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He H, Guttman-Yassky E
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JAK Inhibitors for Atopic Dermatitis: An Update (vol 20, pg 181, 2019)

Capoor MN, Lochman J, McDowell A, Schmitz JE, Solansky M, Zapletalova M, Alamin TF, Coscia MF, Garfin SR, Jancalek R, Ruzicka F, Shamie AN, Smrcka M, Wang JC, Birkenmaier C, Slaby O
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Intervertebral disc penetration by antibiotics used prophylactically in spinal surgery: implications for the current standards and treatment of disc infections

EUROPEAN SPINE JOURNAL 2019 APR; 28(4):783-791
PurposeThe presence of Propionibacterium acnes in a substantial component of resected disc specimens obtained from patients undergoing discectomy or microdiscectomy has led to the suggestion that this prominent human skin and oral commensal may exacerbate the pathology of degenerative disc disease. This hypothesis, therefore, raises the exciting possibility that antibiotics could play an important role in treating this debilitating condition. To date, however, little information about antibiotic penetration into the intervertebral disc is available. MethodsIntervertebral disc tissue obtained from 54 microdiscectomy patients given prophylactic cefazolin (n=25), clindamycin (n=17) or vancomycin (n=12) was assayed by high-performance liquid chromatography, with cefaclor as an internal standard, to determine the concentration of antibiotic penetrating into the disc tissue.ResultsIntervertebral disc tissues from patients receiving the positively charged antibiotic clindamycin contained a significantly greater percentage of the antibacterial dose than the tissue from patients receiving negatively charged cefazolin (P<0.0001) and vancomycin, which has a slight positive charge (P<0.0001).ConclusionPositively charged antibiotics appear more appropriate for future studies investigating potential options for the treatment of low-virulence disc infections. [GRAPHICS]
Sarker M, Lee HT, Mei L, Krokhotin A, de los Reyes SE, Yen L, Costantini LM, Griffith J, Dokholyan NV, Alushin GM, Campbell SL
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Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies

JOURNAL OF MOLECULAR BIOLOGY 2019 APR 5; 431(8):1604-1618
Debilitating heart conditions, notably dilated and hypertrophic cardiomyopathies (CMs), are associated with point mutations in metavinculin, a larger isoform of the essential cytoskeletal protein vinculin. Metavinculin is co-expressed with vinculin at sub-stoichiometric ratios in cardiac tissues. CM mutations in the metavinculin tail domain (MVt) occur within the extra 68-residue insert that differentiates it from the vinculin tail domain (Vt). Vt binds actin filaments (F-actin) and promotes vinculin dimerization to bundle F-actin into thick fibers. While MVt binds to F-actin in a similar manner to Vt, MVt is incapable of F-actin bundling and inhibits Vt-mediated F-actin bundling. We performed F-actin co-sedimentation and negative-stain EM experiments to dissect the coordinated roles of metavinculin and vinculin in actin fiber assembly and the effects of three known metavinculin CM mutations. These CM mutants were found to weakly induce the formation of disordered F-actin assemblies. Notably, they fail to inhibit Vt-mediated F-actin bundling and instead promote formation of large assemblies embedded with linear bundles. Computational models of MVt bound to F-actin suggest that MVt undergoes a conformational change licensing the formation of a protruding sub-domain incorporating the insert, which sterically prevents dimerization and bundling of F-actin by Vt. Sub-domain formation is destabilized by CM mutations, disrupting this inhibitory mechanism. These findings provide new mechanistic insights into the ability of metavinculin to tune actin organization by vinculin and suggest that dysregulation of this process by CM mutants could underlie their malfunction in disease. (C) 2019 Elsevier Ltd. All rights reserved.
Posey JE, O'Donnell-Luria AH, Chong JX, Harel T, Jhangiani SN, Akdemir ZHC, Buyske S, Pehlivan D, Carvalho CMB, Baxter S, Sobreira N, Liu PF, Wu N, Rosenfeld JA, Kumar S, Avramopoulos D, White JJ, Doheny KF, Witmer PD, Boehm C, Sutton VR, Muzny DM, Boerwinkle E, Gunel M, Nickerson DA, Mane S, MacArthur DG, Gibbs RA, Hamosh A, Lifton RP, Matise TC, Rehm HL, Gerstein M, Bamshad MJ, Valle D, Lupski JR
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Insights into genetics, human biology and disease gleaned from family based genomic studies

GENETICS IN MEDICINE 2019 APR; 21(4):798-812
Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the similar to 20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.
Rostol JT, Marraffini LA
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Non-specific degradation of transcripts promotes plasmid clearance during type III-A CRISPR-Cas immunity

NATURE MICROBIOLOGY 2019 APR; 4(4):656-662
Type III-A CRISPR-Cas systems employ the Cas10-Csm complex to destroy bacteriophages and plasmids, using a guide RNA to locate complementary RNA molecules from the invader and trigger an immune response that eliminates the infecting DNA. In addition, these systems possess the non-specific RNase Csm6, which provides further protection for the host. While the role of Csm6 in immunity during phage infection has been determined, how this RNase is used against plasmids is unclear. Here, we show that Staphylococcus epidermidis Csm6 is required for immunity when transcription across the plasmid target is infrequent, leading to impaired target recognition and inefficient DNA degradation by the Cas10-Csm complex. In these conditions, Csm6 causes growth arrest in the host and prevents further plasmid replication through the indiscriminate degradation of host and plasmid transcripts. In contrast, when plasmid target sequences are efficiently transcribed, Csm6 is dispensable and DNA degradation by Cas10 is sufficient for anti-plasmid immunity. Csm6 therefore provides robustness to the type III-A CRISPR-Cas immune response against difficult targets for the Cas10-Csm complex.
He H, Guttman-Yassky E
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JAK Inhibitors for Atopic Dermatitis: An Update

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. AD is driven by barrier dysfunction and abnormal immune activation of Thelper (Th) 2, Th22, and varying degrees of Th1 and Th17 among various subtypes. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and spleen tyrosine kinase (SYK) pathways are involved in signaling of several AD-related cytokines, such as IFN-gamma, IL-4, IL-13, IL-31, IL-33, IL-23, IL-22, and IL-17, mediating downstream inflammation and barrier alterations. While AD is primarily Th2-driven, the clinical and molecular heterogeneity of AD endotypes highlights the unmet need for effective therapeutic options that target more than one immune axis and are safe for long-term use. The JAK inhibitors, which target different combinations of kinases, have overlapping but distinct mechanisms of action and safety profiles. Several topical and oral JAK inhibitors have been shown to decrease AD severity and symptoms. A review of the JAK and SYK inhibitors that are currently undergoing evaluation for efficacy and safety in the treatment of AD summarizes available data on a promising area of therapeutics and further elucidates the complex molecular interactions that drive AD.
Lopez-Cruz A, Sordillo A, Pokala N, Liu Q, McGrath PT, Bargmann CI
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Parallel Multimodal Circuits Control an Innate Foraging Behavior

NEURON 2019 APR 17; 102(2):407-419.e8
Foraging strategies emerge from genetically encoded programs that are similar across animal species. Here, we examine circuits that control a conserved foraging state, local search behavior after food removal, in Caenorhabditis elegans. We show that local search is triggered by two parallel groups of chemosensory and mechanosensory glutamater-gic neurons that detect food-related cues. Each group of sensory neurons suppresses distinct integrating neurons through a G protein-coupled metabotropic glutamate receptor, MGL-1, to release local search. The chemosensory and mechanosensory modules are separate and redundant; glutamate release from either module can drive the full behavior. A transition from local search to global search over several minutes after food removal is associated with two changes in circuit function. First, the spontaneous activity of sensory neurons falls. Second, the motor pattern generator for local search becomes less responsive to sensory input. This multimodal, distributed short-term food memory provides robust control of an innate behavior.
Galea S, Vaughan R
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Tradeoffs Between Equity and Efficiency at the Heart of Population Health Science: A Public Health of Consequence, April 2019

Paris K, Haddad E, Borte M, Brodszki N, Derfalvi B, Marodi L, Hussain I, Darter A, Engl W, Leibl H, McCoy B, Yel L
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Tolerability of subcutaneous immunoglobulin 20%, Ig20Gly, in pediatric patients with primary immunodeficiencies

IMMUNOTHERAPY 2019 APR; 11(5):397-406
Aim: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. Patients & methods: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n=6], 6-11 years [n=22] and 12-17 years [n=22]) receiving Ig20Gly in two Phase II/III trials. Results: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30ml/h/site; 30ml/site) versus 6-11 years (20ml/h/site; 15ml/site) and 2-5 years (18ml/h/site; 14ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. Conclusion: Ig20Gly infused at relatively high rates and volumes was well tolerated in children.
Chaker-Margot M, Klinge S
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Assembly and early maturation of large subunit precursors

RNA 2019 APR; 25(4):465-471
The eukaryotic ribosome is assembled through a complex process involving more than 200 factors. As preribosomal RNA is transcribed, assembly factors bind the nascent pre-rRNA and guide its correct folding, modification, and cleavage. While these early events in the assembly of the small ribosomal subunit have been relatively well characterized, assembly of the large subunit precursors, or pre-60S, is less well understood. Recent structures of nucleolar intermediates of large subunit assembly have shed light on the role of many early large subunit assembly factors, but how these particles emerge is still unknown. Here, we use the expression and purification of truncated pre-rRNAs to examine the initial assembly of pre-60S particles. Using this approach, we can recapitulate the early recruitment of large subunit assembly factors mainly to the domains I, II, and VI of the assembling 25S rRNA.