Pangenome Evolution in theMarine Bacterium Alteromonas

Wehave examined a collection of the free-livingmarine bacterium Alteromonas genomeswith cores diverging in average nucleotide identities ranging from 99.98% to 73.35%, i.e., frommicrobes that can be consideredmembers of a natural clone (like in a clinical epidemiological outbreak) to borderline genus level. The genomes were largely syntenic allowing a precise delimitation of the core and flexible regions in each. The core was 1.4Mb (ca. 30% of the typical strain genome size). Recombination rates along the core were high among strains belonging to the same species (37.7–83.7% of all nucleotide polymorphisms) but they decreased sharply between species (18.9–5.1%). Regarding the flexible genome, itsmain expansion occurred within the boundaries of the species, i.e., strains of the same species already have a large and diverse flexible genome. Flexible regions occupy mostly fixed genomic locations. Four large genomic islands are involved in the synthesis of strain-specific glycosydic receptors that we have called glycotypes. These genomic regions are exchanged by homologous recombination within and between species and there is evidence for their import from distant taxonomic units (other genera within the family). In addition, several hotspots for integration of gene cassettes by illegitimate recombination are distributed throughout the genome. They code for features that give each clone specific properties to interact with their ecological niche andmustflowfast throughout thewholegenus as they are found, withnearly identical sequences, in different species. Models for the generation of this genomic diversity involving phage predation are discussed.This work was funded by the Spanish MINECO (Grants BFPU2013-48007-P)This work was funded by the Generalitat Valenciana PROMETEO (Grants II/2014/012

Polyclonality of Concurrent Natural Populations of Alteromonas macleodii

We have analyzed a natural population of the marine bacterium, Alteromonas macleodii, from a single sample of seawater to evaluate the genomic diversity present. We performed full genome sequencing of four isolates and 161 metagenomic fosmid clones, all of which were assigned to A. macleodii by sequence similarity. Out of the four strain genomes, A. macleodii deep ecotype (AltDE1) represented a different genome, whereas AltDE2 and AltDE3 were identical to the previously described AltDE. Although the core genome (∼80%) had an average nucleotide identity of 98.51%, both AltDE and AltDE1 contained flexible genomic islands (fGIs), that is, genomic islands present in both genomes in the same genomic context but having different gene content. Some of the fGIs encode cell surface receptors known to be phage recognition targets, such as the O-chain of the lipopolysaccharide, whereas others have genes involved in physiological traits (e.g., nutrient transport, degradation, and metal resistance) denoting microniche specialization. The presence in metagenomic fosmids of genomic fragments differing from the sequenced strain genomes, together with the presence of new fGIs, indicates that there are at least two more A. macleodii clones present. The availability of three or more sequences overlapping the same genomic region also allowed us to estimate the frequency and distribution of recombination events among these different clones, indicating that these clustered near the genomic islands. The results indicate that this natural A. macleodii population has multiple clones with a potential for different phage susceptibility and exploitation of resources, within a seemingly unstructured habitat

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: A nationwide study in Spain

Objective To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. Settings The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. Participants This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. Interventions An exploratory factorial analysis was performed to select the most relevant variables of the sample. Primary and secondary outcome measures Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. Results Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/10 5 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade =3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/10 5 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. Conclusions Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/10 5 people/week) was a statistically independent predictor of mortality. Trial registration number CEIM 20/217

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Age distribution of lamproites along the Socovos Fault (southern Spain) and lithospheric scale tearing

Lithospheric-scale tearing is commonly linked to the lateral termination of subduction rollback and slab segmentation. The upper-crustal expression of this process can be associated with the development of arcuate orogenic belts (oroclines) generated by a combination of vertical-axis block rotations and strike-slip faulting. However, the link between such strike-slip faults and slab tearing is relatively poorly constrained. We show here an example from the Gibraltar Arc in the westernmost Mediterranean, where lithospheric-scale tear faulting during the Late Miocene accommodated westward subduction rollback. The dextral strike-slip Socovos Fault in the eastern Betics may represent one of the surface expressions of this process. We document a high concentration of mantle-derived volcanic rocks (lamproites) along the Socovos Fault, which were intruded as dikes during the Late Miocene. Phlogopite and whole-rock 40Ar/39Ar ages of lamproites along the Socovos Fault show a spatial age zonation, with older ages (9.3-8.2Ma) in the east and younger ages (7.3-7.1Ma) in the west. This age distribution of the lamproites along the Socovos Fault is compatible with the westward retreat of the lithospheric slab that was active beneath the eastern Betics in the Late Miocene. We therefore hypothesize that tearing allowed pathways for lamproite melts in the subcontinental lithospheric mantle and lower crust, with the Socovos Fault channelizing these magmas in the upper crust

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Correction for Lopez-Perez et al., Genome Sequence of 'Thalassospira australica' NP3b2T Isolated from St. Kilda Beach, Tasman Sea

This corrects the article "Genome Sequence of 'Thalassospira australica' NP3b2T Isolated from St. Kilda Beach, Tasman Sea" in volume 2, e01139-14. Volume 2, no. 6, e01139-14, 2014. Page 1: The first two sentences of the second paragraph should read as follows. 'Gram-negative, aerobic, moderately halophilic alphaproteobacteria with the ability to utilize hydrocarbons as the sole carbon and energy sources were incorporated into the genus Thalassospira 12 years ago (6). To date, the genus comprises 8 validly named species (7).' Page 1: The reference range cited at the end of the third sentence in the second paragraph should be 22 to 25. Page 2: Reference 6 should be replaced with the following. 6. Lopez-Lopez A, Pujalte MJ, Benlloch S, Mata-Roig M, Rossello-Mora R, Garay E, Rodri;guez-Valera F. 2002. Thalassospira lucentensis gen. nov., sp. nov., a new marine member of the Proteobacteria. Int. J. Syst. Evol. Microbiol. 52:1277–1283. http://dx.doi.org/10.1099/ijs.0.01928-0. Page 2: References 8 to 14 should be deleted

Treatment of hypertension with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and resting metabolic rate: A cross-sectional study

Hypertension in obese and overweight patients is associated with an elevated resting metabolic rate (RMR). The aim of this study was to determine whether RMR is reduced in hypertensive patients treated with angiotensin-converting enzyme inhibitors (ACEI) and blockers (ARB). The RMR was determined by indirect calorimetry in 174 volunteers; 93 (46.5 %) were hypertensive, of which 16 men and 13 women were treated with ACEI/ARB, while 30 men and 19 women with untreated hypertension served as a control group. Treated and untreated hypertensives had similar age, BMI, physical activity, and cardiorespiratory fitness. The RMR normalized to the lean body mass (LBM) was 15% higher in the untreated than ACEI/ARB-treated hypertensive women (p = .003). After accounting for LBM, whole-body fat mass, age, the double product (heart rate x systolic blood pressure), and the distance walked per day, the RMR was 2.9% lower in the patients taking ACEI/ARB (p = .26, treatment x sex interaction p = .005). LBM, age, and the double product explained 78% of the variability in RMR (R2 = 0.78, p < .001). In contrast, fat mass, the distance walked per day, and total T4 or TSH did not add predictive power to the model. Compared to men, a greater RMR per kg of LBM was observed in untreated hypertensive overweight and obese women, while this sex difference was not observed in patients treated with ACEI or ARBs. In conclusion, our results indicate that elevated RMR per kg of LBM may be normalized by antagonizing the renin-angiotensin system