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Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, known to present with ocular manifestations in rare cases. Case Presentation: We describe the case of a 9-year-old previously healthy male who developed a 2-day history of periocular swelling and was found on MRI to have a large sphenoidal mass. Further work up showed involvement of the spinal cord, iliac crests, and kidneys. His initial blood work showed no hematological abnormalities. A bone marrow biopsy taken from the iliac crest demonstrated >90% B lymphoblasts and flow cytometry was positive for CD19. Overall, his investigations were consistent with a diagnosis of precursor B-cell ALL (pre B-ALL). His neuro-ophthalmic exam showed right-sided subtle periocular edema, decreased palpebral fissure height, and proptosis. Posterior exam showed mild nasal elevation of the right optic disc without vessel obscuration and mild tortuosity of the peripheral vessels. He otherwise had no overt signs of afferent or efferent dysfunction despite the proximity of the mass to his optic nerve and globe. Conclusion: This case demonstrates that high-risk pre B-ALL, a childhood cancer not commonly associated with orbital manifestations, can present with orbital edema and normal leukocyte count in an otherwise healthy child.

Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit \"elective\" clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. Prospective observational cohort study. Single Canadian tertiary-care academic pediatric hospital (June 2014-16) servicing 1.2 million people. 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range <1 hour-27 days), most consults (63.2%) required <10minutes to complete and 21/21(100%) specialist survey-respondents reported minimal workload burden. For 515/1064(48.4%) referrals, PCPs received advice for a new or additional course of action; 391/1064(36.7%) referrals resulted in an averted face-to-face specialist visit. In 9 specialties with complete data, the median wait-time was significantly less (p<0.001) for an eConsult (1 day, 95%CI:0.9-1.2) compared with a face-to-face referral (132 days; 95%CI:127-136). The majority (>93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.

Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification. The acetyltransferases KAT2A and KAT2B are essential regulators of transcription, cell cycle progression and DNA repair. Here the authors describe a KAT2A/2B-dependent acetylome, and show that acetylation of the protein kinase PLK4 contributes to the regulation of centrosome number.

In the right place It is becoming clear that the position of genes within the nucleus can influence their expression, and two groups this week report examples of this in yeast. Cabal et al . find that activation of GAL genes confines them to the nuclear periphery. And Taddei et al . report that simply moving the HXK1 gene, by blocking or encouraging its association with the nuclear periphery, significantly alters gene expression. The dynamic motility of GAL genes becomes confined at the nuclear periphery after activation — components of the SAGA histone acetyltransferase complex are required for this confinement, as well as an mRNA export factor. Changes in the transcriptional state of genes have been correlated with their repositioning within the nuclear space 1 . Tethering reporter genes to the nuclear envelope alone can impose repression 2 and recent reports have shown that, after activation, certain genes can also be found closer to the nuclear periphery 3 , 4 , 5 , 6 . The molecular mechanisms underlying these phenomena have remained elusive. Here, with the use of dynamic three-dimensional tracking of a single locus in live yeast ( Saccharomyces cerevisiae ) cells, we show that the activation of GAL genes ( GAL7 , GAL10 and GAL1 ) leads to a confinement in dynamic motility. We demonstrate that the GAL locus is subject to sub-diffusive movement, which after activation can become constrained to a two-dimensional sliding motion along the nuclear envelope. RNA-fluorescence in situ hybridization analysis after activation reveals a higher transcriptional activity for the peripherally constrained GAL genes than for loci remaining intranuclear. This confinement was mediated by Sus1 and Ada2, members of the SAGA histone acetyltransferase complex, and Sac3, a messenger RNA export factor, physically linking the activated GAL genes to the nuclear-pore-complex component Nup1. Deleting ADA2 or NUP1 abrogates perinuclear GAL confinement without affecting GAL1 transcription. Accordingly, transcriptional activation is necessary but not sufficient for the confinement of GAL genes at the nuclear periphery. The observed real-time dynamic mooring of active GAL genes to the inner side of the nuclear pore complex is in accordance with the ‘gene gating’ hypothesis 7 .

BackgroundOrodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders.MethodsWe designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption.ResultsWe discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases.ConclusionsWe have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease.Trial registration numbersNCT01746121 and NCT02397824.

No test currently exists for molecular imaging of pulmonary arterial hypertension (PAH). Adrenomedullin is a vasodilator peptide predominantly cleared by pulmonary endothelial receptors. We developed a linear adrenomedullin derivative radiolabeled with (99m)Tc ((99m)Tc-AM-L) for imaging of pulmonary circulation and tested its capacity to detect anomalies of pulmonary circulation caused by PAH. PAH was induced by monocrotaline in rats and compared with controls. After 5 wk, (99m)Tc-AM-L was injected intravenously. Plasma kinetics were measured, lung activity was determined in vivo after 30 min using a nuclear camera, and lung activity was determined ex vivo in explanted lungs. Expression of adrenomedullin receptors was measured in lung homogenates. The plasma levels of (99m)Tc-AM-L significantly increased in PAH by approximately 2-fold. Uptake by the lungs was homogeneous but greatly reduced in PAH by about 70%. In vivo retention was 14% +/- 1% (mean +/- SD) of the injected dose in controls and 4% +/- 1% in PAH (P < 0.0001). A similar reduction was measured ex vivo (6.0 +/- 1.6 percentage injected dose per gram [%ID/g] vs. 0.95 +/- 0.21 %ID/g, P < 0.0001). The expression of the heterodimeric component of the adrenomedullin receptor, receptor activity modifying protein 2, was also greatly reduced in PAH lungs (P < 0.001). Interestingly, right ventricular uptake of (99m)Tc-AM-L was increased by PAH (P = 0.02) and correlated with the degree of right ventricular hypertrophy (r = 0.83, P = 0.001). Pulmonary uptake of (99m)Tc-AM-L is greatly reduced in monocrotaline-induced PAH. This novel molecular imaging agent may be useful in the diagnosis and follow-up of pulmonary vascular disorders.

Extensive utilization of pesticides against insects provides us with a good model for studying the adaptation of a eukaryotic genome to a strong selective pressure. One mechanism of resistance is the alteration of acetylcholinesterase (EC 3.1.1.7), the molecular target for organophosphates and carbamates. Here, we report the sequence analysis of the Ace gene in several resistant field strains of Drosophila melanogaster. This analysis resulted in the identification of five point mutations associated with reduced sensitivities to insecticides. In some cases, several of these mutations were found to be combined in the same protein, leading to different resistance patterns. Our results suggest that recombination between resistant alleles preexisting in natural populations is a mechanism by which insects rapidly adapt to new selective pressures.

We compared the efficiencies of biochemical methods and polymerase chain reaction (PCR) for the identification of Vibrio parahaemolyticus strains. The 122 isolates studied, identified by biochemical tests as V. parahaemolyticus or Vibrio alginolyticus, were tested by R72H PCR assay. The results obtained with the two methods were consistent for 90% of the strains studied. PCR amplification of the R72H fragment generated two unique amplicons, 387 bp and 320 bp in length. For 11% of the strains from seawater, the results of biochemical identification did not correlate with PCR results. DNA–DNA hybridization experiments provided evidence that some strains identified as V. alginolyticus in biochemical tests should be considered members of the V. parahaemolyticus species. We therefore suggest that biochemical tests are not accurate enough for the identification of V. parahaemolyticus isolates and we demonstrate that amplification of the R72H fragment, whether the amplicon is 320 bp or 387 bp long, is a powerful tool for the reliable identification of V. parahaemolyticus.