Abstract Recent measurements of Galactic polarized dust emission have found a nonzero TB signal, a correlation between the total intensity and the B -mode polarization component. We present evidence ...that this parity-odd signal is driven by the relative geometry of the magnetic field and the filamentary interstellar medium in projection. Using neutral hydrogen morphology and Planck polarization data, we find that the angle between intensity structures and the plane-of-sky magnetic field orientation is predictive of the signs of Galactic TB and EB . Our results suggest that magnetically misaligned filamentary dust structures introduce nonzero TB and EB correlations in the dust polarization, and that the intrinsic dust EB can be predicted from measurements of dust TB and TE over the same sky mask. We predict correlations between TE , TB , EB , and EE / BB , and confirm our predictions using synthetic dust polarization maps from magnetohydrodynamic simulations. We introduce and measure a scale-dependent effective magnetic misalignment angle, ψ ℓ dust ∼ 5 ° for 100 ≲ ℓ ≲ 500, and predict a positive intrinsic dust EB with amplitude D ℓ EB ≲ 2.5 μ K CMB 2 for the same multipole range at 353 GHz over our sky mask. Both the sign and amplitude of the Galactic EB signal can change with the sky area considered. Our results imply that searches for parity violation in the cosmic microwave background must account for the nonzero Galactic EB and TB signals, necessitating revision of existing analyses of the evidence for cosmic birefringence.
Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on ...how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations-serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and re-evaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements.
: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (
).
The mouse is one of the most widely used model organisms for genetic study. The tools available to alter the mouse genome have developed over the preceding decades from forward screens to gene ...targeting in stem cells to the recent influx of CRISPR approaches. In this review, we first consider the history of mice in genetic study, the development of classic approaches to genome modification, and how such approaches have been used and improved in recent years. We then turn to the recent surge of nuclease-mediated techniques and how they are changing the field of mouse genetics. Finally, we survey common classes of alleles used in mice and discuss how they might be engineered using different methods.
ABSTRACT We present the results of precision gamma-ray timing measurements of the binary millisecond pulsar PSR J2339-0533, an irradiating system of the "redback" type, using data from the Fermi ...Large Area Telescope. We describe an optimized analysis method to determine a long-term phase-coherent timing solution spanning more than six years, including a measured eccentricity of the binary orbit and constraints on the proper motion of the system. A major result of this timing analysis is the discovery of an extreme variation of the nominal 4.6 hr orbital period over time, showing alternating epochs of decrease and increase. We inferred a cyclic modulation of with an approximate cycle duration of 4.2 yr and a modulation amplitude of . Considering different possible physical causes, the observed orbital-period modulation most likely results from a variable gravitational quadrupole moment of the companion star due to cyclic magnetic activity in its convective zone.
Using high-resolution data from the Galactic Arecibo L-Band Feed Array HI (GALFA-Hi) survey, we show that linear structure in Galactic neutral hydrogen (Hi) correlates with the magnetic field ...orientation implied by Planck 353 GHz polarized dust emission. The structure of the neutral interstellar medium is more tightly coupled to the magnetic field than previously known. At high Galactic latitudes, where the Planck data are noise dominated, the Hi data provide an independent constraint on the Galactic magnetic field orientation, and hence the local dust polarization angle. We detect strong cross-correlations between template maps constructed from estimates of dust intensity combined with either Hi-derived angles, starlight polarization angles, or Planck 353 GHz angles. The Hi data thus provide a new tool in the search for inflationary gravitational wave B-mode polarization in the cosmic microwave background, which is currently limited by dust foreground contamination.
Malaria reduction and future elimination in China is made more difficult by the importation of cases from neighboring endemic countries, particularly Myanmar, Laos, and Vietnam, and increased travel ...to Africa by Chinese nationals. The increasing prevalence of artemisinin resistant parasites across Southeast Asia highlights the importance of monitoring the parasite importation into China. Artemisinin resistance in the Mekong region is associated with variants of genes encoding the K13 kelch domain protein (pf13k), found in specific genetic backgrounds, including certain alleles of genes encoding the chloroquine resistance transporter (pfcrt) and multidrug resistance transporter PgH1 (pfmdr1).
In this study we investigated the prevalence of drug resistance markers in 72 P. falciparum samples from uncomplicated malaria infections in Tengchong and Yingjiang, counties on the Yunnan-Myanmar border. Variants of pf13k, pfcrt and pfmdr1 are described.
Almost all parasites harboured chloroquine-resistant alleles of pfcrt, whereas pfmdr1 was more diverse. Major mutations in the K13 propeller domain associated with artemisinin resistance in the Mekong region (C580Y, R539T and Y493H) were absent, but F446I and two previously undescribed mutations (V603E and V454I) were identified. Protein structural modelling was carried out in silico on each of these K13 variants, based on recently published crystal structures for the K13 propeller domain. Whereas F446I was predicted to elicit a moderate destabilisation of the propeller structure, the V603E substitution is likely to lead to relatively high protein instability. We plotted these stability estimates, and those for all previously described variants, against published values for in vivo parasitaemia half-life, and found that quadratic regression generates a useful predictive algorithm.
This study provides a baseline of P. falciparum resistance-associated mutations prevalent at the China-Myanmar border. We also show that protein modelling can be used to generate testable predictions as to the impact of pfk13 mutations on in vivo (and potentially in vitro) artemisinin susceptibility.
Plasmodium falciparum parasites resistant to antimalarial treatments have hindered malaria disease control. Sulfadoxine-pyrimethamine (SP) was used globally as a first-line treatment for malaria ...after wide-spread resistance to chloroquine emerged and, although replaced by artemisinin combinations, is currently used as intermittent preventive treatment of malaria in pregnancy and in young children as part of seasonal malaria chemoprophylaxis in sub-Saharan Africa. The emergence of SP-resistant parasites has been predominantly driven by cumulative build-up of mutations in the dihydrofolate reductase (pfdhfr) and dihydropteroate synthetase (pfdhps) genes, but additional amplifications in the folate pathway rate-limiting pfgch1 gene and promoter, have recently been described. However, the genetic make-up and prevalence of those amplifications is not fully understood. We analyse the whole genome sequence data of 4,134 P. falciparum isolates across 29 malaria endemic countries, and reveal that the pfgch1 gene and promoter amplifications have at least ten different forms, occurring collectively in 23% and 34% in Southeast Asian and African isolates, respectively. Amplifications are more likely to be present in isolates with a greater accumulation of pfdhfr and pfdhps substitutions (median of 1 additional mutations; P<0.00001), and there was evidence that the frequency of pfgch1 variants may be increasing in some African populations, presumably under the pressure of SP for chemoprophylaxis and anti-folate containing antibiotics used for the treatment of bacterial infections. The selection of P. falciparum with pfgch1 amplifications may enhance the fitness of parasites with pfdhfr and pfdhps substitutions, potentially threatening the efficacy of this regimen for prevention of malaria in vulnerable groups. Our work describes new pfgch1 amplifications that can be used to inform the surveillance of SP drug resistance, its prophylactic use, and future experimental work to understand functional mechanisms.
Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this ...response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms. We show that inhibition of phospholipid scramblase 1 (PLSCR1) activity reduces intracellular calcium dysregulation, prevents PtdSer externalization, and enables months-long protection of vector-transduced, transgene-expressing cells from microglial phagocytosis. Our study identifies PLSCR1 as a potent target through which the innate immune response to viral vectors, and potentially other stimuli, may be controlled.
•Phosphatidylserine exposure tags virally transduced cells for microglial phagocytosis•Engulfment by microglia is TAM receptor dependent•Inhibition of phospholipid scramblase 1 activity protects from phagocytosis•Rescued cells remain viable allowing prolonged transgene expression
Tufail et al. show that inhibiting phospholipid scramblase 1 activity in virally transduced cells prevents intracellular calcium dysregulation, phosphatidylserine externalization, and TAM receptor-dependent microglial phagocytosis, providing a novel mechanism through which innate immune responses to viral vectors may be controlled.
High-energy Variability of PSR J1311-3430 An, Hongjun; Romani, Roger W.; Johnson, Tyrel ...
The Astrophysical journal,
11/2017, Letnik:
850, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We have studied the variability of the black-widow-type binary millisecond pulsar PSR J1311−3430 from optical to gamma-ray energies. We confirm evidence for orbital modulation in the weak off-pulse ...200 MeV emission, with a peak at , following pulsar inferior conjunction. The peak has a relatively hard spectrum, extending above ∼1 GeV. XMM-Newton and Swift UV observations also show that this source's strong X-ray flaring activity is associated with optical/UV flares. With a duty cycle of ∼7%-19%, this flaring is quite prominent with an apparent power-law intensity distribution. Flares are present at all orbital phases, with a slight preference for . We explore possible connections of these variabilities with the intrabinary shock and magnetic activity on the low-mass secondary.
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