Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma negatively regulates telomere length

Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterized the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss of FAM111B expression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even though FAM111B-deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. When mutated as in HFP, FAM111B was more frequently localized to the nuclear envelope, suggesting that accumulation of the mutated protease at the nuclear periphery may drive the disease pathology

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Genomic Instability Is an Early Event in Aluminium-Induced Tumorigenesis

Genomic instability is generally considered as a hallmark of tumorigenesis and a prerequisite condition for malignant transformation. Aluminium salts are suspected environmental carcinogens that transform mammary epithelial cells in vitro through unknown mechanisms. We report here that long-term culture in the presence of aluminium chloride (AlCl3) enables HC11 normal mouse mammary epithelial cells to form tumours and metastases when injected into the syngeneic and immunocompetent BALB/cByJ strain. We demonstrate that AlCl3 rapidly increases chromosomal structural abnormalities in mammary epithelial cells, while we failed to detect direct modulation of specific mRNA pathways. Our observations provide evidence that clastogenic activity-a well-recognized inducer of genomic instability-might account in part for the transforming abilities of aluminium in mammary epithelial cells

Plasma C-terminal pro-endothelin-1 and the natriuretic pro-peptides NT-proBNP and MR-proANP in very preterm infants with patent ductus arteriosus

BACKGROUND: In very preterm infants, clinical decision-making, such as closing a patent ductus arteriosus (PDA), may be aided by measuring circulating natriuretic and endothelial pro-peptides. OBJECTIVES: To investigate the association between perinatal characteristics, PDA echocardiography and plasma concentrations of stable pro-peptides of B-type natriuretic peptide (NT-proBNP), atrial natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1). METHODS: A prospective, cross-sectional, single-center study was performed in 66 infants who were less than 32 weeks of gestational age. Pro-peptide concentrations were determined at birth and at day 2-3 of life. RESULTS: Plasma concentrations of all 3 pro-peptides increased on average 2- to 5-fold from birth to day 2-3 of life. NT-proBNP and MR-proANP were closely related at birth and at day 2-3 (Rs 0.902 and 0.897, respectively, p < 0.001), whereas CT-proET-1 was related to NT-proBNP and MR-proANP at birth (Rs 0.478 and 0.460, respectively, p < 0.001) but not at day 2-3. Birth weight was negatively related to all 3 pro-peptides at birth (p < 0.01); however, preeclampsia and compromised placental perfusion were associated with elevated NT-proBNP and MR-proANP concentrations at birth. At day 2-3, MR-proANP and NT-proBNP correlated significantly with the ductal diameter (Rs 0.416 and 0.415, respectively, both p = 0.011), whereas CT-proET-1 correlated with the left atrium/aorta ratio (Rs 0.506, p = 0.027). CT-proET-1 was elevated in infants with treated compared to untreated PDA [median (5-95% range) 388 (272-723) vs. 303 (152-422) pmol/l, p = 0.011], but not NT-proBNP or MR-proANP. CONCLUSION: CT-proET-1 is a promising predictor in determining the need for PDA intervention

Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry.

AIMS: To evaluate how recommendations of European guidelines regarding pharmacological and non-pharmacological treatments for heart failure (HF) are adopted in clinical practice. METHODS AND RESULTS: The ESC-HF Long-Term Registry is a prospective, observational study conducted in 211 Cardiology Centres of 21 European and Mediterranean countries, members of the European Society of Cardiology (ESC). From May 2011 to April 2013, a total of 12 440 patients were enrolled, 40.5% with acute HF and 59.5% with chronic HF. Intravenous treatments for acute HF were heterogeneously administered, irrespective of guideline recommendations. In chronic HF, with reduced EF, renin-angiotensin system (RAS) blockers, beta-blockers, and mineralocorticoid antagonists (MRAs) were used in 92.2, 92.7, and 67.0% of patients, respectively. When reasons for non-adherence were considered, the real rate of undertreatment accounted for 3.2, 2.3, and 5.4% of the cases, respectively. About 30% of patients received the target dosage of these drugs, but a documented reason for not achieving the target dosage was reported in almost two-thirds of them. The more relevant reasons for non-implantation of a device, when clinically indicated, were related to doctor uncertainties on the indication, patient refusal, or logistical/cost issues. CONCLUSION: This pan-European registry shows that, while in patients with acute HF, a large heterogeneity of treatments exists, drug treatment of chronic HF can be considered largely adherent to recommendations of current guidelines, when the reasons for non-adherence are taken into account. Observations regarding the real possibility to adhere fully to current guidelines in daily clinical practice should be seriously considered when clinical practice guidelines have to be written

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Placing changes in the microbiome in the context of the American Gut. We accumulated samples over sequencing runs to demonstrate the structural consistency in the data. We demonstrate that while the ICU dataset (https://www.ncbi.nlm.nih.gov/pubmed/27602409) falls within the American Gut samples, they do not fall close to most samples at any of the body sites. We then highlight samples from the United Kingdom, Australia, the United States and other countries to show that nationality does not overcome the variation in body site. We then highlight the utility of the American Gut in meta-analysis by reproducing results from (https://www.ncbi.nlm.nih.gov/pubmed/20668239) and (https://www.ncbi.nlm.nih.gov/pubmed/23861384), using the AGP dataset as the context for dynamic microbiome changes instead of the HMP dataset. We show rapid, complete recovery of C. diff patients following fecal material transplantation and also contextualized the change in an infant gut over time until it settles into an adult state. This demonstrates the power of the American Gut dataset, both as a cohesive study and as a context for other investigations

ag_tree.tre

The SEPP (Mirarab et al Pac Symp Biocomput 2012) fragment insertion tree used for phylogenetic analyses

American Gut Project fecal sOTU counts table

The Deblur sOTU counts table for the fecal samples used in the American Gut Project manuscript. The samples were trimmed to a common read length of 125nt, and processed by Deblur (Amir et al mSystems 2017). Blooms were removed (Amir et al mSystems 2017) and any sample with fewer than 1250 sequences was omitted. This table is not rarefied,

Unweighted UniFrac distances

The unweighted UniFrac distance (Lozupone and Knight AEM 2005) matrix of the 9511 fecal samples used in the American Gut paper. UniFrac was computed using Striped UniFrac (https://github.com/biocore/unifrac). Prior to execution of UniFrac, Deblur (Amir et al mSystems 2017) was run on the samples, all bloom sOTUs were removed (Amir et al mSystems 2017), and samples were rarefied to a depth of 1250 reads (Weiss et al Microbiome 2017). For the phylogeny, fragments were inserted using SEPP (Mirarab et al Pac Symp Biocomput 2012) into the Greengenes 13_5 99% OTU tree (McDonald et al ISME 2012)