Abstract
We present optical photometric and spectroscopic observations of the 02es-like type Ia supernova (SN) 2022ywc. The transient occurred in the outskirts of an elliptical host galaxy and showed ...a striking double-peaked light curve with an early excess feature detected in the ATLAS orange and cyan bands. The early excess is remarkably luminous with an absolute magnitude ∼ − 19, comparable in luminosity to the subsequent radioactively driven second peak. The spectra resemble the hybrid 02es-like SN 2016jhr, which is considered to be a helium shell detonation candidate. We investigate different physical mechanisms that could power such a prominent early excess and rule out massive helium shell detonation, surface
56
Ni distribution, and ejecta–companion interaction. We conclude that SN ejecta interacting with circumstellar material (CSM) is the most viable scenario. Semianalytical modeling with MOSFiT indicates that SN ejecta interacting with ∼0.05
M
⊙
of CSM at a distance of ∼10
14
cm can explain the extraordinary light curve. A double-degenerate scenario may explain the origin of the CSM, by tidally stripped material from either the secondary white dwarf or disk-originated matter launched along polar axes following the disruption and accretion of the secondary white dwarf. A nonspherical CSM configuration could suggest that a small fraction of 02es-like events viewed along a favorable line of sight may be expected to display a very conspicuous early excess like SN 2022ywc.
The majority of insecticidescurrently in use are organophosphorus, carbamate, and synthetic pyrethroid compounds. Organophosphorus insecticides (OPs) produce toxicity by inhibiting the cholinesterase ...enzymes in the nervous system. Monitoring of acetylcholinesterase (AChE) inhibition has been widely used in terrestrial and freshwater aquatic systems as an indicator of OP exposure and effects. This review describes the use of AChE inhibition as a biomarker in the estuarine environment, discusses the relationship between AChE inhibition and other manifestations of OP toxicity, and highlights areas where additional research is needed. A variety of studies with estuarine fish have suggested that brain AChE inhibition levels of >70% are associated with mortality in most species. Selected species, however, appear capable of tolerating much higher levels (>90%) of brain inhibition. Sublethal effects on stamina have been reported for some estuarine fish in association with brain AChE inhibition levels as low as 50%. Most studies suggest, however, that these effects are observed only when brain AChE inhibition is at near‐lethal levels. A number of field studies have successfully used AChE inhibition in fish as a biomarker in the estuarine environment. The use of AChE inhibition as a biomarker in estuarine invertebrates has been less well studied. Although AChE inhibition has been measured in the tissues of a variety of invertebrate species following OP exposure, the relationship between AChE inhibition and lethality is less distinct. Additional work is needed in both fish and invertebrates to better explain species‐specific differences in the relationship between AChE inhibition and mortality and to investigate other physiological perturbations associated with AChE inhibition.
Neoantigen-based therapeutic vaccines have a high potential impact on tumor eradication and patient survival. Mass spectrometry (MS)-based immunopeptidomics has the capacity to identify ...tumor-associated epitopes and pinpoint mutation-bearing major histocompatibility complex (MHC)-binding peptides. This approach presents several challenges, including the identification of low-abundance peptides. In addition, MHC peptides have much lower MS/MS identification rates than tryptic peptides due to their shorter sequence and lack of basic amino acid at C-termini. In this study, we report the development and application of a novel chemical derivatization strategy that combines the analysis of native, dimethylated, and alkylamidated peptides by liquid chromatography–tandem mass spectrometry (LC–MS/MS) to expand the coverage of the MHC peptidome. The results revealed that dimethylation increases hydrophobicity and ionization efficiency of MHC class I peptides, while alkylamidation significantly improves the fragmentation by producing more y-ions during MS/MS fragmentation. Thus, the combination of dimethylation and alkylamidation enabled the identification of peptides that could not be identified from the analysis of their native form. Using this strategy, we identified 3148 unique MHC I peptides from HCT 116 cell lines, compared to only 1388 peptides identified in their native form. Among these, 10 mutation-bearing peptides were identified with high confidence, indicating that this chemical derivatization strategy is a promising approach for neoantigen discovery in clinical applications.
Abstract
We present extensive optical photometry of the afterglow of GRB 221009A. Our data cover 0.9–59.9 days from the time of Swift and Fermi gamma-ray burst (GRB) detections. Photometry in
rizy
...-band filters was collected primarily with Pan-STARRS and supplemented by multiple 1–4 m imaging facilities. We analyzed the Swift X-ray data of the afterglow and found a single decline rate power law
f
(
t
) ∝
t
−1.556±0.002
best describes the light curve. In addition to the high foreground Milky Way dust extinction along this line of sight, the data favor additional extinction to consistently model the optical to X-ray flux with optically thin synchrotron emission. We fit the X-ray-derived power law to the optical light curve and find good agreement with the measured data up to 5−6 days. Thereafter we find a flux excess in the
riy
bands that peaks in the observer frame at ∼20 days. This excess shares similar light-curve profiles to the Type Ic broad-lined supernovae SN 2016jca and SN 2017iuk once corrected for the GRB redshift of
z
= 0.151 and arbitrarily scaled. This may be representative of an SN emerging from the declining afterglow. We measure rest-frame absolute peak AB magnitudes of
M
g
= −19.8 ± 0.6 and
M
r
= − 19.4 ± 0.3 and
M
z
= −20.1 ± 0.3. If this is an SN component, then Bayesian modeling of the excess flux would imply explosion parameters of
M
ej
=
7.1
−
1.7
+
2.4
M
⊙
,
M
Ni
=
1.0
−
0.4
+
0.6
M
⊙
, and
v
ej
=
33,900
−
5700
+
5900
km s
−1
, for the ejecta mass, nickel mass, and ejecta velocity respectively, inferring an explosion energy of
E
kin
≃ 2.6–9.0 × 10
52
erg.
Abstract
We present multiwavelength photometry and spectroscopy of SN 2022jli, an unprecedented Type Ic supernova discovered in the galaxy NGC 157 at a distance of ≈ 23 Mpc. The multiband light ...curves reveal many remarkable characteristics. Peaking at a magnitude of
g
= 15.11 ± 0.02, the high-cadence photometry reveals periodic undulations of 12.5 ± 0.2 days superimposed on the 200-day supernova decline. This periodicity is observed in the light curves from nine separate filter and instrument configurations with peak-to-peak amplitudes of ≃ 0.1 mag. This is the first time that repeated periodic oscillations, over many cycles, have been detected in a supernova light curve. SN 2022jli also displays an extreme early excess that fades over ≈25 days, followed by a rise to a peak luminosity of
L
opt
= 10
42.1
erg s
−1
. Although the exact explosion epoch is not constrained by data, the time from explosion to maximum light is ≳ 59 days. The luminosity can be explained by a large ejecta mass (
M
ej
≈ 12 ± 6
M
⊙
) powered by
56
Ni, but we find it difficult to quantitatively model the early excess with circumstellar interaction and cooling. Collision between the supernova ejecta and a binary companion is a possible source of this emission. We discuss the origin of the periodic variability in the light curve, including interaction of the SN ejecta with nested shells of circumstellar matter and neutron stars colliding with binary companions.
Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential--a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing ...to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9's underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.
The cyclooxygenase-2 (COX-2) enzyme and major lipid product, prostaglandin E2 (PGE2) are elevated in many solid tumors including those of the breast and are associated with a poor prognosis. ...Targeting this enzyme is somewhat effective in preventing tumor progression, but is associated with cardiotoxic secondary effects when used chronically. PGE2 functions by signaling through four EP receptors (EP1-4), resulting in several different cellular responses, many of which are pro-tumorigenic, and there is growing interest in the therapeutic potential of targeting EP4 and EP2. Other members in this signaling pathway are gaining more attention. PGE2 is transported out of and into cells by two unique transport proteins. Multiple Drug Resistance-Associated Protein 4 (MRP4) and Prostaglandin Transporter (PGT) modulate PGE2 signaling by increasing or decreasing the levels of PGE2 available to cells. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) metabolizes PGE2 and silences the pathway in this manner. The purpose of this review is to summarize the extensive data supporting the importance of the COX-2 pathway in tumor biology with a focus on more recently described pathway members and their role in modulating PGE2 signaling. This review describes evidence supporting roles for MRP4, PGT and 15-PGDH in several tumor types with an emphasis on the roles of these proteins in breast cancer. Defining the importance of these latter pathway members will be key to developing new therapeutic approaches that exploit the tumor-promoting COX-2 pathway.
Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to ...intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15-PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer.
We have screened a large tomato EST database against the Arabidopsis genomic sequence and report here the identification of a set of 1025 genes (referred to as a conserved ortholog set, or COS ...markers) that are single or low copy in both genomes (as determined by computational screens and DNA gel blot hybridization) and that have remained relatively stable in sequence since the early radiation of dicotyledonous plants. These genes were annotated, and a large portion could be assigned to putative functional categories associated with basic metabolic processes, such as energy-generating processes and the biosynthesis and degradation of cellular building blocks. We further demonstrate, through computational screens (e.g., against a Medicago truncatula database) and direct hybridization on genomic DNA of diverse plant species, that these COS markers also are conserved in the genomes of other plant families. Finally, we show that this gene set can be used for comparative mapping studies between highly divergent genomes such as those of tomato and Arabidopsis. This set of COS markers, identified computationally and experimentally, may further studies on comparative genomes and phylogenetics and elucidate the nature of genes conserved throughout plant evolution.
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