconius melpomene in order to identify a member of this gene family as a candidate chromophore transporter. We generated and searched a four tissue transcriptome and searched a reference genome for CRAL-TRIO domain genes. We expanded an insect CRAL-TRIO domain gene phylogeny to include H. melpomene and used 18 genomes from 4 subspecies to assess copy number variation. A transcriptome-wide differential expression analysis comparing four tissue types identified a CRAL-TRIO domain gene, Hme CTD31, upregulated in heads suggesting a potential role in vision for this CRAL-TRIO domain gene. RT-PCR and immunohistochemistry confirmed that Hme CTD31 and its protein product are expressed in the retina, specifically in primary and secondary pigment cells and in tracheal cells. Sequencing of eye protein extracts that fluoresce in the ultraviolet identified Hme CTD31 as a possible chromophore binding protein. Although we found several recent duplications and numerous copy number variants in CRAL-TRIO domain genes, we identified a single copy pinta paralog that likely binds the chromophore in butterflies.
Topics: Animals; Butterflies; DNA Copy Number Variations; Evolution, Molecular; Eye Proteins; Gene Expression Profiling; Gene Expression Regulation; Genome, Insect; Insect Proteins; Multigene Family; Phylogeny; Vision, Ocular
PubMed: 29136137
DOI: 10.1093/gbe/evx230 -
Nature Communications Oct 2017Hepatic mitochondria play a central role in the regulation of intermediary metabolism and maintenance of normoglycemia, and there is great interest in assessing rates of...
Hepatic mitochondria play a central role in the regulation of intermediary metabolism and maintenance of normoglycemia, and there is great interest in assessing rates of hepatic mitochondrial citrate synthase flux (V ) and pyruvate carboxylase flux (V ) in vivo. Here, we show that a positional isotopomer NMR tracer analysis (PINTA) method can be used to non-invasively assess rates of V and V fluxes using a combined NMR/gas chromatography-mass spectrometry analysis of plasma following infusion of [3-C]lactate and glucose tracer. PINTA measures V and V fluxes over a wide range of physiological conditions with minimal pyruvate cycling and detects increased hepatic V following treatment with a liver-targeted mitochondrial uncoupler. Finally, validation studies in humans demonstrate that the V /V ratio measured by PINTA is similar to that determined by in vivo NMR spectroscopy. This method will provide investigators with a relatively simple tool to non-invasively examine the role of altered hepatic mitochondrial metabolism.Liver mitochondrial metabolism plays an important role for glucose and lipid homeostasis and its alterations contribute to metabolic disorders, including fatty liver and diabetes. Here Perry et al. develop a method for the measurement of hepatic fluxes by using lactate and glucose tracers in combination with NMR spectroscopy.
Topics: Acetates; Animals; Carbon Isotopes; Carbon-13 Magnetic Resonance Spectroscopy; Citrate (si)-Synthase; Gas Chromatography-Mass Spectrometry; Glutamic Acid; Humans; Lactic Acid; Liver; Magnetic Resonance Spectroscopy; Male; Mitochondria, Liver; Pyruvate Carboxylase; Pyruvic Acid; Rats
PubMed: 28986525
DOI: 10.1038/s41467-017-01143-w -
Technical Innovations & Patient Support... 2017To evaluate the effectiveness of low doses of radiation therapy for symptomatic splenomegaly in malignant and benign diseases.
OBJECTIVES
To evaluate the effectiveness of low doses of radiation therapy for symptomatic splenomegaly in malignant and benign diseases.
PATIENTS AND METHODS
5 patients with symptomatic splenomegaly were treated with low doses of radiation in our centre (January 2008-December 2016). 4/5 patients had malignant neoplasia (acute myeloid leukemia, non Hogdkin lymphoma and prolymphocytic B cell leukemia) and splenomegaly was caused by extramedullary hematopoiesis. 1/5 patient had benign disease (HBV liver cirrhosis) and splenomegaly was caused by vascular ectasia. Median age was 73 years (range 61-86 years). There were 4 females and 1 male. These patients had exclusively splenic pain or abdominal discomfort in 20%, exclusively cytopenias 40% and both 40%. Patients needed radiation therapy for symptomatic control. Dose per fraction was 0.5 Gy every two days; total dose initially prescribed 10 Gy. IGRT were performed in all patients to ensure an appropriate position and to adapt the treatment volume to the changes in the spleen volume along the treatment. Median craneocaudal length size of the spleen was more than 26 cm (range 15.2-34.9 cm).
RESULTS
Median radiation doses were 4.85 Gy (range 2.5-10). Median craneocaudal spleen size reduction was 4.6 cm (0-8 cm). Splenic pain and abdominal disturbances improved in all patients. Median increase of haemoglobin and platelets levels was 1.6 mg/dl and 27.950 cells respectively in the first week after the end of radiotherapy.One patient had to interrupt her treatment due to grade II neutropenia. No other toxicities were described. With a median follow-up of 39 months (16-89 months), only one recurrence was described at 24 months and consisted of thrombocytopenia. The patient received a second course of radiotherapy with excellent response.
CONCLUSION
Low doses of radiation therapy for treatment of symptomatic splenomegaly were effective, with a low rate of side effects. Splenic pain and abdominal discomfort completely improved and cytopenias rised to secure levels.
PubMed: 32095563
DOI: 10.1016/j.tipsro.2017.08.002 -
The New England Journal of Medicine Sep 2017Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.
RESULTS
During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.
CONCLUSIONS
Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .).
Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Cholesterol Ester Transfer Proteins; Coronary Disease; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Oxazolidinones
PubMed: 28847206
DOI: 10.1056/NEJMoa1706444 -
The Open Dentistry Journal 2017For patients whose centric relation (CR) has not been considered at the start and during treatment, the task of achieving an occlusal scheme that works together with the... (Review)
Review
BACKGROUND
For patients whose centric relation (CR) has not been considered at the start and during treatment, the task of achieving an occlusal scheme that works together with the temporomandibular joint, the muscles, and the structures of the stomatognathic apparatus becomes a major concern.
OBJECTIVE
This study aims to describe a reproducible, predictable and to date unreported procedure of selective grinding guided by an occlusal splint and to analyze condylar position (CP) based on the skeletal pattern.
METHODS
A total of 72 symptomatic patients (38 females and 34 males) were classified into three groups: hyperdivergent, intermediate and hypodivergent. CP was quantified by mounted casts on a measures condyle displacement (MCD) device. Helkimo index was also performed in order to assess the severity of the temporomandibular joint (TMJ) disorders attending to clinical dysfunction, occlusal state and anamnestic dysfunction. Once the stability had been obtained, the splint was progressively reduced until the maximum intercuspation (MIC) was achieved.
RESULTS
The vertical displacement was found to be significantly different between the hyperdivergent and other two groups (<0.01). Comparisons of MCD analysis before and after the selective grinding procedure identified a statistically significant difference in the horizontal and vertical CP (<0.01) between the different groups whereas the Helkimo Index showed a clear improvement of TMJ disorders.
CONCLUSION
All facial types, specially the hyperdivergent face type, showed a reduction in condylar displacement (CD) and less craniomandibular symptoms using this procedure, making it an excellent technique for clinicians.
PubMed: 28839479
DOI: 10.2174/1874210601711010301 -
Protein Science : a Publication of the... Apr 2017The spirochete Treponema pallidum is the causative agent of syphilis, a sexually transmitted infection of major global importance. Other closely related subspecies of...
The spirochete Treponema pallidum is the causative agent of syphilis, a sexually transmitted infection of major global importance. Other closely related subspecies of Treponema also are the etiological agents of the endemic treponematoses, such as yaws, pinta, and bejel. The inability of T. pallidum and its close relatives to be cultured in vitro has prompted efforts to characterize T. pallidum's proteins structurally and biophysically, particularly those potentially relevant to treponemal membrane biology, with the goal of possibly revealing the functions of those proteins. This report describes the structure of the treponemal protein Tp0737; this polypeptide has a fold characteristic of a class of periplasmic ligand-binding proteins associated with ABC-type transporters. Although no ligand for the protein was observed in electron-density maps, and thus the nature of the native ligand remains obscure, the structural data described herein provide a foundation for further efforts to elucidate the ligand and thus the function of this protein in T. pallidum.
Topics: ATP-Binding Cassette Transporters; Crystallography, X-Ray; Periplasmic Proteins; Protein Domains; Structure-Activity Relationship; Treponema pallidum
PubMed: 28168761
DOI: 10.1002/pro.3133 -
Clinical Microbiology and Infection :... Nov 2016Treponema pallidum infections causing yaws disease and venereal syphilis are globally widespread in human populations, infecting hundreds of thousands and millions... (Review)
Review
Treponema pallidum infections causing yaws disease and venereal syphilis are globally widespread in human populations, infecting hundreds of thousands and millions annually respectively; endemic syphilis is much less common, and pinta has not been observed in decades. We discuss controversy surrounding the origin, evolution and history of these pathogens in light of available molecular and anthropological evidence. These bacteria (or close relatives) seem to affect many wild African nonhuman primate (NHP) species, though to date only a single NHP Treponema pallidum genome has been published, hindering detection of spillover events and our understanding of potential wildlife reservoirs. Similarly, only ten genomes of Treponema pallidum infecting humans have been published, impeding a full understanding of their diversity and evolutionary history. Research efforts have been hampered by the difficulty of culturing and propagating Treponema pallidum. Here we highlight avenues of research recently opened by the coupling of hybridization capture and next-generation sequencing. We present data generated with such an approach suggesting that asymptomatic bones from NHP occasionally contain enough treponemal DNA to recover large fractions of their genomes. We expect that these methods, which naturally can be applied to modern biopsy samples and ancient human bones, will soon considerably improve our understanding of these enigmatic pathogens and lay rest to old yet unresolved controversies.
Topics: Bone and Bones; Evolution, Molecular; High-Throughput Nucleotide Sequencing; History, 15th Century; Humans; Phylogeny; Sequence Analysis, DNA; Syphilis; Treponema pallidum; Yaws
PubMed: 27498082
DOI: 10.1016/j.cmi.2016.07.027 -
Acta Obstetricia Et Gynecologica... Sep 2016The success of the primary repair of obstetric anal sphincter injury (OASI) is paramount in maintaining adequate fecal continence after childbirth. The factors...
INTRODUCTION
The success of the primary repair of obstetric anal sphincter injury (OASI) is paramount in maintaining adequate fecal continence after childbirth. The factors determining the success or failure of primary repair are unclear. The aim of this study is to investigate modifiable factors determining the success or failure of the primary sphincter repair after OASI.
MATERIAL AND METHODS
Sixty women with OASI were investigated by endoanal ultrasound or magnetic resonance imaging, and with the Wexner incontinence questionnaire. Based on the findings, the women were divided in two groups; successful primary repair group (n = 41) and failed primary repair group (n = 19).
RESULTS
The primary repair failed in 31.7% of the tears. These included more tears repaired by less experienced personnel (p < 0.001) and more repairs performed during on-call hours (p = 0.039) than in the successful primary repair group. Significantly more pain medication was used in the failed group (p = 0.003), and the use of antibiotics and laxatives after the repair was more common in the successful group (p < 0.001). Sphincter injuries were repaired using the overlapping suture technique in 95.1% of the repairs in the successful group compared with 47.4% in the failed group (p = 0.03). The mean (SD) Wexner score was significantly higher in the failed group [5.92 (4.1) vs. 1.88 (4.2), p < 0.001], in agreement with the findings on endoanal ultrasound.
CONCLUSIONS
Postpartum perineal tears should be evaluated by personnel familiar with the diagnosis and repair of OASI. Delaying the primary repair until next morning is recommended if experienced personnel are unavailable during on-call hours.
Topics: Adult; Anal Canal; Analgesics; Anti-Bacterial Agents; Clinical Competence; Delivery, Obstetric; Drug Utilization; Endosonography; Fecal Incontinence; Female; Humans; Laxatives; Magnetic Resonance Imaging; Perineum; Pregnancy; Suture Techniques; Time-to-Treatment; Treatment Failure; Young Adult
PubMed: 27100274
DOI: 10.1111/aogs.12909 -
PloS One 2015This paper reports the first find of pika remains in the Iberian Peninsula, at a site in central Spain. A fragmented mandible of Ochotona cf. pusilla was unearthed from...
This paper reports the first find of pika remains in the Iberian Peninsula, at a site in central Spain. A fragmented mandible of Ochotona cf. pusilla was unearthed from Layer 3 (deposited some 63.4±5.5 ka ago as determined by thermoluminescence) of the Buena Pinta Cave. This record establishes new limits for the genus geographic distribution during the Pleistocene, shifting the previous edge of its known range southwest by some 500 km. It also supports the idea that, even though Europe's alpine mountain ranges represented a barrier that prevented the dispersal into the south to this and other taxa of small mammals from central and eastern Europe, they were crossed or circumvented at the coldest time intervals of the end of the Middle Pleistocene and of the Late Pleistocene. During those periods both the reduction of the forest cover and the emersion of large areas of the continental shelf due to the drop of the sea level probably provided these species a way to surpass this barrier. The pika mandible was found accompanying the remains of other small mammals adapted to cold climates, indicating the presence of steppe environments in central Iberia during the Late Pleistocene.
Topics: Animals; Biological Evolution; Fossils; Lagomorpha; Mandible; Paleontology; Spain
PubMed: 26535576
DOI: 10.1371/journal.pone.0140513 -
PLoS Neglected Tropical Diseases 2015Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares....
BACKGROUND
Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA) strains (Nichols, DAL-1, Mexico A, SS14), 4 T. p. ssp. pertenue (TPE) strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc), 1 T. p. ssp. endemicum (TEN) strain (Bosnia A) and one strain (Cuniculi A) of Treponema paraluisleporidarum ecovar Cuniculus (TPLC) were examined with respect to the presence of nucleotide intrastrain heterogeneous sites.
METHODOLOGY/PRINCIPAL FINDINGS
The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes) were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5), DAL-1 (n = 4), and SS14 (n = 7), TPE strain Samoa D (n = 1), and TEN strain Bosnia A (n = 5). Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K), in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY), in genes involved in cell structure (murC), translation (prfA), general and DNA metabolism (putative SAM dependent methyltransferase, topA), and in seven hypothetical genes.
CONCLUSIONS/SIGNIFICANCE
Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process.
Topics: Bacterial Outer Membrane Proteins; Genome, Bacterial; Humans; Retrospective Studies; Treponema
PubMed: 26436423
DOI: 10.1371/journal.pntd.0004110