681 research outputs found
KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8<sup>+</sup> T cell differentiation
Footprint of Positive Selection in Treponema pallidum subsp. pallidum Genome Sequences Suggests Adaptive Microevolution of the Syphilis Pathogen
In the rabbit model of syphilis, infection phenotypes associated with the Nichols and Chicago strains of Treponema pallidum (T. pallidum), though similar, are not identical. Between these strains, significant differences are found in expression of, and antibody responses to some candidate virulence factors, suggesting the existence of functional genetic differences between isolates. The Chicago strain genome was therefore sequenced and compared to the Nichols genome, available since 1998. Initial comparative analysis suggested the presence of 44 single nucleotide polymorphisms (SNPs), 103 small (â€3 nucleotides) indels, and 1 large (1204 bp) insertion in the Chicago genome with respect to the Nichols genome. To confirm the above findings, Sanger sequencing was performed on most loci carrying differences using DNA from Chicago and the Nichols strain used in the original T. pallidum genome project. A majority of the previously identified differences were found to be due to errors in the published Nichols genome, while the accuracy of the Chicago genome was confirmed. However, 20 SNPs were confirmed between the two genomes, and 16 (80.0%) were found in coding regions, with all being of non-synonymous nature, strongly indicating action of positive selection. Sequencing of 16 genomic loci harboring SNPs in 12 additional T. pallidum strains, (SS14, Bal 3, Bal 7, Bal 9, Sea 81-3, Sea 81-8, Sea 86-1, Sea 87-1, Mexico A, UW231B, UW236B, and UW249C), was used to identify âChicago-â or âNichols -specificâ differences. All but one of the 16 SNPs were âNichols-specificâ, with Chicago having identical sequences at these positions to almost all of the additional strains examined. These mutations could reflect differential adaptation of the Nichols strain to the rabbit host or pathoadaptive mutations acquired during human infection. Our findings indicate that SNPs among T. pallidum strains emerge under positive selection and, therefore, are likely to be functional in nature
A Multifunctional, Charge-Neutral, Chiral Octahedral M12 L12 Cage.
peer reviewedA chiral, octahedral M12 L12 cage, which is charge neutral and contains an internal void of about 2000â
Ă
3 , is reported. The cage was synthesised as an enantiopure complex by virtue of amino-acid-based dicarboxylate ligands, which assemble around copper paddlewheels at the vertices of the octahedron. The cage persists in solution with retention of the fluorescence properties of the parent acid. The solid-state structure contains large pores both within and between the cages, and displays permanent porosity for the sorption of gases with retention of crystallinity. Initial tests show some enantioselectivity of the cage towards guests in solution
Cause of Death in Long-Term Substance Use: A Scoping Study and Review of The Implications For End of Life and Palliative Care
Older people who use substances are more likely than general populations to have complex non-cancer pathologies which are under-represented in palliative care services. Our work explores mortality and morbidity relevant to end of life care and reveals discrepancies in provision for people who use substances, identifying possible explanations. We make recommendations for improved governance to inform policy and practice change
NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology
The NANOGrav 15-year Data Set: Search for Anisotropy in the Gravitational-Wave Background
The North American Nanohertz Observatory for Gravitational Waves (NANOGrav)
has reported evidence for the presence of an isotropic nanohertz gravitational
wave background (GWB) in its 15 yr dataset. However, if the GWB is produced by
a population of inspiraling supermassive black hole binary (SMBHB) systems,
then the background is predicted to be anisotropic, depending on the
distribution of these systems in the local Universe and the statistical
properties of the SMBHB population. In this work, we search for anisotropy in
the GWB using multiple methods and bases to describe the distribution of the
GWB power on the sky. We do not find significant evidence of anisotropy, and
place a Bayesian upper limit on the level of broadband anisotropy such
that . We also derive conservative estimates on the
anisotropy expected from a random distribution of SMBHB systems using
astrophysical simulations conditioned on the isotropic GWB inferred in the
15-yr dataset, and show that this dataset has sufficient sensitivity to probe a
large fraction of the predicted level of anisotropy. We end by highlighting the
opportunities and challenges in searching for anisotropy in pulsar timing array
data.Comment: 19 pages, 11 figures; submitted to Astrophysical Journal Letters as
part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave
Background. For questions or comments, please email [email protected]
The NANOGrav 15-Year Data Set: Detector Characterization and Noise Budget
Pulsar timing arrays (PTAs) are galactic-scale gravitational wave detectors.
Each individual arm, composed of a millisecond pulsar, a radio telescope, and a
kiloparsecs-long path, differs in its properties but, in aggregate, can be used
to extract low-frequency gravitational wave (GW) signals. We present a noise
and sensitivity analysis to accompany the NANOGrav 15-year data release and
associated papers, along with an in-depth introduction to PTA noise models. As
a first step in our analysis, we characterize each individual pulsar data set
with three types of white noise parameters and two red noise parameters. These
parameters, along with the timing model and, particularly, a piecewise-constant
model for the time-variable dispersion measure, determine the sensitivity curve
over the low-frequency GW band we are searching. We tabulate information for
all of the pulsars in this data release and present some representative
sensitivity curves. We then combine the individual pulsar sensitivities using a
signal-to-noise-ratio statistic to calculate the global sensitivity of the PTA
to a stochastic background of GWs, obtaining a minimum noise characteristic
strain of at 5 nHz. A power law-integrated analysis shows
rough agreement with the amplitudes recovered in NANOGrav's 15-year GW
background analysis. While our phenomenological noise model does not model all
known physical effects explicitly, it provides an accurate characterization of
the noise in the data while preserving sensitivity to multiple classes of GW
signals.Comment: 67 pages, 73 figures, 3 tables; published in Astrophysical Journal
Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational
Wave Background. For questions or comments, please email
[email protected]
The NANOGrav 12.5 yr Data Set: Search for Gravitational Wave Memory
We present the results of a Bayesian search for gravitational wave (GW) memory in the NANOGrav 12.5 yr data set. We find no convincing evidence for any gravitational wave memory signals in this data set. We find a Bayes factor of 2.8 in favor of a model that includes a memory signal and common spatially uncorrelated red noise (CURN) compared to a model including only a CURN. However, further investigation shows that a disproportionate amount of support for the memory signal comes from three dubious pulsars. Using a more flexible red-noise model in these pulsars reduces the Bayes factor to 1.3. Having found no compelling evidence, we go on to place upper limits on the strain amplitude of GW memory events as a function of sky location and event epoch. These upper limits are computed using a signal model that assumes the existence of a common, spatially uncorrelated red noise in addition to a GW memory signal. The median strain upper limit as a function of sky position is approximately 3.3 Ă 10â14. We also find that there are some differences in the upper limits as a function of sky position centered around PSR J0613â0200. This suggests that this pulsar has some excess noise that can be confounded with GW memory. Finally, the upper limits as a function of burst epoch continue to improve at later epochs. This improvement is attributable to the continued growth of the pulsar timing array
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