Haemodynamic consequences of targeted single- and dual-site right ventricular pacing in adults with congenital heart disease undergoing surgical pulmonary valve replacement

Aims The purpose of this study was to create an epicardial electroanatomic map of the right ventricle (RV) and then apply post-operative-targeted single- and dual-site RV temporary pacing with measurement of haemodynamic parameters. Cardiac resynchronization therapy is an established treatment for symptomatic left ventricular (LV) dysfunction. In congenital heart disease, RV dysfunction is a common cause of morbidity—little is known regarding the potential benefits of CRT in this setting. Methods and results Sixteen adults (age = 32 ± 8 years; 6 M, 10 F) with right bundle branch block (RBBB) and repaired tetralogy of Fallot (n = 8) or corrected congenital pulmonary stenosis (n = 8) undergoing surgical pulmonary valve replacement (PVR) for pulmonary regurgitation underwent epicardial RV mapping and haemodynamic assessment of random pacing configurations including the site of latest RV activation. The pre-operative pulmonary regurgitant fraction was 49 ± 10%; mean LV end-diastolic volume (EDV) 85 ± 19 mL/min/m2 and RVEDV 183 ± 89 mL/min/m2 on cardiac magnetic resonance imaging. The mean pre-operative QRS duration is 136 ± 26 ms. The commonest site of latest activation was the RV free wall and DDD pacing here alone or combined with RV apical pacing resulted in significant increases in cardiac output (CO) vs. AAI pacing (P < 0.01 all measures). DDDRV alternative site pacing significantly improved CO by 16% vs. AAI (P = 0.018), and 8.5% vs. DDDRV apical pacing (P = 0.02). Conclusion Single-site RV pacing targeted to the region of latest activation in patients with RBBB undergoing PVR induces acute improvements in haemodynamics and supports the concept of ‘RV CRT’. Targeted pacing in such patients has therapeutic potential both post-operatively and in the long term

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Rapid draft sequencing and real-time nanopore sequencing in a hospital outbreak of Salmonella

Background: Foodborne outbreaks of Salmonella remain a pressing public health concern. We recently detected a large outbreak of Salmonella enterica serovar Enteritidis phage type 14b affecting more than 30 patients in our hospital. This outbreak was linked to community, national and European-wide cases. Hospital patients with Salmonella are at high risk, and require a rapid response. We initially investigated this outbreak by whole-genome sequencing using a novel rapid protocol on the Illumina MiSeq; we then integrated these data with whole-genome data from surveillance sequencing, thereby placing the outbreak in a national context. Additionally, we investigated the potential of a newly released sequencing technology, the MinION from Oxford Nanopore Technologies, in the management of a hospital outbreak of Salmonella. Results: We demonstrate that rapid MiSeq sequencing can reduce the time to answer compared to the standard sequencing protocol with no impact on the results. We show, for the first time, that the MinION can acquire clinically relevant information in real time and within minutes of a DNA library being loaded. MinION sequencing permits confident assignment to species level within 20 min. Using a novel streaming phylogenetic placement method samples can be assigned to a serotype in 40 min and determined to be part of the outbreak in less than 2 h. Conclusions: Both approaches yielded reliable and actionable clinical information on the Salmonella outbreak in less than half a day. The rapid availability of such information may facilitate more informed epidemiological investigations and influence infection control practices

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G>A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers

Rapid niche expansion by selection on functional genomic variation after ecosystem recovery

It is well recognized that environmental degradation caused by human activities can result in dramatic losses of species and diversity. However, comparatively little is known about the ability of biodiversity to re-emerge following ecosystem recovery. Here, we show that a European whitefish subspecies, the gangfisch Coregonus lavaretus macrophthalmus, rapidly increased its ecologically functional diversity following the restoration of Lake Constance after anthropogenic eutrophication. In fewer than ten generations, gangfisch evolved a greater range of gill raker numbers (GRNs) to utilize a broader ecological niche. A sparse genetic architecture underlies this variation in GRN. Several co-expressed gene modules and genes showing signals of positive selection were associated with GRN and body shape. These were enriched for biological pathways related to trophic niche expansion in fishes. Our findings demonstrate the potential of functional diversity to expand following habitat restoration, given a fortuitous combination of genetic architecture, genetic diversity and selection

Plastid phylogenomics resolves ambiguous relationships within the orchid family and provides a solid timeframe for biogeography and macroevolution

Recent phylogenomic analyses based on the maternally inherited plastid organelle have enlightened evolutionary relationships between the subfamilies of Orchidaceae and most of the tribes. However, uncertainty remains within several subtribes and genera for which phylogenetic relationships have not ever been tested in a phylogenomic context. To address these knowledge-gaps, we here provide the most extensively sampled analysis of the orchid family to date, based on 78 plastid coding genes representing 264 species, 117 genera, 18 tribes and 28 subtribes. Divergence times are also provided as inferred from strict and relaxed molecular clocks and birth–death tree models. Our taxon sampling includes 51 newly sequenced plastid genomes produced by a genome skimming approach. We focus our sampling efforts on previously unplaced clades within tribes Cymbidieae and Epidendreae. Our results confirmed phylogenetic relationships in Orchidaceae as recovered in previous studies, most of which were recovered with maximum support (209 of the 262 tree branches). We provide for the first time a clear phylogenetic placement for Codonorchideae within subfamily Orchidoideae, and Podochilieae and Collabieae within subfamily Epidendroideae. We also identify relationships that have been persistently problematic across multiple studies, regardless of the different details of sampling and genomic datasets used for phylogenetic reconstructions. Our study provides an expanded, robust temporal phylogenomic framework of the Orchidaceae that paves the way for biogeographical and macroevolutionary studies.Universidad de Costa Rica/[814-B8-257]/UCR/Costa RicaUniversidad de Costa Rica/[814-B6-140]/UCR/Costa RicaIDEA WILD/[]//Estados UnidosSociedad Colombiana de Orquideología/[]/SCO/ColombiaFundação de Amparo à Pesquisa do Estado de São Paulo/[11/08308-9]/FAPESP/BrasilFundação de Amparo à Pesquisa do Estado de São Paulo/[13/19124-1]/FAPESP/BrasilSwiss Orchid Foundation/[]//SuizaRoyal Botanic Gardens, Kew/[]//InglaterraSwedish Research Council/[2019-05191]//SueciaSwedish Foundation for Strategic Research/[FFL15-0196]/SSF/SueciaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Jardín Botánico Lankester (JBL

Myocarditis in CD8-Depleted SIV-Infected Rhesus Macaques after Short-Term Dual Therapy with Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Background: Although highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. Methodology/Principal Findings: We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/−)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05), but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05). Interferon-γ (IFN-γ), IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. Conclusions/Significance: These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection

The genome of the Trinidadian guppy, Poecilia reticulata, and variation in the Guanapo population

For over a century, the live bearing guppy, Poecilia reticulata, has been used to study sexual selection as well as local adaptation. Natural guppy populations differ in many traits that are of intuitively adaptive significance such as ornamentation, age at maturity, brood size and body shape. Water depth, light supply, food resources and predation regime shape these traits, and barrier waterfalls often separate contrasting environments in the same river. We have assembled and annotated the genome of an inbred single female from a high-preda- tion site in the Guanapo drainage. The final assembly comprises 731.6 Mb with a scaffold N50 of 5.3 MB. Scaffolds were mapped to linkage groups, placing 95% of the genome assembly on the 22 autosomes and the X-chromosome. To investigate genetic variation in the population used for the genome assembly, we sequenced 10 wild caught male individu- als. The identified 5 million SNPs correspond to an average nucleotide diversity (π) of 0.0025. The genome assembly and SNP map provide a rich resource for investigating adap- tation to different predation regimes. In addition, comparisons with the genomes of other Poeciliid species, which differ greatly in mechanisms of sex determination and maternal resource allocation, as well as comparisons to other teleost genera can begin to reveal how live bearing evolved in teleost fish

The inference of gray whale (Eschrichtius robustus) historical population attributes from whole-genome sequences

Commercial whaling caused extensive demographic declines in many great whale species, including gray whales that were extirpated from the Atlantic Ocean and dramatically reduced in the Pacific Ocean. The Eastern Pacific gray whale has recovered since the 1982 ban on commercial whaling, but the Western Pacific gray whale-once considered possibly extinct-consists of only about 200 individuals and is considered critically endangered by some international authorities. Herein, we use whole-genome sequencing to investigate the demographic history of gray whales from the Pacific and use environmental niche modelling to make predictions about future gene flow.Our sequencing efforts and habitat niche modelling indicate that: i) western gray whale effective population sizes have declined since the last glacial maximum; ii) contemporary gray whale genomes, both eastern and western, harbor less autosomal nucleotide diversity than most other marine mammals and megafauna; iii) the extent of inbreeding, as measured by autozygosity, is greater in the Western Pacific than in the Eastern Pacific populations; and iv) future climate change is expected to open new migratory routes for gray whales.Our results indicate that gray whale genomes contain low nucleotide diversity and have been subject to both historical and recent inbreeding. Population sizes over the last million years likely peaked about 25,000 years before present and have declined since then. Our niche modelling suggests that novel migratory routes may develop within the next century and if so this could help retain overall genetic diversity, which is essential for adaption and successful recovery in light of global environmental change and past exploitation

Stem rust resistance in wheat is suppressed by a subunit of the mediator complex

Stem rust is an important disease of wheat that can be controlled using resistance genes. The gene SuSr-D1 identified in cultivar 'Canthatch' suppresses stem rust resistance. SuSr-D1 mutants are resistant to several races of stem rust that are virulent on wild-type plants. Here we identify SuSr-D1 by sequencing flow-sorted chromosomes, mutagenesis, and map-based cloning. The gene encodes Med15, a subunit of the Mediator Complex, a conserved protein complex in eukaryotes that regulates expression of protein-coding genes. Nonsense mutations in Med15b.D result in expression of stem rust resistance. Time-course RNAseq analysis show a significant reduction or complete loss of differential gene expression at 24h post inoculation in med15b.D mutants, suggesting that transcriptional reprogramming at this time point is not required for immunity to stem rust. Suppression is a common phenomenon and this study provides novel insight into suppression of rust resistance in wheat. Stem rust is an important disease of wheat and resistance present in some cultivars can be suppressed by the SuSr-D1 locus. Here the authors show that SuSr-D1 encodes a subunit of the Mediator Complex and that nonsense mutations are sufficient to abolish suppression and confer stem rust resistance