Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles ...of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria.
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•Phylogenetic analysis identifies 30 Plasmodium berghei protein phosphatases (PPs)•Functional analysis reveals role for six PPs in sexual development/sporogony•Two N-myristoylated PPs play key roles in sex allocation and parasite transmission•RNA-Seq highlights significantly altered gene clusters in the N-myristoylated PP mutants
Protein phosphorylation regulated by kinases and phosphatases plays important roles in the Plasmodium life cycle. By performing a genome-wide functional screen, Guttery et al. examine protein phosphatases in Plasmodium berghei and identify phosphatases likely essential for asexual development in host blood as well as those required for sexual/sporogony development in mosquitos.
Advances in research and technology in recent years in the field of controlled atmosphere (CA) storage have led to the development of many new protocols that recommend lower oxygen (O2) levels than ...those historically deemed “safe”. As some of these protocols and technologies have been adopted by commercial CA storage rooms, especially in the apple industry, it is now opportune to review the relationships between O2 levels, respiration, fermentation, and fruit quality retention. Lowering O2 levels during apple storage slows respiration, reduces ethylene biosynthesis, and slows fruit maturation and senescence. In addition, low O2 influences the expression of genes associated with cellular energy consumption. When O2 levels become limiting, aerobic mitochondrial respiration is inhibited and plant tissues engage in the energetically less-efficient fermentation pathway. The accumulation of fermentation-related volatiles may lead to off-flavours and odours. At low levels, or for short durations, fermentation is generally not a problem and may even be commercially beneficial. Plants that are limited in their ability to ferment succumb to low-O2 stress more quickly than those that can readily ferment anaerobically. Increasing market pressure to reduce chemical residues in apple, as well as in all fruits and vegetables, is encouraging researchers, CA system manufacturers and suppliers, and some commercial storage operators to explore alternative methods to improve storage procedures. The future of CA storage may reside in a better understanding of what constitutes the lower O2 limit for metabolism and energy demands, improved product-response sensing capabilities, and the application of more dynamic forms of CA storage technology.
c-Myc is an oncogenic transcription factor capable of activating transcription by all three nuclear RNA polymerases, thus acting as a high-level coordinator of protein synthesis capacity and cell ...growth rate. c-Myc recruits RNA polymerase I-related transcription factors to the rDNA when quiescent cells are stimulated to re-enter the cell cycle. Using a model system of cell lines with variable c-Myc status, we show that on stimulation c-Myc rapidly induces gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. c-Myc activation is both necessary and sufficient for this change in rDNA chromatin conformation. c-Myc activation induces association of TTF-1 with the rDNA, and c-Myc is physically associated with induced rDNA gene loops. The origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that c-Myc induces nucleolar chromatin hubs. Induction of rDNA gene loops may be an early step in the reprogramming of quiescent cells as they re-enter the growth cycle.
Background
Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) ...remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma.
Methods
An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed.
Results
Of 112 patients, median age at T-VEC initiation was 69 years (range 21–93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (
n
= 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (
n
= 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (
p
= 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE).
Conclusions
T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.
The matter environment of galaxies is connected to the physics of galaxy formation and evolution. In particular, the average matter distribution around galaxy pairs is a strong test for galaxy ...models. Utilising galaxy-galaxy-galaxy lensing as a direct probe, we map out the distribution of correlated surface mass-density around galaxy pairs in the Canada-France-Hawaii Telescope Lensing Survey (CFHTLenS). We have compared, for the first time, these so-called excess mass maps to predictions provided by a recent semi-analytic model, which is implanted within the dark-matter Millennium Simulation. We analysed galaxies with stellar masses between 109 − 1011 M⊙ in two photometric redshift bins, for lens redshifts z ≲ 0.6. The projected separation of the galaxy pairs ranges between 170 − 300 h−1 kpc, thereby focusing on pairs inside groups and clusters. To allow us a better interpretation of the maps, we discuss the impact of chance pairs, that is galaxy pairs that appear close to each other in projection only. We have introduced an alternative correlation map that is less affected by projection effects but has a lower signal-to-noise ratio. Our tests with synthetic data demonstrate that the patterns observed in both types of maps are essentially produced by correlated pairs which are close in redshift (Δz ≲ 5 × 10−3). We also verify the excellent accuracy of the map estimators. In an application to the galaxy samples in the CFHTLenS, we obtain a 3σ − 6σ significant detection of the excess mass and an overall good agreement with the galaxy model predictions. There are, however, a few localised spots in the maps where the observational data disagrees with the model predictions on a ≈3.5σ confidence level. Although we have no strong indications for systematic errors in the maps, this disagreement may be related to the residual B-mode pattern observed in the average of all maps. Alternatively, misaligned galaxy pairs inside dark matter halos or lensing by a misaligned distribution of the intra-cluster gas might also cause the unanticipated bulge in the distribution of the excess mass between lens pairs.
Mounting evidence points to the heterogeneity of osteoarthritis (OA) pain, increasing the need for more comprehensive assessment of the efficacy of standard interventions. This study investigated ...whether 14 days of the selective Cox-2 inhibitor etoricoxib (60 mg/day) would modify self-report of pain intensity and quality, and physical measures of hyperalgesia and function in individuals with knee OA.
This double-blind placebo-controlled trial included 80 community-recruited volunteers with painful knee OA (≥3/10 VAS), randomly allocated to Active or Placebo groups. Self-report measures of pain, stiffness, function Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and pain quality (PainDETECT, Pain Quality Assessment Scale PQAS) and physical measures of locomotion and local (knee) and widespread (elbow) hyperalgesia were assessed at Days 0, 4 and 14. Repeated Measures ANOVA analysed group differences.
Significant group × time interaction effects were found for all measures of pain (all p < 0.001), with WOMAC pain sub-score improving by 30.7% by Day 14 and index knee mechanical hyperalgesia improving by 32.6%, whilst Placebo group values worsened. Both self-report and physical tests of function improved (p < 0.001–p = 0.006): WOMAC-function by 28.4%, sit-to-stand and walk time by 13%, pain during locomotion tasks by 12.4–32.6%. Pain quality also significantly improved for the Active and declined for the Placebo group (p < 0.001): PainDETECT score reduced by 23.6% and PQAS paroxsysmal and surface sub-scores by 36.9% and 29.4%. There were also significant improvements in local cold hyperalgesia and widespread mechanical hyperalgesia (10–13.8%).
Just 14 days of etoricoxib significantly improves pain intensity and quality, function and local and widespread hyperalgesia, measured by both self-report and physical tests.
We present the first results of our search for new, extended planetary nebulae (PNe) based on careful, systematic, visual scrutiny of the imaging data from the Isaac Newton Telescope Photometric H ...alpha Survey of the Northern Galactic plane (IPHAS). The newly uncovered PNe will help to improve the census of this important population of Galactic objects that serve as key windows into the late-stage evolution of low- to intermediate-mass stars. They will also facilitate study of the faint end of the ensemble Galactic PN luminosity function. The sensitivity and coverage of IPHAS allows PNe to be found in regions of greater extinction in the Galactic plane and/or those PNe in a more advanced evolutionary state and at larger distances compared to the general Galactic PN population. Using a set of newly revised optical diagnostic diagrams in combination with access to a powerful, new, multiwavelength imaging data base, we have identified 159 true, likely and possible PNe for this first catalogue release. The ability of IPHAS to unveil PNe at low Galactic latitudes and towards the Galactic Anticentre, compared to previous surveys, makes this survey an ideal tool to contribute to the improvement of our knowledge of the whole Galactic PN population.
We present a study of the dust, stars and atomic gas (H i) in an H i-selected sample of local galaxies (z < 0.035) in the Herschel Astrophysical Terahertz Large Area Survey fields. This H i-selected ...sample reveals a population of very high gas fraction (>80 per cent), low stellar mass sources that appear to be in the earliest stages of their evolution. We compare this sample with dust- and stellar-mass-selected samples to study the dust and gas scaling relations over a wide range of gas fractions (proxy for evolutionary state of a galaxy). The most robust scaling relations for gas and dust are those linked to near-ultraviolet - r (specific star formation rate) and gas fraction; these do not depend on sample selection or environment. At the highest gas fractions, our additional sample shows that the dust content is well below expectations from extrapolating scaling relations for more evolved sources, and dust is not a good tracer of the gas content. The specific dust mass for local galaxies peaks at a gas fraction of ~75 per cent. The atomic gas depletion time is also longer for high gas fraction galaxies, opposite to the trend found for molecular gas depletion time-scale. We link this trend to the changing efficiency of conversion of H i to H sub( 2) as galaxies increase in stellar mass surface density during their evolution. Finally, we show that galaxies start out barely obscured and increase in obscuration as they evolve, yet there is no clear and simple link between obscuration and global galaxy properties.
The number of proposed prognostic models for coronavirus disease 2019 (COVID-19) is growing rapidly, but it is unknown whether any are suitable for widespread clinical implementation.We independently ...externally validated the performance of candidate prognostic models, identified through a living systematic review, among consecutive adults admitted to hospital with a final diagnosis of COVID-19. We reconstructed candidate models as per original descriptions and evaluated performance for their original intended outcomes using predictors measured at the time of admission. We assessed discrimination, calibration and net benefit, compared to the default strategies of treating all and no patients, and against the most discriminating predictors in univariable analyses.We tested 22 candidate prognostic models among 411 participants with COVID-19, of whom 180 (43.8%) and 115 (28.0%) met the endpoints of clinical deterioration and mortality, respectively. Highest areas under receiver operating characteristic (AUROC) curves were achieved by the NEWS2 score for prediction of deterioration over 24 h (0.78, 95% CI 0.73-0.83), and a novel model for prediction of deterioration <14 days from admission (0.78, 95% CI 0.74-0.82). The most discriminating univariable predictors were admission oxygen saturation on room air for in-hospital deterioration (AUROC 0.76, 95% CI 0.71-0.81), and age for in-hospital mortality (AUROC 0.76, 95% CI 0.71-0.81). No prognostic model demonstrated consistently higher net benefit than these univariable predictors, across a range of threshold probabilities.Admission oxygen saturation on room air and patient age are strong predictors of deterioration and mortality among hospitalised adults with COVID-19, respectively. None of the prognostic models evaluated here offered incremental value for patient stratification to these univariable predictors.
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