Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes ...comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Host plants used by phytophagous insects can have significant consequences on demography parameters, overall lifetime fitness and their subsequent population dynamics. Here, we conduct a comparative ...demographic study between the specialist Zeugodacus cucumis (French) and generalist Bactrocera tryoni (Froggatt) (Diptera: Tephritidae) to determine whether the host plants used by these fly species play any role in their overall lifetime fitness and explains current host use patterns. These two fly species are pests within the north‐eastern region of Australia and we further aimed to use complete life‐history data to determine the population parameters and models that would help identify the sensitive life‐history stage that could be targeted for effective field management. Eggs collected from laboratory‐reared flies were inoculated into organically grown fruits of both the primary and alternate host plant cultivars of both fly species. The proportion surviving each life stage from egg through to adult and fecundity were monitored for all cohorts from the different plant cultivars. Complete stage‐base life‐tables for cohorts of each fly species developing from each fruit cultivar were constructed, and the key demographic parameters and population models were analysed using PopTools matrix model programme. Our results showed that the host used by each fly species had significant consequences on fly demographic parameters and hence their overall lifetime fitness. The generalist B. tryoni was able to compensate for the fitness loss experienced at the pre‐adult stage by having adults with higher fecundity, but this was not the case for the specialist Z. cucumis. Stage‐base population models revealed that the population growth rate of both species was highly sensitive at the adult reproductive stage, indicating that manipulating probability of survival at this life stage would effectively manage populations of these pest species. This study provides the empirical evidence of undertaking complete life history demography studies of phytophagous insects to accurately understand their lifetime fitness consequences of using a certain host, their observed host use patterns, and overall population dynamics. We suggest that any efforts to manage dacine fruit fly pest population should consider life‐history consequences of host use.
Here, we conduct a comparative demographic study between the specialist Zeugodacus cucumis (French) and generalist Bactrocera tryoni (Froggatt) to determine whether the host plants used by these fly species play any role in their overall lifetime fitness and explain current host use patterns. This study provides the empirical evidence of undertaking complete life history demography studies of phytophagous insects to accurately understand their lifetime fitness consequences of using a certain host, their observed host use patterns, and overall population dynamics. We suggest that any efforts to manage dacine fruit fly pest population should consider life‐history consequences of host use.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Understanding plant community responses to combinations of biotic and abiotic factors is critical for predicting ecosystem response to environmental change. However, studies of plant community ...regulation have seldom considered how responses to such factors vary with the different phases of the plant growth cycle. To address this deficit we studied an aquatic plant community in an ecosystem subject to gradients in mute swan (Cygnus olor) herbivory, riparian shading, water temperature and distance downstream of the river source. We quantified abundance, species richness, evenness, flowering and dominance in relation to biotic and abiotic factors during the growth-, peak-, and recession-phases of the plant growth cycle. We show that the relative importance of biotic and abiotic factors varied between plant community properties and between different phases of the plant growth cycle. Herbivory became more important during the later phases of peak abundance and recession due to an influx of swans from adjacent pasture fields. Shading by riparian vegetation also had a greater depressing effect on biomass in later seasons, probably due to increased leaf abundance reducing light intensity reaching the aquatic plants. The effect of temperature on community diversity varied between upstream and downstream sites by altering the relative competitiveness of species at these sites. These results highlight the importance of seasonal patterns in the regulation of plant community structure and function by multiple factors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Successful matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) relies on the selection of the most appropriate matrix and optimization of the matrix application ...parameters. In order to achieve reproducible high spatial-resolution imaging data, several commercially available automated matrix application platforms have become available. However, the high cost of these commercial matrix sprayers is restricting access into this emerging research field. Here, we report an automated platform for matrix deposition, employing a converted commercially available 3D printer ($300) and other parts commonly found in an analytical chemistry lab as a low-cost alternative to commercial sprayers. Using printed fluorescent rhodamine B microarrays and employing experimental design, the matrix deposition parameters were optimized to minimize surface analyte diffusion. Finally, the optimized matrix application method was applied to image three-dimensional MCF-7 cell culture spheroid sections (ca. 500 μm diameter tissue samples) and sections of mouse brain. Using this system, we demonstrate robust and reproducible observations of endogenous metabolite and steroid distributions with a high spatial resolution.
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IJS, KILJ, NUK, PNG, UL, UM
Introduction
Alpha‐fetoprotein (AFP) has a valuable role in postoperative surveillance for hepatocellular carcinoma (HCC) recurrence. The utility of pretreatment or baseline AFP remains ...controversial. The present study hypothesized that elevated baseline AFP levels are associated with worse overall survival in HCC patients.
Methods
Adult HCC patients were identified using the National Cancer Database (2004‐2013). Patients were stratified according to baseline AFP measurements into the following groups: Negative (<20), Borderline (20‐199), Elevated (200‐1999), and Highly Elevated (>2000). The primary outcome was overall survival (OS), which was analyzed by log‐rank test and graphed using Kaplan‐Meier method. Multivariate regression modeling was used to determine hazard ratios (HR) for OS.
Results
Of 41 107 patients identified, 15 809 (33.6%) were Negative. Median overall survival was highest in the Negative group, followed by Borderline, Elevated, and Highly Elevated (28.7 vs 18.9 vs 8.8 vs 3.2 months; P < 0.001). On multivariate analysis, overall survival hazard ratios for the Borderline, Elevated, and Highly Elevated groups were 1.18 (P = 0.267), 1.94 (P < 0.001), and 1.77 (P = 0.007), respectively (reference Negative).
Conclusion
Baseline AFP independently predicted overall survival in HCC patients regardless of treatment plan. A baseline AFP value is a simple and effective method to assist in expected survival for HCC patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The aim of this prospective, phase II trial was to determine the response of muscle-invasive bladder cancer (MIBC) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy ...(RT; GemX).
Fifty patients with transitional cell carcinoma, stage T2-3, N0, M0 after transurethral resection and magnetic resonance imaging, were recruited. Gemcitabine was given intravenously at 100 mg/m(2) on days 1, 8, 15, and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions. Chemotherapy was stopped for Radiation Therapy Oncology Group (RTOG) grade 3 bladder or bowel toxicity. The primary end points were tumor response, toxicity, and survival.
All patients completed RT; 46 tolerated all four cycles of gemcitabine. Two patients stopped after two cycles, and two stopped after three cycles, because of bowel toxicity. Forty-seven patients had a post-treatment cystoscopy; 44 (88%) achieved a complete endoscopic response. At a median follow-up of 36 months (range, 15 to 62 months), 36 patients were alive, and 32 of these had a functional and intact bladder. Fourteen patients died; seven died as a result of metastatic MIBC, five died as a result of intercurrent disease, and two died as a result of treatment-associated deaths. Four patients underwent cystectomy; three because of recurrent disease and one because of toxicity. One patient required a bowel resection for late toxicity. By using Kaplan-Meier analyses, 3-year cancer-specific survival was 82%, and overall survival was 75%.
Concurrent gemcitabine-based chemoradiotherapy (ie, GemX) produces a high response rate in MIBC and has durable local control and acceptable toxicity, which allows patients to preserve their own bladder. This treatment modality warrants additional investigation in a phase III setting.
•Five of six outcomes had no increased risk following COVID-19 monovalent mRNA vaccines (primary series and booster doses).•No consistent risk of pulmonary embolism was observed after exposure to ...COVID-19 monovalent mRNA vaccines.•Results support the favorable safety profile of COVID-19 mRNA vaccines administered in the U.S. elderly population.
Our near-real-time safety monitoring of 16 adverse events (AEs) following COVID-19 mRNA vaccination identified potential elevation in risk for six AEs following primary series and monovalent booster dose administration. The crude association with AEs does not imply causality. Accordingly, we conducted robust evaluation of potential associations.
We conducted two self-controlled case series studies of COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) in U.S. Medicare beneficiaries aged ≥ 65 years. Adjusted incidence rate ratio (IRRs) and 95 % confidence intervals (CIs) were estimated following primary series doses for acute myocardial infarction (AMI), pulmonary embolism (PE), immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC); and following monovalent booster doses for AMI, PE, ITP, Bell’s Palsy (BP) and Myocarditis/Pericarditis (Myo/Peri).
The primary series study included 3,360,981 individuals who received 6,388,542 primary series doses; the booster study included 6,156,100 individuals with one monovalent booster dose. The AMI IRR following BNT162b2 primary series and booster was 1.04 (95 % CI: 0.91 to 1.18) and 1.06 (95 % CI: 1.003 to 1.12), respectively; for mRNA-1273 primary series and booster, 1.01 (95 % CI: 0.82 to 1.26) and 1.05 (95 % CI: 0.998 to 1.11), respectively. The hospital inpatient PE IRR following BNT162b2 primary series and booster was 1.19 (95 % CI: 1.03 to 1.38) and 0.86 (95 % CI: 0.78 to 0.95), respectively; for mRNA-1273 primary series and booster, 1.15 (95 % CI: 0.94 to 1.41) and 0.87 (95 % CI: 0.79 to 0.96), respectively. The studies’ results do not support that exposure to COVID-19 mRNA vaccines elevate the risk of ITP, DIC, Myo/Peri, and BP.
We did not find an increased risk for AMI, ITP, DIC, BP, and Myo/Peri and there was not consistent evidence for PE after exposure to COVID-19 mRNA primary series or monovalent booster vaccines. These results support the favorable safety profile of COVID-19 mRNA vaccines administered in the U.S. elderly population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Skeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol ...levels. The E3 ubiquitin ligase MuRF1 (muscle RING finger protein 1) is transcriptionally upregulated by DEX treatment. Differentiated myotubes treated with DEX undergo depletion of myosin heavy chain protein (MYH), which physically associates with MuRF1. This loss of MYH can be blocked by inhibition of MuRF1 expression. When wild-type and MuRF1−/− mice are treated with DEX, the MuRF1−/− animals exhibit a relative sparing of MYH. In vitro, MuRF1 is shown to function as an E3 ubiquitin ligase for MYH. These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bedrock uplift in Antarctica is dominated by a combination of glacial isostatic adjustment (GIA) and elastic response to contemporary mass change. Here, we present spatially extensive GPS ...observations of Antarctic bedrock uplift, using 52% more stations than previous studies, giving enhanced coverage, and with improved precision. We observe rapid elastic uplift in the northern Antarctic Peninsula. After considering elastic rebound, the GPS data suggests that modeled or empirical GIA uplift signals are often over‐estimated, particularly the magnitudes of the signal maxima. Our observation that GIA uplift is misrepresented by modeling (weighted root‐mean‐squares of observation‐model differences: 4.9–5.0 mm/yr) suggests that, apart from a few regions where large ice mass loss is occurring, the spatial pattern of secular ice mass change derived from Gravity Recovery and Climate Experiment (GRACE) data and GIA models may be unreliable, and that several recent secular Antarctic ice mass loss estimates are systematically biased, mainly too high.
Key Points
Spatially extensive GPS observations of Antarctic GIA show low rates
GIA models are systematically biased, mainly too high
Recent secular Antarctic ice mass loss estimates are also systematically biased
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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