26 research outputs found
Traversable Lorentzian wormhole on the Shtanov-Sahni braneworld with matter obeying the energy conditions
In this paper we have explored the possibility of constructing a traversable
wormhole on the Shtanov-Sahni braneworld with a timelike extra dimension. We
find that the Weyl curvature singularity at the throat of the wormhole can be
removed with physical matter satisfying the NEC , even in the
absence of any effective -term or any type of charge source on the
brane. (The NEC is however violated by the effective matter description on the
brane arising due to effects of higher dimensional gravity.) Besides satisfying
NEC the matter constituting the wormhole also satisfies the Strong Energy
Condition (SEC), , leading to the interesting possibility that
normal matter on the brane may be harnessed into a wormhole. Incidentally,
these conditions also need to be satisfied to realize a non-singular bounce and
cyclic cosmology on the brane\cite{Sahni4} where both past and future
singularities can be averted. Thus, such a cyclic universe on the brane,
constituted of normal matter can naturally contain wormholes. The wormhole
shape function on the brane with a time-like extra dimension represents the
tubular structure of the wormhole spreading out at large radial distances much
better than in wormholes constructed in a braneworld with a spacelike extra
dimension and have considerably lower mass resulting in minimization of the
amount of matter required to construct a wormhole. Wormholes in the
Shtanov-Sahni (SS) braneworld also have sufficiently low tidal forces,
facilitating traversability. Additionally they are found to be stable and
exhibit a repulsive geometry. We are left with the intriguing possibilty that
both types of curvature singularity can be resolved with the SS model, which we
discuss at the end of the concluding section.Comment: 31 Pages, 16 Figure
Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants
Importance: Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed.
Objective: To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A.
Design, setting, and participants: This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome-associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome-associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021.
Main outcomes and measures: For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome-associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV.
Results: In total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77).
Conclusions and relevance: In this case series, the presence of PGVs in 9 cancer syndrome-associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing
Toward Computationally Designed Self-Reporting Biosensors Using Leave-One-Out Green Fluorescent Protein
Leave-one-out green
fluorescent protein (LOO<i>n</i>-GFP)
is a circularly permuted and truncated GFP lacking the <i>n</i>th β-strand element. LOO7-GFP derived from the wild-type sequence
(LOO7-WT) folds and reconstitutes fluorescence upon addition of β-strand
7 (S7) as an exogenous peptide. Computational protein design may be
used to modify the sequence of LOO7-GFP to fit a different peptide
sequence, while retaining the reconstitution activity. Here we present
a computationally designed leave-one-out GFP in which wild-type strand
7 has been replaced by a 12-residue peptide (HA) from the H5 antigenic
region of the Thailand strain of H5N1 influenza virus hemagglutinin.
The DEEdesign software was used to generate a sequence library with
mutations at 13 positions around the peptide, coding for approximately
3 × 10<sup>5</sup> sequence combinations. The library was coexpressed
with the HA peptide in <i>E. coli</i> and colonies were
screened for in vivo fluorescence. Glowing colonies were sequenced,
and one (LOO7-HA4) with 7 mutations was purified and characterized.
LOO7-HA4 folds, fluoresces in vivo and in vitro, and binds HA. However,
binding results in a decrease in fluorescence instead of the expected
increase, caused by the peptide-induced dissociation of a novel, glowing
oligomeric complex instead of the reconstitution of the native structure.
Efforts to improve binding and recover reconstitution using in vitro
evolution produced colonies that glowed brighter and matured faster.
Two of these were characterized. One lost all affinity for the HA
peptide but glowed more brightly in the unbound oligomeric state.
The other increased in affinity to the HA peptide but still did not
reconstitute the fully folded state. Despite failing to fold completely,
peptide binding by computational design was observed and was improved
by directed evolution. The ratio of HA to S7 binding increased from
0.0 for the wild-type sequence (no binding) to 0.01 after computational
design (weak binding) and to 0.48 (comparable binding) after in vitro
evolution. The novel oligomeric state is composed of an open barrel
Mispacking and the Fitness Landscape of the Green Fluorescent Protein Chromophore Milieu
The
autocatalytic
maturation of the chromophore in green fluorescent protein (GFP)
was thought to require the precise positioning of the side chains
surrounding it in the core of the protein, many of which are strongly
conserved among homologous fluorescent proteins. In this study, we
screened for green fluorescence in an exhaustive set of point mutations
of seven residues that make up the chromophore microenvironment, excluding
R96 and E222 because mutations at these positions have been previously
characterized. Contrary to expectations, nearly all amino acids were
tolerated at all seven positions. Only four point mutations knocked
out fluorescence entirely. However, chromophore maturation was found
to be slower and/or fluorescence reduced in several cases. Selected
combinations of mutations showed nonadditive effects, including cooperativity
and rescue. The results provide
guidelines for the computational engineering of GFPs