Spectrometer Scan Mechanism for Encountering Jovian Orbit Trojan Asteroids

This paper describes the design, testing, and lessons learned during the development of the Lucy Ralph (L'Ralph) Scan Mirror System (SMS), composed of the Scan Mirror Mechanism (SMM), Differential Position Sensor System (DPSS) and Mechanism Control Electronics (MCE). The L'Ralph SMS evolved from the Advanced Topographic Laser Altimeter System (ATLAS) Beam Steering Mechanism (BSM), so design comparisons will be made. Lucy is scheduled to launch in October 2021, embarking upon a 12-year mission to make close range encounters in 2025 and 2033 with seven Trojan asteroids and one main belt asteroid that are within the Jovian orbit. The L'Ralph instrument is based upon the New Horizons Ralph instrument, which is a panchromatic and color visible imager and infrared spectroscopic mapper that slewed the spacecraft for imaging. The L'Ralph SMM is to provide scanning for imaging to eliminate the need to slew the spacecraft. One purpose of this paper is to gain understanding of the reasoning behind some of the design features as compared with the ATLAS BSM. We will identify similarities and differences between the ATLAS BSM and the L'Ralph SMM that resulted from the latter's unique requirements. Another purpose of this paper is to focus upon "Lessons Learned" that came about during the development of the L'Ralph SMM and its MCE, both mechanism engineering issues and solutions as well as Ground Support Equipment (GSE) issues and solutions that came about during the validation of requirements process. At the time of this writing, the L'Ralph SMM has been flight qualified and delivered to the project

Manipulating Replisome Dynamics to Enhance Lambda Red-Mediated Multiplex Genome Engineering

Disrupting the interaction between primase and helicase in Escherichia coli increases Okazaki fragment (OF) length due to less frequent primer synthesis. We exploited this feature to increase the amount of ssDNA at the lagging strand of the replication fork that is available for λ Red-mediated Multiplex Automatable Genome Engineering (MAGE). Supporting this concept, we demonstrate that MAGE enhancements correlate with OF length. Compared with a standard recombineering strain (EcNR2), the strain with the longest OFs displays on average 62% more alleles converted per clone, 239% more clones with 5 or more allele conversions and 38% fewer clones with 0 allele conversions in 1 cycle of co-selection MAGE (CoS-MAGE) with 10 synthetic oligonucleotides. Additionally, we demonstrate that both synthetic oligonucleotides and accessible ssDNA targets on the lagging strand of the replication fork are limiting factors for MAGE. Given this new insight, we generated a strain with reduced oligonucleotide degradation and increased genomic ssDNA availability, which displayed 111% more alleles converted per clone, 527% more clones with 5 or more allele conversions and 71% fewer clones with 0 allele conversions in 1 cycle of 10-plex CoS-MAGE. These improvements will facilitate ambitious genome engineering projects by minimizing dependence on time-consuming clonal isolation and screening

Janus: Launch of a NASA SmallSat Mission to Near-Earth Binary Asteroids

Janus is a two-spacecraft SmallSat mission to fly by two different pairs of binary near Earth asteroids, (175706) 1996 FG3 and (35107) 1991 VH. The two identical Janus spacecraft are scheduled to launch during a launch period opening 1 August 2022 as secondary payloads with the NASA Psyche mission, on a SpaceX Falcon Heavy launch vehicle. Janus is led by principal investigator Dr. Dan Scheeres at the University of Colorado Boulder and managed, built, and operated by Lockheed Martin. These planetary SmallSats share many deep space challenges similar to larger missions: Janus must execute deep space maneuvers to achieve hundreds of meters per second ΔV to reach its destinations, close a telecommunication link at ranges up to 2.4 AU, autonomously manage a several-month-long telecommunications blackout during solar conjunction, operate at a maximum Sun range of 1.62 AU, and survive for approximately four years in interplanetary space before encountering their target asteroids. During the encounters, the spacecraft will return high resolution visible and infra-red images of the asteroids. In getting Janus to the pad, the implementation team successfully managed an aggressive mission schedule despite COVID-19 related supply chain impacts and work environments, all while remaining on target for the SIMPLEx-2 cost cap. Janus is a pathfinder for achievable and affordable SmallSat science missions and demonstrates the valuable partnership between an experienced deep space mission engineering team, the SmallSat commercial component industry, and a forward- looking NASA model for Class-D science missions

Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome

BACKGROUND & AIMS: Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations. METHODS: We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy. RESULTS: A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy. CONCLUSIONS: Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy

Clinicopathological and molecular characterisation of “multiple classifier” endometrial carcinomas

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

PAM-flexible genome editing with an engineered chimeric Cas9

CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning

Pilot evaluation of the psychometric properties of a self-medication Risk Assessment Tool among elderly patients in a community setting

<p>Abstract</p> <p>Background</p> <p>Although community pharmacists in the United Kingdom are expected to assess elderly patients' needs for additional support in managing their medicines, there is limited data on potentially useful assessment tools. We sought to evaluate a 13-item assessment instrument among community dwelling elderly patients, 65 years and above. The instrument is composed of a cognitive risk sub-scale of 6 items and a physical risk sub-scale of 7 items.</p> <p>Findings</p> <p>The instrument was administered to elderly patients in a survey performed in a community to the west of Glasgow, Scotland. The survey recruited 37 participants, 31 from 4 community pharmacies and 6 patients whose medication management tasks were managed by the West Glasgow Community Health and Care Partnership (managed patients). Community pharmacists independently rated 29 of the 37 participants' comprehension of, and dexterity in handling their medicines. We assessed scale reliability, convergent validity and criterion validity. In sub-analyses, we assessed differences in scores between the managed patients and those recruited from the community pharmacies, and between multi-compartment compliance aid users and non-users. The instrument showed satisfactory internal consistency (Cronbach's alpha of 0.792 for 13-item scale). There was significant strong negative correlation between the cognitive risk sub-scores and community pharmacists' assessment of comprehension (ρ = -0.546, p = 0.0038); and physical risk sub-scores and community pharmacists' assessment of dexterity (ρ = -0.491, p = 0.0093). The Area Under the Receiver Operator Characteristic Curve (AUC ± SE; 95%CI) showed that the instrument had good discriminatory capacity (0.86 ± 0.07; 0.68, 0.96). The best cut-off (sensitivity, specificity) was ≥4 (65%, 100%). In the sub-analyses, managed patients had significantly higher cognitive risk sub-scores (6.5 versus 4.0, p = 0.0461) compared to non-managed patients. There was a significant difference in total risk score (4 versus 2, p = 0.0135) and cognitive risk sub-score (4 versus 1.5, p = 0.0029) between users and non-users of multi-compartment compliance aids.</p> <p>Conclusions</p> <p>This instrument shows potential for use in identifying elderly patients who may have problems managing their own medicines in the community setting. However, more robust validity and reliability assessments are needed prior to introduction of the tool into routine practice.</p

The positive impact of conservation action

Governments recently adopted new global targets to halt and reverse the loss of biodiversity. It is therefore crucial to understand the outcomes of conservation actions. We conducted a global meta-analysis of 186 studies (including 665 trials) that measured biodiversity over time and compared outcomes under conservation action with a suitable counterfactual of no action. We find that in two-thirds of cases, conservation either improved the state of biodiversity or at least slowed declines. Specifically, we find that interventions targeted at species and ecosystems, such as invasive species control, habitat loss reduction and restoration, protected areas, and sustainable management, are highly effective and have large effect sizes. This provides the strongest evidence to date that conservation actions are successful but require transformational scaling up to meet global targets

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

Pulmonary Metagenomic Sequencing Suggests Missed Infections in Immunocompromised Children

This article is made available for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing.BACKGROUND: Despite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children. METHODS: We collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort. RESULTS: We identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P < .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P < .001). CONCLUSIONS: An optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease