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Found 34611 matches. Displaying 141-150
Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu QS, Timberlake AT, Dong WL, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang JW, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, Lopez-Giraldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, Kahle KT
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Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation

NEURON 2019 FEB 6; 101(3):429-443.e4
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for similar to 30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.
LaCava J
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RNA Binding Proteins as Regulators of Retrotransposon-Induced Exonization

BIOESSAYS 2019 FEB; 41(2):? Article 1800263
Capalbo A, Chokoshvili D, Dugoff L, Franasiak J, Gleicher N, Pennings G, Simon C
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Should the reproductive risk of a couple aiming to conceive be tested in the contemporary clinical context?

FERTILITY AND STERILITY 2019 FEB; 111(2):229-238
Veale DJ, McGonagle D, McInnes IB, Krueger JG, Ritchlin CT, Elewaut D, Kanik KS, Hendrikx T, Berstein G, Hodge J, Telliez JB
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The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

RHEUMATOLOGY 2019 FEB; 58(2):197-205
The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.
Klinge S, Woolford JL
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Ribosome assembly coming into focus

In the past 25 years, genetic and biochemical analyses of ribosome assembly in yeast have identified most of the factors that participate in this complex pathway and have generated models for the mechanisms driving the assembly. More recently, the publication of numerous cryo-electron microscopy structures of yeast ribosome assembly intermediates has provided near-atomic resolution snapshots of ribosome precursor particles. Satisfyingly, these structural data support the genetic and biochemical models and provide additional mechanistic insight into ribosome assembly. In this Review, we discuss the mechanisms of assembly of the yeast small ribosomal subunit and large ribosomal subunit in the nucleolus, nucleus and cytoplasm. Particular emphasis is placed on concepts such as the mechanisms of RNA compaction, the functions of molecular switches and molecular mimicry, the irreversibility of assembly checkpoints and the roles of structural and functional proofreading of pre-ribosomal particles.
Harmsen S, Rogalla S, Huang RM, Spaliviero M, Neuschmelting V, Hayakawa Y, Lee Y, Tailor Y, Toledo-Crow R, Kang JW, Samii JM, Karabeber H, Davis RM, White JR, van de Rijn M, Gambhir SS, Contag CH, Wang TC, Kircher MF
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Detection of Premalignant Gastrointestinal Lesions Using Surface-Enhanced Resonance Raman Scattering-Nanoparticle Endoscopy

ACS NANO 2019 FEB; 13(2):1354-1364
Cancers of the gastrointestinal (GI) tract are among the most frequent and most lethal cancers worldwide. An important reason for this high mortality is that early disease is typically asymptomatic, and patients often present with advanced, incurable disease. Even in high-risk patients who routinely undergo endoscopic screening, lesions can be missed due to their small size or subtle appearance. Thus, current imaging approaches lack the sensitivity and specificity to accurately detect incipient GI tract cancers. Here we report our finding that a single dose of a high-sensitivity surface-enhanced resonance Raman scattering nanoparticle (SERRS-NP) enables reliable detection of precancerous GI lesions in animal models that closely mimic disease development in humans. Some of these animal models have not been used previously to evaluate imaging probes for early cancer detection. The studies were performed using a commercial Raman imaging system, a newly developed mouse Raman endoscope, and finally a clinically applicable Raman endoscope for larger animal studies. We show that this SERRS-NP-based approach enables robust detection of small, premalignant lesions in animal models that faithfully recapitulate human esophageal, gastric, and colorectal tumorigenesis. This method holds promise for much earlier detection of GI cancers than currently possible and could lead therefore to marked reduction of morbidity and mortality of these tumor types.
Loss of organized sleep electrophysiology is a characteristic finding following severe brain injury. The return of structured elements of sleep architecture has been associated with positive prognosis across injury etiologies, suggesting a role for sleep dynamics as biomarkers of wakeful neuronal circuit function. In a continuing study of one minimally conscious state patient studied over the course of similar to 81/2 years, we sought to investigate whether changes in daytime brain activation induced by central thalamic deep brain stimulation (CT-DBS) influenced sleep electrophysiology. In this patient subject, we previously reported significant improvements in sleep electrophysiology during 51/2 years of CT-DBS treatment, including increased sleep spindle frequency and SWS delta power. We now present novel findings that many of these improvements in sleep electrophysiology regress following CT-DBS discontinuation; these regressions in sleep features correlate with a significant decrease in behavioral responsiveness. We also observe the re-emergence of alpha-delta sleep, which had been previously suppressed by daytime CT-DBS in this patient subject. Importantly, CT-DBS was only active during the daytime and has been proposed to mediate recovery of consciousness by driving synaptic activity across frontostriatal systems through the enhancement of thalamocortical output. Accordingly, the improvement of sleep dynamics during daytime CT-DBS and their subsequent regression following CT-DBS discontinuation implicates wakeful synaptic activity as a robust modulator of sleep electrophysiology. We interpret these findings in the context of the "synaptic homeostasis hypothesis," whereby we propose that daytime upregulation of thalamocortical output in the severely injured brain may facilitate organized frontocortical circuit activation and yield net synaptic potentiation during wakefulness, providing a homeostatic drive that reconstitutes sleep dynamics over time. Furthermore, we consider common large-scale network dynamics across several neuropsychiatric disorders in which alpha-delta sleep has been documented, allowing us to formulate a novel mechanistic framework for alpha-delta sleep generation. We conclude that the bi-directional modulation of sleep electrophysiology by daytime thalamocortical activity in the severely injured brain: (1) emphasizes the cyclical carry-over effects of state-dependent circuit activation on large-scale brain dynamics, and (2) further implicates sleep electrophysiology as a sensitive indicator of wakeful brain activation and covert functional recovery in the severely injured brain.
Park D, Park SH, Kim YS, Choi BS, Kim JK, Kim NS, Choi IY
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NGS sequencing reveals that many of the genetic variations in transgenic rice plants match the variations found in natural rice population

GENES & GENOMICS 2019 FEB; 41(2):213-222
BackgroundAs the transformation process can induce mutations in host plants, molecular characterization of the associated genomic changes is important not only for practical food safety but also for understanding the fundamental theories of genome evolution.ObjectivesTo investigate a population-scale comparative study of the genome-wide spectrum of sequence variants in the transgenic genome with the variations present in 3000 rice varieties.ResultsOn average, we identified 19,273 SNPs (including Indels) per transgenic line in which 10,729 SNPs were at the identical locations in the three transgenic rice plants. We found that these variations were predominantly present in specific regions in chromosomes 8 and 10. Majority (88%) of the identified variations were detected at the same genomic locations as those in natural rice population, implying that the transgenic induced mutations had a tendency to be common alleles.ConclusionGenomic variations in transgenic rice plants frequently occurred at the same sites as the major alleles found in the natural rice population, which implies that the sequence variations occur within the limits of a biological system to ensure survival.
Shabani M, Aleyasin S, Kashef S, Zoghi S, Deswarte C, Casanova JL, Bustamante J, Rezaei N
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A Novel Recessive Mutation of Interferon- Receptor 1 in a Patient with Mycobacterium tuberculosis in Bone Marrow Aspirate

Shukla AP, Dickison M, Coughlin N, Karan A, Mauer E, Truong W, Casper A, Emiliano AB, Kumar RB, Saunders KH, Igel LI, Aronne LJ
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The impact of food order on postprandial glycaemic excursions in prediabetes

Data suggest that nutrient order during a meal significantly impacts postprandial glucose and insulin excursions in type 2 diabetes, while its effects in prediabetes have not been reported. Fifteen participants with prediabetes consumed the same meal on 3 days in random order: carbohydrate first, followed 10 minutes later by protein and vegetables (CF); protein and vegetables first, followed 10 minutes later by carbohydrate (PVF); or vegetables first followed by protein and carbohydrate (VF). Blood was sampled for glucose and insulin measurements at 0, 30, 60, 90, 120, 150 and 180 minutes. Incremental glucose peaks were similarly attenuated by >40% in the PVF and VF meal conditions compared with CF. The incremental area under the curve for glucose was 38.8% lower following the PVF meal order, compared with CF, and postprandial insulin excursions were significantly lower in the VF meal condition compared with CF. The CF meal pattern showed marked glycaemic variability whereas glucose levels were stable in the PVF and VF meal conditions. Food order presents a novel, simple behavioural strategy to reduce glycaemic excursions in prediabetes.