Showing papers by "University of Bordeaux published in 2019"
TL;DR: Obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy.
Abstract: Summary Background Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. Methods In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18–75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. Findings Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3–36·0) and targeted biopsy (32·3%, 26·5–38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8–8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6–11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). Interpretation There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. Funding French National Cancer Institute.
625 citations
TL;DR: Patients with chronic atrophic gastritis or intestinal metaplasia (IM) are at risk for gastric adenocarcinoma, and identification and surveillance of patients with precancerous gastric conditions is cost-effective.
Abstract: Patients with chronic atrophic gastritis or intestinal metaplasia (IM) are at risk for gastric adenocarcinoma. This underscores the importance of diagnosis and risk stratification for these patients. High definition endoscopy with chromoendoscopy (CE) is better than high definition white-light endoscopy alone for this purpose. Virtual CE can guide biopsies for staging atrophic and metaplastic changes and can target neoplastic lesions. Biopsies should be taken from at least two topographic sites (antrum and corpus) and labelled in two separate vials. For patients with mild to moderate atrophy restricted to the antrum there is no evidence to recommend surveillance. In patients with IM at a single location but with a family history of gastric cancer, incomplete IM, or persistent Helicobacter pylori gastritis, endoscopic surveillance with CE and guided biopsies may be considered in 3 years. Patients with advanced stages of atrophic gastritis should be followed up with a high quality endoscopy every 3 years. In patients with dysplasia, in the absence of an endoscopically defined lesion, immediate high quality endoscopic reassessment with CE is recommended. Patients with an endoscopically visible lesion harboring low or high grade dysplasia or carcinoma should undergo staging and treatment. H. pylori eradication heals nonatrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions, and it is recommended. H. pylori eradication is also recommended for patients with neoplasia after endoscopic therapy. In intermediate to high risk regions, identification and surveillance of patients with precancerous gastric conditions is cost-effective.
507 citations
TL;DR: This survey classifies the IoT security threats and challenges for IoT networks by evaluating existing defense techniques and provides a comprehensive review of NIDSs deploying different aspects of learning techniques for IoT, unlike other top surveys targeting the traditional systems.
Abstract: Pervasive growth of Internet of Things (IoT) is visible across the globe. The 2016 Dyn cyberattack exposed the critical fault-lines among smart networks. Security of IoT has become a critical concern. The danger exposed by infested Internet-connected Things not only affects the security of IoT but also threatens the complete Internet eco-system which can possibly exploit the vulnerable Things (smart devices) deployed as botnets. Mirai malware compromised the video surveillance devices and paralyzed Internet via distributed denial of service attacks. In the recent past, security attack vectors have evolved bothways, in terms of complexity and diversity. Hence, to identify and prevent or detect novel attacks, it is important to analyze techniques in IoT context. This survey classifies the IoT security threats and challenges for IoT networks by evaluating existing defense techniques. Our main focus is on network intrusion detection systems (NIDSs); hence, this paper reviews existing NIDS implementation tools and datasets as well as free and open-source network sniffing software. Then, it surveys, analyzes, and compares state-of-the-art NIDS proposals in the IoT context in terms of architecture, detection methodologies, validation strategies, treated threats, and algorithm deployments. The review deals with both traditional and machine learning (ML) NIDS techniques and discusses future directions. In this survey, our focus is on IoT NIDS deployed via ML since learning algorithms have a good success rate in security and privacy. The survey provides a comprehensive review of NIDSs deploying different aspects of learning techniques for IoT, unlike other top surveys targeting the traditional systems. We believe that, this paper will be useful for academia and industry research, first, to identify IoT threats and challenges, second, to implement their own NIDS and finally to propose new smart techniques in IoT context considering IoT limitations. Moreover, the survey will enable security individuals differentiate IoT NIDS from traditional ones.
494 citations
University of Oklahoma1, European Institute of Oncology2, Sungkyunkwan University3, Hebron University4, University of New South Wales5, University of Bordeaux6, University of Paris-Sud7, Netherlands Cancer Institute8, University of Edinburgh9, University of Toronto10, University of Texas MD Anderson Cancer Center11, Memorial Sloan Kettering Cancer Center12, Medical College of Wisconsin13, Harvard University14, AstraZeneca15
TL;DR: Standard-of-care therapy for patients newly diagnosed with advanced ovarian cancer consists of frontline cytoreductive surgery and adjuvant platinum chemotherapy and approximately 70% of patients have a relapse within 3 years.
Abstract: (ed from N Engl J Med 2018;379:2495–2505)Standard-of-care therapy for patients newly diagnosed with advanced ovarian cancer consists of frontline cytoreductive surgery and adjuvant platinum chemotherapy. Approximately 70% of these patients have a relapse within 3 years.
481 citations
University of Würzburg1, National University of Comahue2, Spanish National Research Council3, Swedish University of Agricultural Sciences4, University of Lisbon5, Universidade Federal de Goiás6, Stanford University7, Commonwealth Scientific and Industrial Research Organisation8, National University of Río Negro9, ETH Zurich10, Cornell University11, University of California, Davis12, The Nature Conservancy13, Wageningen University and Research Centre14, University of British Columbia15, Great Lakes Bioenergy Research Center16, University of California, Santa Cruz17, University of Padua18, University of New England (Australia)19, Lund University20, University of Göttingen21, University of La Rochelle22, Institut national de la recherche agronomique23, Federal University of Ceará24, University of Freiburg25, Concordia University Wisconsin26, University of Belgrade27, National University of Tucumán28, Michigan State University29, University of Brasília30, University of Greenwich31, University of Reading32, University of Wisconsin-Madison33, National Institute of Amazonian Research34, Boise State University35, University of Texas at Austin36, University of Haifa37, Kansas State University38, University of Hamburg39, Bioversity International40, University of California, Santa Barbara41, Seattle University42, University of Vienna43, University of Florida44, Centro Agronómico Tropical de Investigación y Enseñanza45, National Audubon Society46, University of Buenos Aires47, Virginia Tech48, University of Bordeaux49, University of Auckland50, University of California, Berkeley51, University College Dublin52, Trinity College, Dublin53, University of Tokyo54, Federal University of Bahia55, Lincoln University (New Zealand)56, National Institute for Environmental Studies57, International Food Policy Research Institute58, Xi'an Jiaotong-Liverpool University59
TL;DR: Using a global database from 89 studies (with 1475 locations), the relative importance of species richness, abundance, and dominance for pollination; biological pest control; and final yields in the context of ongoing land-use change is partitioned.
Abstract: Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by a few dominant species or rely on high richness remains unclear. Using a global database from 89 studies (with 1475 locations), we partition the relative importance of species richness, abundance, and dominance for pollination; biological pest control; and final yields in the context of ongoing land-use change. Pollinator and enemy richness directly supported ecosystem services in addition to and independent of abundance and dominance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society.
434 citations
Centre national de la recherche scientifique1, IFREMER2, ETH Zurich3, Cardiff University4, University of Bern5, Université Paris-Saclay6, University of Bordeaux7, Federal Fluminense University8, Leibniz Institute for Baltic Sea Research9, University of St Andrews10, University of New Hampshire11, Oregon State University12, École pratique des hautes études13, Royal Holloway, University of London14, University of Nantes15, Hofstra University16, Lamont–Doherty Earth Observatory17, Uppsala University18, Woods Hole Oceanographic Institution19, University of Edinburgh20, Geological Survey of Denmark and Greenland21, Instituto Geológico y Minero de España22, University of Connecticut23, Georgia Institute of Technology24, University of Colorado Boulder25, University of the Algarve26, British Antarctic Survey27, VU University Amsterdam28, University of Bremen29, Max Planck Society30, Thermo Fisher Scientific31, University of Cambridge32, University of Paris33, University College London34, Ghent University35, Aix-Marseille University36, Autonomous University of Barcelona37, University of California, Santa Barbara38, Utrecht University39
TL;DR: This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean.
Abstract: Rapid changes in ocean circulation and climate have been observed in marine-sediment and ice cores over the last glacial period and deglaciation, highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. One obstacle hindering progress in our understanding of the interactions between past ocean circulation and climate changes is the difficulty of accurately dating marine cores. Here, we present a set of 92 marine sediment cores from the Atlantic Ocean for which we have established age-depth models that are consistent with the Greenland GICC05 ice core chronology, and computed the associated dating uncertainties, using a new deposition modeling technique. This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean. Moreover, this data set is of direct use in paleoclimate modeling studies.
399 citations
TL;DR: A single-arm multicenter phase 2 trial demonstrates clinical efficacy of neoadjuvant PD-L1 blockade in patients with resectable muscle-invasive bladder cancer ineligible for cisplatin and examines biomarkers associated with patient outcome.
Abstract: Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
362 citations
TL;DR: Evidence is reported that MRI markers of VBI have major clinical significance, and an association of high PVS burden with increased risk of stroke, dementia, and death is suggested.
Abstract: Importance Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated. Objective To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. Data Source We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. Study Selection Data were taken from prospective, longitudinal cohort studies including 50 or more adults. Data Extraction and Synthesis We performed inverse variance–weighted meta-analyses with random effects andzscore–based meta-analyses for WMH burden. The significance threshold wasP Main Outcomes and Measures Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. Results Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12;P Conclusions and Relevance We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit–risk ratio for available prevention strategies in individuals with covert VBI.
336 citations
University of Würzburg1, Lund University2, Swedish University of Agricultural Sciences3, Commonwealth Scientific and Industrial Research Organisation4, University of Reading5, Wageningen University and Research Centre6, University of Padua7, University of Rennes8, University of Salamanca9, Agrocampus Ouest10, Sant'Anna School of Advanced Studies11, Spanish National Research Council12, Aix-Marseille University13, University of Kiel14, University of Freiburg15, University of Jyväskylä16, University of Koblenz and Landau17, University of Marburg18, Technische Universität München19, University of Natural Resources and Life Sciences, Vienna20, National University of Río Negro21, Instituto Nacional de Biodiversidad22, University of Giessen23, University of Belgrade24, Institut national de la recherche agronomique25, University of Extremadura26, University of Bordeaux27, University of Bern28, CABI29, University of Göttingen30, Pir Mehr Ali Shah Arid Agriculture University31
TL;DR: In landscapes with high edge density, 70% of pollinator and 44% of natural enemy species reached highest abundances and pollination and pest control improved 1.7- and 1.4-fold respectively, suggesting that enhancing edge density in European agroecosystems can promote functional biodiversity and yield-enhancing ecosystem services.
Abstract: Managing agricultural landscapes to support biodiversity and ecosystem services is a key aim of a sustainable agriculture. However, how the spatial arrangement of crop fields and other habitats in landscapes impacts arthropods and their functions is poorly known. Synthesising data from 49 studies (1515 landscapes) across Europe, we examined effects of landscape composition (% habitats) and configuration (edge density) on arthropods in fields and their margins, pest control, pollination and yields. Configuration effects interacted with the proportions of crop and non-crop habitats, and species’ dietary, dispersal and overwintering traits led to contrasting responses to landscape variables. Overall, however, in landscapes with high edge density, 70% of pollinator and 44% of natural enemy species reached highest abundances and pollination and pest control improved 1.7- and 1.4-fold respectively. Arable-dominated landscapes with high edge densities achieved high yields. This suggests that enhancing edge density in European agroecosystems can promote functional biodiversity and yield-enhancing ecosystem services.
321 citations
Vanderbilt University Medical Center1, Vanderbilt University2, University of Pennsylvania3, National Institute for Health Research4, Queen Mary University of London5, Veterans Health Administration6, Emory University7, VA Boston Healthcare System8, University of Ioannina9, Imperial College London10, University of Leicester11, University of Bordeaux12, University of Michigan13, University of Cambridge14, McMaster University15, University of Dundee16, COMSATS Institute of Information Technology17, University of Newcastle18, Lund University19, Leiden University Medical Center20, University Medical Center Groningen21, University of Edinburgh22, King's College London23, Guy's and St Thomas' NHS Foundation Trust24, University of Texas Health Science Center at Houston25, University of Liverpool26, Broad Institute27, Boston University28, University of London29, University of Bristol30, Washington University in St. Louis31, university of lille32, Wellcome Trust Centre for Human Genetics33, University of Eastern Finland34, Wellcome Trust Sanger Institute35, National Institutes of Health36, Population Health Research Institute37, Brigham and Women's Hospital38, University of Sassari39, Wellcome Trust40, University of Oxford41, Harokopio University42, University of Washington43, Harvard University44, Stanford University45, VA Palo Alto Healthcare System46
TL;DR: Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.
Abstract: In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
310 citations
TL;DR: This single-arm, multicentre, phase 1b-2 trial assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastzumab-resistant, advanced HER2-positive breast cancer.
Abstract: Summary Background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer. Methods We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed. Findings Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6–18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9–12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7–29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3–5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3–5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2. Interpretation Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients. Funding Merck, International Breast Cancer Study Group.
TL;DR: In first-in-human trials, pulsed field ablation preferentially affected myocardial tissue, allowing facile ultra-rapid PV isolation with excellent durability and chronic safety.
University of Bordeaux1, Wichita State University2, University of Manchester3, Mansfield University of Pennsylvania4, Florida State University5, Pacific Northwest National Laboratory6, University of Washington7, Amgen8, University of Natural Resources and Life Sciences, Vienna9, Washington State University10, Loughborough University11, University of Liège12, Florida International University13, Agilent Technologies14, Waters Corporation15, University of Bern16, University of Minnesota17, Vanderbilt University18, French Institute of Health and Medical Research19, Birkbeck, University of London20, West Virginia University21
TL;DR: A guide to ion mobility mass spectrometry experiments, which covers both linear and nonlinear methods: what is measured, how the measurements are done, and how to report the results, including the uncertainties of mobility and collision cross section values.
Abstract: Here we present a guide to ion mobility mass spectrometry experiments, which covers both linear and nonlinear methods: what is measured, how the measurements are done, and how to report the results, including the uncertainties of mobility and collision cross section values. The guide aims to clarify some possibly confusing concepts, and the reporting recommendations should help researchers, authors and reviewers to contribute comprehensive reports, so that the ion mobility data can be reused more confidently. Starting from the concept of the definition of the measurand, we emphasize that (i) mobility values (K0) depend intrinsically on ion structure, the nature of the bath gas, temperature, and E/N; (ii) ion mobility does not measure molecular surfaces directly, but collision cross section (CCS) values are derived from mobility values using a physical model; (iii) methods relying on calibration are empirical (and thus may provide method‐dependent results) only if the gas nature, temperature or E/N cannot match those of the primary method. Our analysis highlights the urgency of a community effort toward establishing primary standards and reference materials for ion mobility, and provides recommendations to do so.
VU University Amsterdam1, University of Texas Southwestern Medical Center2, Cardiovascular Institute of the South3, Johns Hopkins University4, Vanderbilt University Medical Center5, University of California, San Diego6, University of Pennsylvania7, McGill University8, University of Bordeaux9, Maastricht University10, Université libre de Bruxelles11
TL;DR: This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging and an update is provided on the latest insights in the pathobiology of right ventricular failure.
Abstract: The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.
TL;DR: In the absence of overt stimulation, there was a notably high level of ongoing protein synthesis in both pre- and postsynaptic compartments, including excitatory and inhibitory axon terminals.
Abstract: There is ample evidence for localization of messenger RNAs (mRNAs) and protein synthesis in neuronal dendrites; however, demonstrations of these processes in presynaptic terminals are limited. We used expansion microscopy to resolve pre- and postsynaptic compartments in rodent neurons. Most presynaptic terminals in the hippocampus and forebrain contained mRNA and ribosomes. We sorted fluorescently labeled mouse brain synaptosomes and then sequenced hundreds of mRNA species present within excitatory boutons. After brief metabolic labeling, >30% of all presynaptic terminals exhibited a signal, providing evidence for ongoing protein synthesis. We tested different classic plasticity paradigms and observed distinct patterns of rapid pre- and/or postsynaptic translation. Thus, presynaptic terminals are translationally competent, and local protein synthesis is differentially recruited to drive compartment-specific phenotypes that underlie different forms of plasticity.
TL;DR: Postoperative atrial fibrillation (POAF) complicates 20–40% of cardiac surgical procedures and 10–20% of non-cardiac thoracic operations, and can be prevented by targeting autonomic alterations and inflammation.
Abstract: Postoperative atrial fibrillation (POAF) complicates 20-40% of cardiac surgical procedures and 10-20% of non-cardiac thoracic operations. Typical features include onset at 2-4 days postoperatively, episodes that are often fleeting and a self-limited time course. Associated adverse consequences of POAF include haemodynamic instability, increased risk of stroke, lengthened hospital and intensive care unit stays and greater costs. Underlying mechanisms are incompletely defined but include intraoperative and postoperative phenomena, such as inflammation, sympathetic activation and cardiac ischaemia, that combine to trigger atrial fibrillation, often in the presence of pre-existing factors, making the atria vulnerable to atrial fibrillation induction and maintenance. A better understanding of the underlying mechanisms might enable the identification of new therapeutic targets. POAF can be prevented by targeting autonomic alterations and inflammation. β-Blocker prophylaxis is the best-established preventive therapy and should be started or continued before cardiac surgery, unless contraindicated. When POAF occurs, rate control usually suffices, and routine rhythm control is unnecessary; rhythm control should be reserved for patients who develop haemodynamic instability or show other indications that rate control alone will be insufficient. In this Review, we summarize the epidemiological and clinical features of POAF, the available pathophysiological evidence from clinical and experimental investigations, the results of prophylactic and therapeutic approaches and the consensus recommendations of various national and international societies.
TL;DR: Therapeutic strategies aimed at preserving and/or restoring the integrity of the endothelial glycocalyx, reversing the procoagulant and pro-inflammatory phenotype of injured endothelial cells and slowing renal fibrosis hold promise for the treatment of renal disease.
Abstract: The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.
TL;DR: It is demonstrated that the single nickase and not the nuclease approach is preferable, not only for modeling disease but also and more importantly for the safe management of future CRISPR-Cas9-mediated gene therapies.
Abstract: CRISPR-Cas9 is a promising technology for genome editing. Here we use Cas9 nucleaseinduced double-strand break DNA (DSB) at the UROS locus to model and correct congenital erythropoietic porphyria. We demonstrate that homology-directed repair is rare compared with NHEJ pathway leading to on-target indels and causing unwanted dysfunctional protein. Moreover, we describe unexpected chromosomal truncations resulting from only one Cas9 nuclease-induced DSB in cell lines and primary cells by a p53-dependent mechanism. Altogether, these side effects may limit the promising perspectives of the CRISPR-Cas9 nuclease system for disease modeling and gene therapy. We show that the single nickase approach could be safer since it prevents on-and off-target indels and chromosomal truncations. These results demonstrate that the single nickase and not the nuclease approach is preferable, not only for modeling disease but also and more importantly for the safe management of future CRISPR-Cas9-mediated gene therapies.
University of Würzburg1, National University of Comahue2, Spanish National Research Council3, Swedish University of Agricultural Sciences4, Universidade Federal de Goiás5, University of Lisbon6, Stanford University7, Commonwealth Scientific and Industrial Research Organisation8, National University of Río Negro9, ETH Zurich10, Cornell University11, University of California, Davis12, The Nature Conservancy13, Wageningen University and Research Centre14, University of British Columbia15, Great Lakes Bioenergy Research Center16, University of California, Berkeley17, University of Padua18, University of New England (United States)19, Lund University20, University of Göttingen21, University of La Rochelle22, Institut national de la recherche agronomique23, Federal University of Ceará24, Concordia University Wisconsin25, University of Belgrade26, National University of Tucumán27, Michigan State University28, University of Brasília29, University of Greenwich30, University of Reading31, University of Wisconsin-Madison32, Boise State University33, University of Texas at Austin34, University of Haifa35, Kansas State University36, University of Freiburg37, University of Hamburg38, University of California, Santa Barbara39, Seattle University40, University of Vienna41, University of Florida42, Centro Agronómico Tropical de Investigación y Enseñanza43, National Audubon Society44, University of Buenos Aires45, Virginia Tech46, University of Bordeaux47, University of Auckland48, University College Dublin49, Trinity College, Dublin50, University of Tokyo51, Federal University of Bahia52, Lincoln University (Pennsylvania)53, National Institute for Environmental Studies54, International Food Policy Research Institute55, Xi'an Jiaotong-Liverpool University56
TL;DR: Using a global database from 89 crop systems, the relative importance of abundance and species richness for pollination, biological pest control and final yields in the context of on-going land-use change is partitioned.
Abstract: Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by few abundant species or rely on high richness remains unclear. Using a global database from 89 crop systems, we partition the relative importance of abundance and species richness for pollination, biological pest control and final yields in the context of on-going land-use change. Pollinator and enemy richness directly supported ecosystem services independent of abundance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society.
École Polytechnique Fédérale de Lausanne1, Harvard University2, Czech Technical University in Prague3, University of Minnesota4, Texas A&M University5, University of Sussex6, Istituto Italiano di Tecnologia7, University of Edinburgh8, Delft University of Technology9, University of Southampton10, University of Colorado Colorado Springs11, Centre national de la recherche scientifique12, University of Bordeaux13, University College London14, Newcastle University15
TL;DR: This study reports results from the second community-wide single-molecule localization microscopy software challenge, which tested over 30 software packages on realistic simulated data for multiple popular 3D image acquisition modes, as well as 2D localization microscopes.
Abstract: With the widespread uptake of two-dimensional (2D) and three-dimensional (3D) single-molecule localization microscopy (SMLM), a large set of different data analysis packages have been developed to generate super-resolution images. In a large community effort, we designed a competition to extensively characterize and rank the performance of 2D and 3D SMLM software packages. We generated realistic simulated datasets for popular imaging modalities-2D, astigmatic 3D, biplane 3D and double-helix 3D-and evaluated 36 participant packages against these data. This provides the first broad assessment of 3D SMLM software and provides a holistic view of how the latest 2D and 3D SMLM packages perform in realistic conditions. This resource allows researchers to identify optimal analytical software for their experiments, allows 3D SMLM software developers to benchmark new software against the current state of the art, and provides insight into the current limits of the field.
28 Oct 2019
TL;DR: In this paper, the authors discuss the associated scientific and technological challenges and highlights recent advances of atom interferometry in metrology, geophysics, space, civil engineering, oil and minerals exploration, and navigation.
Abstract: Since the first proof-of-principle experiments over 25 years ago, atom interferometry has matured to a versatile tool that can be used in fundamental research in particle physics, general relativity and cosmology. At the same time, atom interferometers are currently moving out of the laboratory to be used as ultraprecise quantum sensors in metrology, geophysics, space, civil engineering, oil and minerals exploration, and navigation. This Perspective discusses the associated scientific and technological challenges and highlights recent advances. Quantum sensors based on atom interferometry are moving from fundamental research towards commercial applications in metrology, geophysics, space, civil engineering, oil and minerals exploration, and navigation, but a number of challenges need to be overcome.
TL;DR: In this article, a P2-type Na0.72[Li 0.24Mn 0.76]O2 was reported, exhibiting an initial charge capacity of ∼210 mAh/g ( 0.72 Na) based on pure anionic redox reaction (ARR).
TL;DR: This review focuses on two noncanonical classes of DNA helices: G-quadruplexes and the i-motif, which have been utilized toward some remarkable constructions and applications.
Abstract: DNA has played an early and powerful role in the development of bottom-up nanotechnologies, not least because of DNA's precise, predictable, and controllable properties of assembly on the nanometer scale. Watson-Crick complementarity has been used to build complex 2D and 3D architectures and design a number of nanometer-scale systems for molecular computing, transport, motors, and biosensing applications. Most of such devices are built with classical B-DNA helices and involve classical A-T/U and G-C base pairs. However, in addition to the above components underlying the iconic double helix, a number of alternative pairing schemes of nucleobases are known. This review focuses on two of these noncanonical classes of DNA helices: G-quadruplexes and the i-motif. The unique properties of these two classes of DNA helix have been utilized toward some remarkable constructions and applications: G-wires; nanostructures such as DNA origami; reconfigurable structures and nanodevices; the formation and utilization of hemin-utilizing DNAzymes, capable of generating varied outputs from biosensing nanostructures; composite nanostructures made up of DNA as well as inorganic materials; and the construction of nanocarriers that show promise for the therapeutics of diseases.
TL;DR: In this paper, it was shown that these three pentaquark-like resonances can be naturally accommodated in a contact-range effective field theory description that incorporates heavy-quark spin symmetry.
Abstract: A recent analysis by the LHCb Collaboration suggests the existence of three narrow pentaquarklike states—the Pc(4312), Pc(4440), and Pc(4457)—instead of just one in the previous analysis [the Pc(4450)]. The closeness of the Pc(4312) to the D¯Σc threshold and the Pc(4440) and Pc(4457) to the D¯*Σc threshold suggests a molecular interpretation of these resonances. We show that these three pentaquarklike resonances can be naturally accommodated in a contact-range effective field theory description that incorporates heavy-quark spin symmetry. This description leads to the prediction of all the seven possible S-wave heavy antimeson-baryon molecules [that is, there should be four additional molecular pentaquarks in addition to the Pc(4312), Pc(4440), and Pc(4457)], providing the first example of a heavy-quark spin symmetry molecular multiplet that is complete. If this is confirmed, it will not only give us an impressive example of the application of heavy-quark symmetries and effective field theories in hadron physics, it will also uncover a clear and powerful ordering principle for the molecular spectrum, reminiscent of the SU(3)-flavor multiplets to which the light hadron spectrum conforms.
University of Adelaide1, Memorial Sloan Kettering Cancer Center2, University of Texas MD Anderson Cancer Center3, Kobe University4, University of Paris5, Dana Corporation6, Sapienza University of Rome7, Singapore General Hospital8, University of Michigan9, University of Jena10, Charité11, Cardiff University12, Oregon Health & Science University13, Veterans Health Administration14, University of Utah15, University of Amsterdam16, University of Bordeaux17, Novartis18, Goethe University Frankfurt19, Catholic University of Korea20
TL;DR: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.
Abstract: Background Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those ...
University of Bordeaux1, University of Cologne2, Complutense University of Madrid3, Scripps Research Institute4, University of Belgrade5, Harvard University6, Technion – Israel Institute of Technology7, University of Erlangen-Nuremberg8, University of Exeter9, Johns Hopkins University School of Medicine10
TL;DR: It is shown persulfidation is an evolutionarily conserved modification and waves of persulfide are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function, and an age-associated decline is reported that is conserved across evolutionary boundaries.
University of Paris1, University College London2, Royal Observatory of Belgium3, University of Montpellier4, University of Liège5, University of Antwerp6, University of Geneva7, Leibniz Institute for Astrophysics Potsdam8, University of Bordeaux9, University of Nice Sophia Antipolis10, University of La Laguna11, Spanish National Research Council12, University of Grenoble13, Max Planck Society14, University of Antofagasta15, Atos16, University of Edinburgh17, University of Ljubljana18, INAF19, Australian National University20
TL;DR: In this paper, the authors describe the validation and properties of the median radial velocities published in Gaia DR2, which provide a full-sky coverage and are complete with respect to the astrometric data to within 77.2% (for G ≤ 12.5 mag).
Abstract: Context. For Gaia DR2, 280 million spectra collected by the Radial Velocity Spectrometer instrument on board Gaia were processed, and median radial velocities were derived for 9.8 million sources brighter than G RVS = 12 mag.Aims. This paper describes the validation and properties of the median radial velocities published in Gaia DR2.Methods. Quality tests and filters were applied to select those of the 9.8 million radial velocities that have the quality to be published in Gaia DR2. The accuracy of the selected sample was assessed with respect to ground-based catalogues. Its precision was estimated using both ground-based catalogues and the distribution of the Gaia radial velocity uncertainties. Results. Gaia DR2 contains median radial velocities for 7 224 631 stars, with T eff in the range [3550, 6900] K, which successfully passed the quality tests. The published median radial velocities provide a full-sky coverage and are complete with respect to the astrometric data to within 77.2% (for G ≤ 12.5 mag). The median radial velocity residuals with respect to the ground-based surveys vary from one catalogue to another, but do not exceed a few 100 m s−1 . In addition, the Gaia radial velocities show a positive trend as a function of magnitude, which starts around G RVS ~ 9 mag and reaches about + 500 m s−1 at G RVS = 11.75 mag. The origin of the trend is under investigation, with the aim to correct for it in Gaia DR3. The overall precision, estimated from the median of the Gaia radial velocity uncertainties, is 1.05 km s−1 . The radial velocity precision is a function of many parameters, in particular, the magnitude and effective temperature. For bright stars, G RVS ∈ [4, 8] mag, the precision, estimated using the full dataset, is in the range 220–350 m s−1 , which is about three to five times more precise than the pre-launch specification of 1 km s−1 . At the faint end, G RVS = 11.75 mag, the precisions for T eff = 5000 and 6500 K are 1.4 and 3.7 km s−1 , respectively.
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01 Sep 2019TL;DR: Global evaluation of the entire spine and the measurement of the aforementioned parameters allow to determine the extent of the correction to be performed during surgery, and enables us to understand the complications involved in this type of surgery: transitional syndrome or junctional syndromes.
Abstract: The static sagittal balance of the normal spine is a physiological alignment of the spine in the most efficient manner by the muscular forces. During gait, this balance is constantly thwarted by single-foot support. This analysis involves the study of parameters which are now well defined. The pelvic incidence is constant, and the sacral slope and the pelvic tilt are positional. The cervical parameters are the upper (O-C2) and lower cervical curvatures (C2-C7), the C7 slope, the spino-cranial angle and the vertical cervical offset. At the thoracic and lumbar level, they are, respectively, kyphosis and lordosis. The OD-HA (odontoid hip axis) angle is the most efficient parameter to analyse the global balance. The average values of these parameters are reported with the new 3D measurements by Le Huec et al. The relationship between these different parameters was analysed, and Roussouly proposed his classification of the different spine shape. Ageing makes it possible to show compensation mechanisms at three levels: spinal, pelvic and lower limbs. Understanding these different data allows for better planning of the surgical management of the patients. Global evaluation of the entire spine and the measurement of the aforementioned parameters allow to determine the extent of the correction to be performed during surgery. Taking these parameters into account also enables us to understand the complications involved in this type of surgery: transitional syndromes or junctional syndromes. Integration of these parameters into the study of gait is an area still under investigation. These slides can be retrieved under Electronic Supplementary Material .
TL;DR: Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astroCytic functions in response to AD pathology.
TL;DR: Both historical and more recent findings are discussed on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action.
Abstract: Metformin is a drug from the biguanide family that is used for decades as the first-line therapeutic choice for the treatment of type 2 diabetes. Despite its worldwide democratization, owing to its clinical efficacy, high safety profile and cheap cost, the exact mechanism(s) of action of this anti-hyperglycemic molecule with pleiotropic properties still remains to be fully elucidated. The concept that metformin would exert some of its actions though modulation of the mitochondrial bioenergetics was initially forged in the 50s but undeniably revived at the beginning of the twenty-first century when it was shown to induce a weak but specific inhibition of the mitochondrial respiratory-chain complex 1. Furthermore, metformin has been reported to reduce generation of reactive oxygen species at the complex 1 and to prevent mitochondrial-mediated apoptosis, suggesting that it can protect against oxidative stress-induced cell death. Nevertheless, despite some recent progress and the demonstration of its key role in the inhibition of hepatic gluconeogenesis, the exact nature of the mitochondrial interaction between the drug and the complex 1 is still poorly characterized. Recent studies reported that metformin may also have anti-neoplastic properties by inhibiting cancer cell growth and proliferation, at least partly through its mitochondrial action. As such, many trials are currently conducted for exploring the repositioning of metformin as a potential drug for cancer therapy. In this mini-review, we discuss both historical and more recent findings on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action.