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Summary ParagraphMacrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by ‘non-professional phagocytes’, local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXRα, and tissue-specific retinoids for RARγ activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.

Background Intestinal microbiota is critical for maintaining animal health and homeostasis. However, involvement of the fungal community, also known as the mycobiota, in animal health and disease is poorly understood. This study was aimed to examine the association between the intestinal mycobiota and the severity of necrotic enteritis (NE), an economically significant poultry disease. Methods A total of 90 day-of-hatch Cobb broilers were infected with Eimeria maxima on d 10, followed by an oral challenge with C. perfringens on d 14 to induce NE, while another 10 broilers were served as mock-infected controls. On d 17, the lesions in the jejunum were scored, and the ileal digesta were subjected to DNA isolation and real-time PCR quantification of total bacterial and fungi populations. Internal transcribed spacer 2 (ITS2) amplicon sequencing was also performed to profile the ileal mycobiota composition. Changes in the ileal mycobiota in response to NE were investigated. Spearman correlation analysis was further conducted to identify the correlations between relative abundances of individual ileal fungi and the severity of NE. Results While the total bacterial population in the ileum was increased by 2- to 3-fold in NE chickens, the total fungal population was progressively declined in more exacerbated NE, with the most severely infected chickens showing a nearly 50-fold reduction relative to mock-infected controls. Richness of the ileal mycobiota also tended to reduce in chickens with NE (P = 0.06). Compositionally, among 30 most abundant fungal amplicon sequence variants (ASVs), 11 were diminished and 7 were enriched (P P > 0.05). Multiple Wallemia and Aspergillus species were markedly diminished in NE (P P Conclusions Dysbiosis of the ileal mycobiota is induced evidently by NE and the extent of the dysbiosis is positively correlated with disease severity. These findings suggest a possible role of the intestinal mycobiota in NE pathogenesis and highlight the mycobiota as a new potential target for NE mitigation in poultry.

A 1:1,000,000-scale lithostratigraphic assemblage map of the Lau Basin (southwestern Pacific Ocean) has been created using remote predictive mapping (RPM) techniques developed by geological surveys on land. Formation-level geological units were identified in training sets at scales of 1:100,000–1:200,000 in different parts of the basin and then extrapolated to the areas where geological data are sparse. The final compilation is presented together with a quantitative analysis of assemblage-level crustal growth based on area-age relationships of the assigned units. The data sets used to develop mapping criteria and an internally consistent legend for the compilation included high-resolution ship-based multibeam, satellite- and ship-based gravity, magnetics, seafloor imaging, and sampling data. The correlation of units was informed by published geochronological information and kinematic models of basin opening. The map covers >1,000,000 km2 of the Lau-Tonga arc-backarc system, subdivided into nine assemblage types: forearc crust (9% by area), crust of the active volcanic arc (7%), backarc rifts and spreading centers (20%), transitional arc-backarc crust (13%), relict arc crust (38%), relict backarc crust (8%), and undivided arc-backarc assemblages (

Findings from randomised control trials inform the development of evidence-based eating disorder (ED) practice guidelines internationally. Only recently are data beginning to emerge regarding how these treatments perform outside of research settings. This study aimed to evaluate treatment pathways and outcomes for a specialist child and adolescent ED service across a five-year period.All consecutive referrals between August 2009 and January 2014 seen at the Maudsley Centre for Child and Adolescent Eating Disorders in London were included. Data are reported on for all young people who were offered treatment (N = 357).Most young people referred to the service were diagnosed with anorexia nervosa (AN)/Atypical AN (81%). Treatment for AN/Atypical AN (median 11 months) was predominantly ED focused family therapy (99%). Treatment for bulimia nervosa (BN)/Atypical BN (median seven months) was most commonly a combination of cognitive behavioural therapy and ED focused family therapy (87%). At discharge, 77% of the AN/Atypical AN group had a good or intermediate outcome and 59% of the BN/Atypical BN group reported no or fewer than weekly bulimic episodes. 27% of the AN/Atypical AN group had enhanced treatment with either day- and/or inpatient admissions (AIM group). The %mBMI at 3 months of treatment was strongest predictor of the need for treatment enhancement and more modestly EDE-Q and age at assessment. The AIM group at assessment had significantly lower weight, and higher ED and comorbid symptomatology and went on to have significantly longer treatment (16 vs. 10 months). At discharge, this group had significantly fewer good and more poor outcomes on the Morgan Russell criteria, but similar outcomes regarding ED and comorbid symptoms and quality of life. When analysis was adjusted for %mBMI at assessment, 1 and 3 months of treatment, differences in Morgan Russell outcomes and %mBMI were small and compatible with no difference in outcome by treatment group.This study shows that outcomes in routine clinical practice in a specialist community-based service compare well to those reported in research trials. The finding from research trials that early weight gain is associated with improved outcomes was also replicated in this study. Enhancing outpatient treatment with day treatment and/or inpatient care is associated with favourable outcome for most of the young people, although a longer duration of treatment is required.Most research reports on outcomes for clinical trials. This study aimed to evaluate outcomes in a ‘real world’ setting of a specialist child and adolescent eating disorder service (ED) in the UK. Case notes of 357 young people seen for treatment between August 2009 and January 2014 were reviewed. Demographic and treatment characteristics, physical health, ED symptoms, other psychological symptoms and quality of life data are reported. Most young people referred had anorexia nervosa or related difficulties and most received ED focused family therapy. At the end of treatment, the majority had a good or intermediate outcome, regardless of ED diagnosis. In a quarter of the young people, their treatment was enhanced with day or inpatient admissions. This group had more severe difficulties at assessment and had longer treatment but had similar outcomes at the end of treatment.

Reactive oxygen species (ROS) within the cell are rapidly detoxified by antioxidants such as glutathione. Depletion of glutathione will therefore increase levels of intracellular ROS, which can lead to oxidative DNA damage and the induction of apoptosis. The working hypothesis was that Ogg1 null mouse embryonic fibroblasts (mOgg1(-/-) MEFs) would be more sensitive in response to GSH depletion due to their deficiency in the removal of the oxidative DNA modification, 8-oxo-7,8-dihydroguanine (8-oxoG). Following GSH depletion, an increase in intracellular ROS and a subsequent induction of apoptosis was measured in mOgg1(-/-) MEFs; as expected. Unexpectedly, an elevated basal level of ROS was identified in mOgg1(-/-) MEFs compared to wild type MEFs; which we suggest is partly due to the differential expression of key anti-oxidant genes. The elevated basal ROS levels in mOgg1(-/-) MEFs were not accompanied by a deficiency in ATP production or a large increase in 8-oxoG levels. Although 8-oxoG levels did increase following GSH depletion in mOgg1(-/-) MEFs; this increase was significantly lower than observed following treatment with a non-toxic dose of hydrogen peroxide. Reconstitution of Ogg1 into mOgg1(-/-) MEFs resulted in an increased viability following glutathione depletion, however this rescue did not differ between a repair-proficient and a repair-impaired variant of Ogg1. The data indicates that induction of apoptosis in response to oxidative stress in mOgg1(-/-) MEFs is independent of DNA damage and OGG1-initiated DNA repair.

The recalcitrance exhibited by microbial biofilms to conventional disinfectants has motivated the development of new chemical strategies to control and eradicate biofilms. The activities of several small phenolic compounds and their trichloromethylsulfenyl ester derivatives were evaluated against planktonic cells and mature biofilms of Staphylococcus epidermidis and Pseudomonas aeruginosa. Some of the phenolic parent compounds are well-studied constituents of plant essential oils, for example, eugenol, menthol, carvacrol, and thymol. The potency of sulfenate ester derivatives was markedly and consistently increased toward both planktonic cells and biofilms. The mean fold difference between the parent and derivative minimum inhibitory concentration against planktonic cells was 44 for S. epidermidis and 16 for P. aeruginosa. The mean fold difference between the parent and derivative biofilm eradication concentration for 22 tested compounds against both S. epidermidis and P. aeruginosa was 3. This work demonstrates the possibilities of a new class of biofilm-targeting disinfectants deploying a sulfenate ester functional group to increase the antimicrobial potency toward microorganisms in biofilms.

The goal of this study was to quantify the variability of confocal laser scanning microscopy (CLSM) time-lapse images of early colonizing biofilms to aid in the design of future imaging experiments. To accomplish this a large imaging dataset consisting of 16 independent CLSM microscopy experiments was leveraged. These experiments were designed to study interactions between human neutrophils and single cells or aggregates of Staphylococcus aureus (S. aureus) during the initial stages of biofilm formation. Results suggest that in untreated control experiments, variability differed substantially between growth phases (i.e., lag or exponential). When studying the effect of an antimicrobial treatment (in this case, neutrophil challenge), regardless of the inoculation level or of growth phase, variability changed as a frown-shaped function of treatment efficacy (i.e., the reduction in biofilm surface coverage). These findings were used to predict the best experimental designs for future imaging studies of early biofilms by considering differing (i) numbers of independent experiments; (ii) numbers of fields of view (FOV) per experiment; and (iii) frame capture rates per hour. A spreadsheet capable of assessing any user-specified design is included that requires the expected mean log reduction and variance components from user-generated experimental results. The methodology outlined in this study can assist researchers in designing their CLSM studies of antimicrobial treatments with a high level of statistical confidence.

As the extent of damage to environmental systems from our business-as-usual activity becomes ever more alarming, Universities as core social institutions are under pressure to help society lead the transition to a sustainable future. Their response to the issues, that they themselves have helped reveal, has, however, been widely criticised for being wholly inadequate. Universities can be observed to engage with sustainability issues inad-hocways, with the scale of attention and commitment dependant mainly on the level of pressure exerted by stakeholders that works to overcome aspects of inherent inertia. Sustainability initiatives can therefore be regarded mainly as bolt-ons. This mirrors how other sectors, including businesses, have tended to respond. As the environmental and social crisis mounts and the window for adaptive change to ensure long-term wellbeing for all narrows, the pressure for deeper systemic change builds. It is in this context that transformation to a “purpose-driven organisation” has emerged as a systemic approach to change, enabling an organisation to align deeply and rapidly with society's long-term best interest and hence a sustainable future. Nowhere has this concept been taken forward more obviously than in the business sector. As business leadership towards purpose becomes more apparent, so the lack of action in this area by universities appears starker. In this paper we clarify what it means to be a purpose-driven organisation, why and how it represents a deep holistic response to unsustainability, and what core questions emerging from the business world university leaders can ask themselves to begin the practical journey to transform their institutions into purpose-driven universities.

A novel Motional Stark Effect spectroscopy system has been designed for application at the DIII-D tokamak. The system is optimized for studies of the poloidal and toroidal magnetic field in the plasma pedestal region with frame rates of up to 10 kHz. Light from an existing high-photon-throughput collection lens is analyzed using four single-channel f/2.8 Czerny–Turner spectrometers that use custom-made lens systems instead of mirrors. Each spectrometer has two separate outgoing legs and is operated in a positive grating order, which allows for simultaneous observations of D-alpha and D-beta spectra. Forward modeling using the code FIDASIM shows a radial resolution of the system close to 0.6 cm and sufficiently good spectral resolution when masking the high throughput light collection lens in the horizontal direction to avoid overly strong Doppler broadening of beam emission lines. Moreover, a detailed sensitivity study considering realistic levels of readout and photon noise shows that the poloidal and toroidal magnetic field strengths can be inferred with an uncertainty of less than 1%, which will allow the inference of changes of the plasma current during transient events.

Standard doses of antibiotics do not efficiently treat chronic infections of the soft tissue and bone. In this Personal View, we advocate for improving treatment of these infections by taking the infectious microenvironment into account. The infectious microenvironment can cause sensitive bacteria to lose their susceptibility to antibiotics that are effective in standard laboratory susceptibility testing. We propose that bacteria behave substantially different in standard laboratory conditions than they do in actual infections. The infectious microenvironment could impose changes in growth and metabolic activity that result in increased protection against antibiotics. Therefore, we advocate that improved antibiotic treatment of chronic infection is achievable when antibiotics are recommended on the basis of susceptibility testing in relevant in vitro conditions that resemble actual infectious microenvironments. We recommend establishing knowledge of the relevant conditions of the chemical and physical composition of the infectious microenvironment. Recent advances in RNA sequencing, metabolomics, and microscopy have made it possible for the characterisation of the microenvironment of infections and to validate the clinical relevance of in vitro conditions to actual infections.

Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway., Post-translational modifications are critical for regulating the DNA damage response. Here, the authors identify a methylation-deubiquitination crosstalk between methyltransferase PRMT1 and deubiquitinase USP11, showing that the enzymes regulate each other’s functions in DNA repair.

The adenovirus 12 early region 1B55K (Ad12E1B55K) protein has long been known to cause non-random damage to chromosomes 1 and 17 in human cells. These sites, referred to as Ad12 modification sites, have marked similarities to classic fragile sites. In the present report we have investigated the effects of Ad12E1B55K on the cellular DNA damage response and on DNA replication, considering our increased understanding of the pathways involved. We have compared human skin fibroblasts expressing Ad12E1B55K (55K+HSF), but no other viral proteins, with the parental cells. Appreciable chromosomal damage was observed in 55K+HSFs compared to parental cells. Similarly, an increased number of micronuclei was observed in 55K+HSFs, both in cycling cells and after DNA damage. We compared DNA replication in the two cell populations; 55K+HSFs showed increased fork stalling and a decrease in fork speed. When replication stress was introduced with hydroxyurea the percentage of stalled forks and replication speeds were broadly similar, but efficiency of fork restart was significantly reduced in 55K+HSFs. After DNA damage, appreciably more foci were formed in 55K+HSFs up to 48 h post treatment. In addition, phosphorylation of ATM substrates was greater in Ad12E1B55K-expressing cells following DNA damage. Following DNA damage, 55K+HSFs showed an inability to arrest in cell cycle, probably due to the association of Ad12E1B55K with p53. To confirm that Ad12E1B55K was targeting components of the double-strand break repair pathways, co-immunoprecipitation experiments were performed which showed an association of the viral protein with ATM, MRE11, NBS1, DNA-PK, BLM, TOPBP1 and p53, as well as with components of the replisome, MCM3, MCM7, ORC1, DNA polymerase δ, TICRR and cdc45, which may account for some of the observed effects on DNA replication. We conclude that Ad12E1B55K impacts the cellular DNA damage response pathways and the replisome at multiple points through protein–protein interactions, causing genomic instability.

Summary Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

The ATRX ATP-dependent chromatin remodelling/helicase protein associates with the DAXX histone chaperone to deposit histone H3.3 over repetitive DNA regions. Because ATRX-protein interactions impart functions, such as histone deposition, we used proximity-dependent biotinylation (BioID) to identify proximal associations for ATRX. The proteomic screen captured known interactors, such as DAXX, NBS1, and PML, but also identified a range of new associating proteins. To gauge the scope of their roles, we examined three novel ATRX-associating proteins that likely differed in function, and for which little data were available. We found CCDC71 to associate with ATRX, but also HP1 and NAP1, suggesting a role in chromatin maintenance. Contrastingly, FAM207A associated with proteins involved in ribosome biosynthesis and localized to the nucleolus. ATRX proximal associations with the SLF2 DNA damage response factor help inhibit telomere exchanges. We further screened for the proteomic changes at telomeres when ATRX, SLF2, or both proteins were deleted. The loss caused important changes in the abundance of chromatin remodelling, DNA replication, and DNA repair factors at telomeres. Interestingly, several of these have previously been implicated in alternative lengthening of telomeres. Altogether, this study expands the repertoire of ATRX-associating proteins and functions., Author summary ATRX is a protein that is needed to keep repetitive DNA regions organized. It does so in part by binding the DAXX histone chaperone to deposit histone proteins on DNA and assemble structures known as nucleosomes. While important, ATRX has additional functions that remain understudied. To better understand its various biological roles, we first identified the other proteins that are found in its proximity. ATRX-associating proteins were implicated in a range of functions, in addition to histone deposition. Our results suggest that ATRX-associating proteins likely help compact DNA after it is assembled into nucleosomes, and also promote its stability. We then examined the effect of ATRX on telomeres (repetitive DNA regions at the end of chromosomes). ATRX and at least one of its associating proteins suppressed spurious DNA exchanges at telomeres. To understand why, we then identified proteomic changes that occur at telomeres when ATRX was deleted. Loss of ATRX altered the enrichment of a surprising number of proteins at telomeres, including several DNA damage response and chromatin remodelling proteins.

Replisomes follow a schedule in which replication of DNA in euchromatin is early in S phase while sequences in heterochromatin replicate late. Impediments to DNA replication, referred to as replication stress, can stall replication forks triggering activation of the ATR kinase and downstream pathways. While there is substantial literature on the local consequences of replisome stalling–double strand breaks, reversed forks, or genomic rearrangements–there is limited understanding of the determinants of replisome stalling vs. continued progression. Although many proteins are recruited to stalled replisomes, current models assume a single species of “stressed” replisome, independent of genomic location. Here we describe our approach to visualizing replication fork encounters with the potent block imposed by a DNA interstrand crosslink (ICL) and our discovery of an unexpected pathway of replication restart (traverse) past an intact ICL. Additionally, we found two biochemically distinct replisomes distinguished by activity in different stages of S phase and chromatin environment. Each contains different proteins that contribute to ICL traverse.

Necrotic enteritis (NE), an economically devastating disease of poultry caused by pathogenic Clostridium perfringens, is known to induce small intestinal lesions and dysbiosis. However, the intestinal microbes that are associated with NE severity are yet to be characterized. Here, we investigated the link between the ileal microbiota and disease severity in a chicken model of clinical NE using 16S rRNA gene sequencing. Our results indicated that richness and Shannon Index of the ileal microbiota were drastically reduced (pC. perfringens increased from 0.02% in healthy chickens to 58–70% in chickens with severe infection, a majority of the ileal microbes were markedly diminished, albeit varying in their sensitivity to NE. Compositionally, a large group of ileal microbes showed a significant correlation with NE severity. Firmicutes, such as group A and B Lactobacillus, Lactobacillus reuteri, Subdoligranulum variabile, Mediterraneibacter, and Staphylococcus as well as two genera of Actinobacteria (Corynebacterium and Kocuria) and two highly related Cyanobacteria were progressively declined as NE was aggravated. Other Firmicutes, such as Weissella, Romboutsia, Kurthia, Cuneatibacter, Blautia, and Aerococcus, appeared much more sensitive and were rapidly abolished in chickens even with mild NE. On the other hand, Enterococcus cecorum and two Escherichia/Shigella species were only enriched in the ileal microbiota of chickens with extremely severe NE, while several other species such as Streptococcus gallolyticus and Bacteroides fragilis remained unaltered by NE. Functionally, secondary bile acid biosynthesis was predicted to be suppressed by NE, while biosynthesis of aromatic and branched-amino acids and metabolism of a majority of amino acids were predicted to be enhanced in the ileum of NE-afflicted chickens. These intestinal microbes showing a strong correlation with NE severity may provide important leads for the development of novel diagnostic or therapeutic approaches to NE and possibly other enteric diseases.

We study flow driven through a finite-length planar rigid channel by a fixed upstream flux, where a segment of one wall is replaced by a pre-stressed elastic beam subject to uniform external pressure. The steady and unsteady systems are solved using a finite element method. Previous studies have shown that the system can exhibit three steady states for some parameters (termed the upper, intermediate and lower steady branches, respectively). Of these, the intermediate branch is always unstable while the upper and lower steady branches can (independently) become unstable to self-excited oscillations. We show that for some parameter combinations the system is unstable to both upper and lower branch oscillations simultaneously. However, we show that these two instabilities eventually merge together for large enough Reynolds numbers, exhibiting a nonlinear limit cycle which retains characteristics of both the upper and lower branches of oscillations. Furthermore, we show that increasing the beam pre-tension suppresses the region of multiple steady states but preserves the onset of oscillations. Conversely, increasing the beam thickness (a proxy for increasing bending stiffness) suppresses both multiple steady states and the onset of oscillations., 17 pages, 9 figures

There is concern that in-person schooling during the coronavirus disease 2019 (COVID-19) pandemic will facilitate disease transmission. Through asymptomatic surveillance and contact tracing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we found low rates of asymptomatic SARS-CoV-2 infection and little in-school transmission of COVID-19 when physical distancing and masking strategies were enforced despite a high community prevalence of COVID-19.

Humans interact with the oceans in diverse and profound ways. The scope, magnitude, footprint and ultimate cumulative impacts of human activities can threaten ocean ecosystems and have changed over time, resulting in new challenges and threats to marine ecosystems. A fundamental gap in understanding how humanity is affecting the oceans is our limited knowledge about the pace of change in cumulative impact on ocean ecosystems from expanding human activities – and the patterns, locations and drivers of most significant change. To help address this, we combined high resolution, annual data on the intensity of 14 human stressors and their impact on 21 marine ecosystems over 11 years (2003–2013) to assess pace of change in cumulative impacts on global oceans, where and how much that pace differs across the ocean, and which stressors and their impacts contribute most to those changes. We found that most of the ocean (59%) is experiencing significantly increasing cumulative impact, in particular due to climate change but also from fishing, land-based pollution and shipping. Nearly all countries saw increases in cumulative impacts in their coastal waters, as did all ecosystems, with coral reefs, seagrasses and mangroves at most risk. Mitigation of stressors most contributing to increases in overall cumulative impacts is urgently needed to sustain healthy oceans.

Background Adult studies have demonstrated intra-season declines in influenza vaccine effectiveness (VE) with increasing time since vaccination; however, data in children are limited. Methods We conducted a prospective, test-negative study of children ages 6 months through 17 years hospitalized with acute respiratory illness at 7 pediatric medical centers each season in the New Vaccine Surveillance Network during the 2015-2016 through 2019-2020 influenza seasons. Cases were children with an influenza-positive molecular test; controls were influenza-negative children. Controls were matched to cases by illness onset date using 3:1 nearest neighbor matching. We estimated VE [100% x (1 – odds ratio)] by comparing the odds of receipt of ≥ 1 dose of influenza vaccine ≥ 14 days before the onset of illness that resulted in hospitalization among influenza-positive children to influenza-negative children. Changes in VE over time between vaccination date and illness onset date during each season were estimated using multivariable logistic regression models. Results Of 8,430 hospitalized children (4,781 [57%] male; median age 2.4 years), 4,653 (55%) received ≥ 1 dose of influenza vaccine. On average, 48% and 85% of children were vaccinated by the end of October and December, respectively. Influenza-positive cases (n=1,000; 12%) were less likely to be vaccinated than influenza-negative controls (39% vs. 61%, p< 0.001) and overall VE against hospitalization was 53% (95% CI: 46%, 60%). Pooling data across 5 seasons, the odds of any influenza-associated hospitalization increased 0.96% (95% CI: -0.76%, 2.71%) per week with a corresponding weekly decrease in VE of 0.45% (p=0.275). Odds of hospitalization with time since vaccination increased 0.66% (95% CI: -0.76%, 2.71%) per week in children ≤ 8 years (n=3,084) and 2.16% (95% CI: -1.68%, 6.15%) per week in children 9-17 years (n=771). No significant differences were observed by virus subtype or lineage. Figure 1. Declines in influenza VE over time from 2015-2016 through 2019-2020, overall (a) and by age group (b: ≤ 8 years; c: 9-17 years) Conclusion We observed minimal intra-season declines in VE against influenza-associated hospitalization in U.S. children. Vaccination following Advisory Committee on Immunization Practices guidelines and current timing of vaccine receipt is the best strategy for prevention of influenza-associated hospitalization in children. Disclosures Marian G. Michaels, MD, MPH, Viracor (Grant/Research Support, performs assay for research study no financial support) John V. Williams, MD, GlaxoSmithKline (Advisor or Review Panel member, Independent Data Monitoring Committee)Quidel (Advisor or Review Panel member, Scientific Advisory Board) Elizabeth P. Schlaudecker, MD, MPH, Pfizer (Grant/Research Support)Sanofi Pasteur (Advisor or Review Panel member) Natasha B. Halasa, MD, MPH, Genentech (Other Financial or Material Support, I receive an honorarium for lectures - it’s a education grant, supported by genetech)Quidel (Grant/Research Support, Other Financial or Material Support, Donation of supplies/kits)Sanofi (Grant/Research Support, Other Financial or Material Support, HAI/NAI testing) Natasha B. Halasa, MD, MPH, Genentech (Individual(s) Involved: Self): I receive an honorarium for lectures - it’s a education grant, supported by genetech, Other Financial or Material Support, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Grant/Research Support, Research Grant or Support Janet A. Englund, MD, AstraZeneca (Consultant, Grant/Research Support)GlaxoSmithKline (Research Grant or Support)Meissa Vaccines (Consultant)Pfizer (Research Grant or Support)Sanofi Pasteur (Consultant)Teva Pharmaceuticals (Consultant) Christopher J. Harrison, MD, GSK (Grant/Research Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Flor M. Munoz, MD, Biocryst (Scientific Research Study Investigator)Gilead (Scientific Research Study Investigator)Meissa (Other Financial or Material Support, DSMB)Moderna (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Pfizer (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Virometix (Other Financial or Material Support, DSMB)

Background Parent-reported influenza vaccination history may be valuable clinically and in influenza vaccine effectiveness (VE) studies. Few studies have assessed the validity of parental report among hospitalized children. Methods Parents of 2597 hospitalized children 6 months–17 years old were interviewed from November 1, 2015 to June 30, 2016, regarding their child’s sociodemographic and influenza vaccination history. Parent-reported 2015–2016 influenza vaccination history was compared with documented vaccination records (considered the gold standard for analysis) obtained from medical records, immunization information systems, and providers. Multivariable logistic regression analyses were conducted to determine potential factors associated with discordance between the 2 sources of vaccination history. Using a test-negative design, we estimated VE using vaccination history obtained through parental report and documented records. Results According to parental report, 1718 (66%) children received the 2015–2016 influenza vaccine, and of those, 1432 (83%) had documentation of vaccine receipt. Percent agreement was 87%, with a sensitivity of 96% (95% confidence interval [CI], 95%–97%) and a specificity of 74% (95% CI, 72%–77%). In the multivariable logistic regression, study site and child’s age 5–8 years were significant predictors of discordance. Adjusted VE among children who received ≥1 dose of the 2015–2016 influenza vaccine per parental report was 61% (95% CI, 43%–74%), whereas VE using documented records was 55% (95% CI, 33%–69%). Conclusions Parental report of influenza vaccination was sensitive but not as specific compared with documented records. However, VE against influenza-associated hospitalizations using either source of vaccination history did not differ substantially. Parental report is valuable for timely influenza VE studies.

Background Intestinal microbiota plays a key role in nutrient digestion and utilization with a profound impact on feed efficiency of livestock animals. However, the intestinal microbes that are critically involved in feed efficiency remain elusive. Methods To identify intestinal bacteria associated with residual feed intake (RFI) in chickens, male Cobb broiler chicks were individually housed from day 14 to day 35. Individual RFI values were calculated for 56 chickens. Luminal contents were collected from the ileum, cecum, and cloaca of each animal on day 35. Bacterial DNA was isolated and subjected to 16S rRNA gene sequencing. Intestinal microbiota was classified to the feature level using Deblur and QIIME 2. High and low RFI groups were formed by selecting 15 and 17 chickens with the most extreme RFI values for subsequent LEfSe comparison of the difference in the microbiota. Spearman correlation analysis was further performed to identify correlations between the intestinal microbiota composition and RFI. Results No significant difference in evenness, richness, and overall diversity of the microbiota in the ileum, cecum, or cloaca was observed between high and low RFI chickens. However, LEfSe analysis revealed a number of bacterial features being differentially enriched in either high or low RFI chickens. Spearman correlation analysis further identified many differentially enriched bacterial features to be significantly correlated with RFI (P Oscillibacter and Butyricicoccus were more abundant in low-RFI, high-efficiency chickens, several other SCFA producers such as Subdoligranulum variabile and two related Peptostreptococcaceae members were negatively associated with feed efficiency. Moreover, a few closely-related Lachnospiraceae family members showed a positive correlation with feed efficiency, while others of the same family displayed an opposite relationship. Conclusions Our results highlight the complexity of the intestinal microbiota and a need to differentiate the bacteria to the species, subspecies, and even strain levels in order to reveal their true association with feed efficiency. Identification of RFI-associated bacteria provides important leads to manipulate the intestinal microbiota for improving production efficiency, profitability, and sustainability of poultry production.

Improving the health of coastal and open sea marine ecosystems represents a substantial challenge for sustainable marine resource management, since it requires balancing human benefits and impacts on the ocean. This challenge is often exacerbated by incomplete knowledge and lack of tools that measure ocean and coastal ecosystem health in a way that allows consistent monitoring of progress towards predefined management targets. The lack of such tools often limits capabilities to enact and enforce effective governance. We introduce the Baltic Health Index (BHI) as a transparent, collaborative and repeatable assessment tool. The Index complements existing, more ecological-oriented, approaches by including a human dimension on the status of the Baltic Sea, an ecosystem impacted by multiple anthropogenic pressures and governed by a multitude of comprehensive national and international policies. Using a large amount of social-ecological data available, we assessed the health of the Baltic Sea for nine goals that represent the status towards set targets, for example, clean waters, biodiversity, food provision, natural products extraction and tourism. Our results indicate that the overall health of the Baltic Sea is suboptimal (a score of 76 out of 100), and a substantial effort is required to reach the management objectives and associated targets. Subregionally, the lowest BHI scores were measured for carbon storage, contaminants and lasting special places (i.e. marine protected areas), albeit with large spatial variation. Overall, the likely future status of all goals in the BHI averaged for the entire Baltic Sea is better than the present status, indicating a positive trend towards a healthier Baltic Sea. However, in some Baltic Sea basins, the trend for specific goals was decreasing, highlighting locations and issues that should be the focus of management priorities. The BHI outcomes can be used to identify both pan-Baltic and subregional scale management priorities and to illustrate the interconnectedness between goals linked by cumulative pressures. Hence, the information provided by the BHI tool and its further development will contribute towards the fulfilment of the UN Agenda 2030 and its Sustainability Development Goals. A free Plain Language Summary can be found within the Supporting Information of this article. A free Plain Language Summary can be found within the Supporting Information of this article.

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