Sonnearnold5471

OBJECTIVE Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. DESIGN We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. RESULTS We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. CONCLUSIONS These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Thoracic oesophageal diverticula are often associated with spastic motility disorders. Despite correction of the underlying motility disorder, in a subgroup of patients, symptoms persist, primarily regurgitation. Surgical diverticulectomy is then proposed; however, as the approach is thoracoscopic or via thoracotomy, it is associated with significant morbidity and cost. Descriptions of endoscopic techniques for the treatment of symptomatic midoesophageal diverticula are few. We propose the novel technique of diverticular myotomy (DM) to treat this disorder. In this case series, we describe two patients who successfully underwent DM with no adverse outcomes and excellent clinical results at 24-month follow-up. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND AND OBJECTIVES Recent guidelines recommend out-of-clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared the prevalence of BP phenotypes between 561 black patients, with and without CKD, taking antihypertensive medication who underwent ambulatory BP monitoring at baseline (between 2000 and 2004) in the Jackson Heart Study. CKD was defined as an albumin-to-creatinine ratio ≥30 mg/g or eGFR less then 60 ml/min per 1.73 m2. Sustained controlled BP was defined by BP at goal both inside and outside of the clinic and sustained uncontrolled BP as BP above goal both inside and outside of the clinic. Masked uncontrolled hypertension was defined by controlled clinic-measured BP with uncontrolled out-of-clinic BP. RESULTS CKD was associated with a higher multivariable-adjusted prevalence ratio for uncontrolled versus controlled clinic BP (prevalence ratio, 1.44; 95% CI, 1.02 to 2.02) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 1.66; 95% CI, 1.16 to 2.36). There were no statistically significant differences in the prevalence of uncontrolled daytime or nighttime BP, nondipping BP, white-coat effect, and masked uncontrolled hypertension between participants with and without CKD after multivariable adjustment. After multivariable adjustment, reduced eGFR was associated with masked uncontrolled hypertension versus sustained controlled BP (prevalence ratio, 1.42; 95% CI, 1.00 to 2.00), whereas albuminuria was associated with uncontrolled clinic BP (prevalence ratio, 1.76; 95% CI, 1.20 to 2.60) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 2.02; 95% CI, 1.36 to 2.99). CONCLUSIONS The prevalence of BP phenotypes defined using ambulatory BP monitoring is high among adults with CKD taking antihypertensive medication. Copyright © 2020 by the American Society of Nephrology.BACKGROUND AND OBJECTIVES Hypertension is highly prevalent in patients with CKD as is cognitive impairment and frailty, but the link between them is understudied. Our objective was to determine the association between ambulatory BP patterns, cognitive function, physical function, and frailty among patients with nondialysis-dependent CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Ambulatory BP readings were obtained on 1502 participants of the Chronic Renal Insufficiency Cohort. We evaluated the following exposures (1) BP patterns (white coat, masked, sustained versus controlled hypertension) and (2) dipping patterns (reverse, extreme, nondippers versus normal dippers). Outcomes included the following (1) cognitive impairment scores from the Modified Mini Mental Status Examination of less then 85, less then 80, and less then 75 for participants less then 65, 65-79, and ≥80 years, respectively; (2) physical function, measured by the short physical performance battery (SPPB), with higher scores (0-12) iniable adjustment, there was no association between BP or dipping patterns and incident frailty or cognitive impairment. CONCLUSIONS In patients with CKD, dipping and BP patterns are not associated with incident or prevalent cognitive impairment or prevalent frailty. Copyright © 2020 by the American Society of Nephrology.In the cereal crop sorghum (Sorghum bicolor) inflorescence morphology variation underlies yield variation and confers adaptation across precipitation gradients, but its genetic basis is poorly understood. We characterized the genetic architecture of sorghum inflorescence morphology using a global nested association mapping (NAM) population (2200 recombinant inbred lines) and 198,000 phenotypic observations from multi-environment trials for four inflorescence morphology traits (upper branch length, lower branch length, rachis length, and rachis diameter). Trait correlations suggest that lower and upper branch length are under somewhat independent control, while lower branch length and rachis diameter are highly pleiotropic. Joint linkage and genome-wide association mapping revealed an oligogenic architecture with 1-22 QTL per trait, each explaining 0.1%-5.0% of variation across the entire NAM population. There is a significant enrichment (2.2-fold) of QTL colocalizing with grass inflorescence gene homologs, notably with orthologs of maize Ramosa2 and rice Aberrant Panicle Organization1 and TAWAWA1 Still, many QTL do not colocalize with inflorescence gene homologs. In global georeferenced germplasm, allelic variation at the major inflorescence QTL is geographically patterned but only weakly associated with the gradient of annual precipitation. Comparison of NAM with diversity panel association suggests that naive association models may capture some true associations not identified by mixed linear models. Overall, the findings suggest that global inflorescence diversity in sorghum is largely controlled by oligogenic, epistatic, and pleiotropic variation in ancestral regulatory networks. The findings also provide a basis for genomics-enabled breeding of locally-adapted inflorescence morphology. Copyright © The Author(s) 2020. Published by the Genetics Society of America.Leptopilina boulardi (Hymenoptera Figitidae) is a specialist parasitoid of Drosophila The Drosophila-Leptopilina system has emerged as a suitable model for understanding several aspects of host-parasitoid biology. However, a good quality genome of the wasp counterpart was lacking. Here, we report a whole-genome assembly of L. boulardi to bring it in the scope of the applied and fundamental research on Drosophila parasitoids with access to epigenomics and genome editing tools. The 375Mb draft genome has an N50 of 275Kb with 6315 scaffolds >500bp and encompasses >95% complete BUSCOs. Using a combination of ab-initio and RNA-Seq based methods, 25259 protein-coding genes were predicted and 90% (22729) of them could be annotated with at least one function. We demonstrate the quality of the assembled genome by recapitulating the phylogenetic relationship of L. boulardi with other Hymenopterans. The key developmental regulators like Hox genes and sex determination genes are well conserved in L. boulardi, and so is the basic toolkit for epigenetic regulation. The search for epigenetic regulators has also revealed that L. boulardi genome possesses DNMT1 (maintenance DNA methyltransferase), DNMT2 (tRNA methyltransferase) but lacks the de novo DNA methyltransferase (DNMT3). Also, the heterochromatin protein 1 family appears to have expanded as compared to other hymenopterans. The draft genome of L. boulardi (Lb17) will expedite the research on Drosophila parasitoids. This genome resource and early indication of epigenetic aspects in its specialization make it an interesting system to address a variety of questions on host-parasitoid biology. Copyright © The Author(s) 2020. Published by the Genetics Society of America.The physical connections established by recombination are normally sufficient to ensure proper chromosome segregation during female Meiosis I. GSK269962A manufacturer However, nonexchange chromosomes (such as the Muller F element or "dot" chromosome in D. melanogaster) can still segregate accurately because they remain connected by heterochromatic tethers. A recent study examined female meiosis in the closely related species D. melanogaster and D. simulans, and found a nearly two-fold difference in the mean distance the obligately nonexchange dot chromosomes were separated during Prometaphase. That study proposed two speculative hypotheses for this difference, the first being the amount of heterochromatin in each species, and the second being the species' differing tolerance for common inversions in natural populations. We tested these hypotheses by examining female meiosis in 12 additional Drosophila species. While neither hypothesis had significant support, we did see 10-fold variation in dot chromosome sizes, and 5-fold variation in the frequency of chromosomes out on the spindle, which were both significantly correlated with chromosome separation distances. In addition to demonstrating that heterochromatin abundance changes chromosome behavior, this implies that the duration of Prometaphase chromosome movements must be proportional to the size of the F element in these species. Additionally, we examined D. willistoni, a species that lacks a free dot chromosome. We observed that chromosomes still move out on the meiotic spindle, and the F element was always positioned closest to the spindle poles. This result is consistent with models where one role of the dot chromosomes is to help organize the meiotic spindle. Copyright © The Author(s) 2020. Published by the Genetics Society of America.