CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in ...CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function <1% (n = 5)) and Group B (normal mRNA, immature protein, function <1% (n = 10)) variants were unresponsive to modulator treatment. However, Group C (normal mRNA, mature (fully glycosylated) protein, function >1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit.
Hydrogen gas is thought to be the ideal fuel for a world in which air pollution has been alleviated, global warming has been arrested, and the environment has been protected in an economically ...sustainable manner. Hydrogen and electricity could team to provide attractive options in transportation and power generation. Interconversion between these two forms of energy suggests on-site utilization of hydrogen to generate electricity, with the electrical power grid serving in energy transportation, distribution utilization, and hydrogen regeneration as needed. A challenging problem in establishing H2 as a source of energy for the future is the renewable and environmentally friendly generation of large quantities of H2 gas. Thus, processes that are presently conceptual in nature, or at a developmental stage in the laboratory, need to be encouraged, tested for feasibility, and otherwise applied toward commercialization.
A
bstract
We consider a supersymmetric type-I seesaw framework with non-universal scalar masses at the GUT scale to explain the long-standing discrepancy of the anomalous magnetic moment of the muon. ...We find that it is difficult to accommodate the muon g-2 while keeping charged-lepton flavor violating processes under control for the conventional SO(10)-based relation between the up sector and neutrino sector. However, such tension can be relaxed by adding a Georgi-Jarlskog factor for the Yukawa matrices, which requires a non-trivial GUT-based model. In this model, we find that both observables are compatible for small mixings, CKM-like, in the neutrino Dirac Yukawa matrix.
A
bstract
Motivated by the XENON1T excess in electron-recoil measurements, we investigate the prospects of probing axion-like particles (ALP) in lepton flavor violation experiments. In particular, we ...identify such ALP as a pseudo-Goldstone from the spontaneous breaking of the flavor symmetries that explain the mixing structure of the Standard Model leptons. We present the case of the flavor symmetries being a non-Abelian U(2) and the ALP originating from its U(1) subgroup, which is anomaly-free with the Standard Model group. We build two explicit realistic examples that reproduce leptonic masses and mixings and show that the ALP which is consistent with XENON1T anomaly could be probed by the proposed LFV experiments.
Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this ...paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.
The present study aims to determine the volatile compositions of 15 different accessions of native Sardinian populations of
(Pignatti & Metlesics) Greuter,
(L.) C. H. Stirt. (
), and Spanish native ...accessions of
. Furthermore, we particularly focused on the essential oil characterization of these accessions and discriminated within populations with low furocoumarin content useful for fodder production in Mediterranean environments or furocoumarin extraction for pharmaceutical utilization. The plant extracts were analyzed by GC/MS, showing great variability in the content and composition. No differences were found in
(L.) C.H. Stirt. var.
essential oils, while the varieties
(L.) C.H. Stirt. var.
P. Méndez, Fern. Galván & A. Santos and
(L.) C.H. Stirt. var.
P. Méndez, Fern. Galván & A. Santos are characterized by the presence of a high concentration of long-chain alcohols and of salicylic acid benzylic ester. In
var.
, we observed a different profile with predominance of a large concentration of alcohols as dodecanol and tetradecanol. The endemic
can be identified for the predominant presence of farnesene. In methanolic fractions, we detected the presence of maltol, methyl citrate, methyl cumarate, santonin, and methyl linoleate.
showed a low content of psoralens, and the accession of
from Siliqua indicated the presence of apocynin.
We have observed the Andromeda galaxy, Messier 31 (M31), at 6.7 GHz with the Sardinia Radio Telescope. We mapped the radio emission in the C-band, re-analyzed WMAP and Planck maps, as well as other ...ancillary data, and we have derived an overall integrated flux density spectrum from the radio to the infrared. This allowed us to estimate the emission budget from M31. Integrating over the whole galaxy, we found strong and highly significant evidence for anomalous microwave emission (AME), at the level of Jy at the peaking frequency of 25 GHz. Decomposing the spectrum into known emission mechanisms such as free-free, synchrotron, thermal dust, and AME arising from electric dipole emission from rapidly rotating dust grains, we found that the overall emission from M31 is dominated, at frequencies below 10 GHz, by synchrotron emission with a spectral index of , with subdominant free-free emission. At frequencies 10 GHz, AME has a similar intensity to that of synchrotron and free-free emission, overtaking them between 20 and 50 GHz, whereas thermal dust emission dominates the emission budget at frequencies above 60 GHz, as expected.
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