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In charge detection mass spectrometry (CDMS), ions are passed through a detection tube and the m / z ratio and charge are determined for each ion. The uncertainty in the charge and m / z determinations can be dramatically reduced by embedding the detection tube in an electrostatic linear ion trap (ELIT) so that ions oscillate back and forth through the detection tube. The resulting time domain signal can be analyzed by fast Fourier transforms (FFTs). The ion’s m / z is proportional to the square of the oscillation frequency, and its charge is derived from the FFT magnitude. The ion oscillation frequency is dependent on the physical dimensions of the trap as well as the ion energy. A new ELIT has been designed for CDMS using the central particle method. In the new design, the kinetic energy dependence of the ion oscillation frequency is reduced by an order of magnitude. An order of magnitude reduction in energy dependence should have led to an order of magnitude reduction in the uncertainty of the m / z determination. In practice, a factor of four improvements was achieved. This discrepancy is probably mainly due to the trajectory dependence of the ion oscillation frequency. The new ELIT design uses a duty cycle of 50%. We show that a 50% duty cycle produces the lowest uncertainty in the charge determination. This is due to the absence of even-numbered harmonics in the FFT, which in turn leads to an increase in the magnitude of the peak at the fundamental frequency. Graphical Abstract ᅟ

Nuclear pore complexes play central roles as gatekeepers of RNA and protein transport between the cytoplasm and nucleoplasm. However, their large size and dynamic nature have impeded a full structural and functional elucidation. Here we determined the structure of the entire 552-protein nuclear pore complex of the yeast Saccharomyces cerevisiae at sub-nanometre precision by satisfying a wide range of data relating to the molecular arrangement of its constituents. The nuclear pore complex incorporates sturdy diagonal columns and connector cables attached to these columns, imbuing the structure with strength and flexibility. These cables also tie together all other elements of the nuclear pore complex, including membrane-interacting regions, outer rings and RNA-processing platforms. Inwardly directed anchors create a high density of transport factor-docking Phe-Gly repeats in the central channel, organized into distinct functional units. This integrative structure enables us to rationalize the architecture, transport mechanism and evolutionary origins of the nuclear pore complex. The structure of the yeast nuclear pore complex, determined at sub-nanometre precision using an integrative approach that combines a wide range of data, reveals details of its architecture, transport mechanism and evolutionary origins. Structure of yeast nuclear pore complex Nuclear pore complexes (NPCs) are the gateways for the transport of RNA and proteins into and out of the nucleus. Although previous work has provided structural insights into parts of NPCs, getting a full picture of these complexes has proved difficult owing to their large size and dynamic nature. A multidisciplinary team of researchers now report the structure of the entire 552-protein NPC of the yeast at a sub-nanometre level using an integrative approach including mass spectrometry, cryo-electron tomography and chemical crosslinking. The structure provides a detailed view of the functional elements of the NPC and clarifies its architecture, mechanism of action and evolutionary origins.

While complex intra- and interspecies microbial community dynamics are apparent during chronic infections and likely alter patient health outcomes, our understanding of these interactions is currently limited. For example, Pseudomonas aeruginosa and Staphylococcus aureus are often found to coinfect the lungs of patients with cystic fibrosis (CF), yet these organisms compete under laboratory conditions. Recent observations that coinfection correlates with decreased health outcomes necessitate we develop a greater understanding of these interbacterial interactions. In this study, we tested the hypothesis that P. aeruginosa and/or S. aureus adopts phenotypes that allow coexistence during infection. We compared competitive interactions of P. aeruginosa and S. aureus isolates from mono- or coinfected CF patients employing in vitro coculture models. P. aeruginosa isolates from monoinfected patients were more competitive toward S. aureus than P. aeruginosa isolates from coinfected patients. We also observed that the least competitive P. aeruginosa isolates possessed a mucoid phenotype. Mucoidy occurs upon constitutive activation of the sigma factor AlgT/U, which regulates synthesis of the polysaccharide alginate and dozens of other secreted factors, including some previously described to kill S. aureus . Here, we show that production of alginate in mucoid strains is sufficient to inhibit anti- S. aureus activity independent of activation of the AlgT regulon. Alginate reduces production of siderophores, 2-heptyl-4-hydroxyquinolone- N -oxide (HQNO), and rhamnolipids—each required for efficient killing of S. aureus . These studies demonstrate alginate overproduction may be an important factor driving P. aeruginosa coinfection with S. aureus . IMPORTANCE Numerous deep-sequencing studies have revealed the microbial communities present during respiratory infections in cystic fibrosis (CF) patients are diverse, complex, and dynamic. We now face the challenge of determining the influence of these community dynamics on patient health outcomes and identifying candidate targets to modulate these interactions. We make progress toward this goal by determining that the polysaccharide alginate produced by mucoid strains of P. aeruginosa is sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompete S. aureus , when the microbes are grown in coculture; thus we propose a mechanism whereby mucoid P. aeruginosa can coexist with S. aureus . Finally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens. Numerous deep-sequencing studies have revealed the microbial communities present during respiratory infections in cystic fibrosis (CF) patients are diverse, complex, and dynamic. We now face the challenge of determining the influence of these community dynamics on patient health outcomes and identifying candidate targets to modulate these interactions. We make progress toward this goal by determining that the polysaccharide alginate produced by mucoid strains of P. aeruginosa is sufficient to inhibit multiple secreted antimicrobial agents produced by this organism. Importantly, these secreted factors are required to outcompete S. aureus , when the microbes are grown in coculture; thus we propose a mechanism whereby mucoid P. aeruginosa can coexist with S. aureus . Finally, the approach used here can serve as a platform to investigate the interactions among other CF pathogens.

INTRODUCTION:Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel artificial intelligence (AI) system, compared with standard high-definition colonoscopy, for APC measurement.METHODS:This was a US-based, multicenter, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE). Eligible average-risk subjects (45 years or older) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified intention-to-treat analysis was performed for all patients who completed colonoscopy with the primary outcome of APC. Secondary outcomes included positive predictive value (total number of adenomas divided by total polyps removed) and adenoma detection rate.RESULTS:In modified intention-to-treat analysis, of 1,031 subjects (age: 59.1 ± 9.8 years; 49.9% male), 510 underwent CAC vs 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared with CC: 0.99 ± 1.6 vs 0.85 ± 1.5, P = 0.02, incidence rate ratio 1.17 (1.03-1.33, P = 0.02) with no significant difference in the withdrawal time: 11.28 ± 4.59 minutes vs 10.8 ± 4.81 minutes; P = 0.11 between the 2 groups. Difference in positive predictive value of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI −9.56% to −1.48%. There were no significant differences in adenoma detection rate (46.9% vs 42.8%), advanced adenoma (6.5% vs 6.3%), sessile serrated lesion detection rate (12.9% vs 10.1%), and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared with CC: 1.68 ± 2.1 vs 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; P < 0.01).DISCUSSION:Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared with conventional high-definition colonoscopy without any increase in colonoscopy withdrawal time, thus supporting the use of AI-assisted colonoscopy to improve colonoscopy quality (ClinicalTrials.gov NCT04979962).

The United Nations Guiding Principles on Business and Human Rights conceive of human rights due diligence (HRDD) as covering potential impacts across value chains, including downstream. The proposed EU Corporate Sustainability Due Diligence Directive and the revision process of the OECD Guidelines for Multinational Enterprises have sparked renewed discussion on how and whether companies should conduct HRDD downstream to identify and prevent or mitigate adverse human rights impacts. Whilst some debate has occurred previously on downstream HRDD, this has predominantly centred on specific sectors, products and services where the links to egregious human rights harms may be more readily identifiable. This piece seeks to inform the current debate by broadening the examples of sectors, products and services and current business practice which demonstrate the critical need for, and ability of, companies to consider human rights risks downstream.

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations. Here, the authors have performed a multi-population GWAS meta-analysis of pediatric steroid sensitive nephrotic syndrome cases to discover 12 loci (4 novel), fine-map HLA, implicate kidney and immune factors, and associate the polygenic risk score with earlier disease onset.

Operational oceanography can be described as the provision of routine oceanographic information needed for decision-making purposes. It is dependent upon sustained research and development through the end-to-end framework of an operational service, from observation collection to delivery mechanisms. The core components of operational oceanographic systems are a multi-platform observation network, a data management system, a data assimilative prediction system, and a dissemination/accessibility system. These are interdependent, necessitating communication and exchange between them, and together provide the mechanism through which a clear picture of ocean conditions, in the past, present, and future, can be seen. Ocean observations play a critical role in all aspects of operational oceanography, not only for assimilation but as part of the research cycle, and for verification and validation of products. Data assimilative prediction systems are advancing at a fast pace, in tandem with improved science and the growth in computing power. To make best use of the system capability these advances would be matched by equivalent advances in operational observation coverage. This synergy between the prediction and observation systems underpins the quality of products available to stakeholders, and justifies the need for sustained ocean observations. In this white paper, the components of an operational oceanographic system are described, highlighting the critical role of ocean observations, and how the operational systems will evolve over the next decade to improve the characterization of ocean conditions, including at finer spatial and temporal scales.

Acute decompensated cirrhosis (DC) and acute-on-chronic liver failure are common reasons for hospital admission that have a high in-hospital mortality rate (10%–20%). Patients require a detailed assessment for precipitating factors and management of complications such as infections, ascites, acute kidney injury and hepatic encephalopathy. Multiple reports have demonstrated unwarranted variability in the care of patients with DC. In 2014, the British Society of Gastroenterology (BSG)/British Association for the Study of the Liver (BASL) DC care bundle (DCCB) was introduced to provide a structured approach for the management of patients with DC in the first 24 hours. Usage of the DCCB has been shown to improve care of patients with DC. However, despite evidence indicating the beneficial impact of the DCCB, overall usage across the UK was only 11.4% in a national audit. Our aim was to update the DCCB to incorporate recent advances in care and improve its usability and develop a strategy to improve its usage nationally. The updated bundle was developed by a multidisciplinary group of specialists from BSG, BASL and the Society for Acute Medicine with the quality of evidence supporting the bundle recommendations assessed using the Grading of Recommendation Assessment Development and Evaluation tool. Proposed minimum standards for audit were also developed. Finally, a strategy to promote usage of the bundle including education/training at a national and local level, improving accessibility for the bundle, and promotion of frameworks for use at an institutional level to improve and monitor utilisation of DCCB.

In traditional electrospray mass spectrometry, charge state resolution in the mass to charge (m/z) domain is necessary to elucidate ion mass. As analyte masses exceed a megadalton and beyond, intrinsic heterogeneity in the sample population precludes charge state resolution and, therefore, mass elucidation. Charge detection mass spectrometry (CDMS) is a single-particle technique in which the m/z and the charge (z) of each particle are measured concurrently in an electrostatic linear ion trap (ELIT). Simultaneous measurement of m/z and z eliminates the need for charge state resolution and allows the direct determination of ion masses in the multi-megadalton regime such as large protein complexes, metal nanoparticles and whole viruses. A new CDMS instrument with several key improvements over the prototype previously used in the Jarrold group has been designed, built and characterized. The most crucial of these improvements is an energy independent ELIT which provides a five-fold improvement in m/z resolution. A computational method was also developed to produce future ELIT designs tuned to the specific needs of the experiment, such as lower capacitance to ground, higher charge precision, lower ion trajectory dependence, etc. In addition to the new ELIT, and the ELIT design method, other ion optical components were implemented or improved. An RF only, segmented quadrupole was implemented to provide a more confined and collimated beam to the downstream mass analyzers. A simplified and improved design of the asymmetric einzel lens from the prototype instrument was also implemented. Additionally, the new instrument includes an interface tuned to transmit multi-megadalton ions.