221 research outputs found
The role of MYH and microsatellite instability in the development of sporadic colorectal cancer
Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration
The Richmond Agitation-Sedation Scale modified for palliative care inpatients (RASS-PAL): a pilot study exploring validity and feasibility in clinical practice
Invasiveness, biology, ecology, and management of the fall armyworm, Spodoptera frugiperda.
First online
Novel Allosteric Sites on Ras for Lead Generation
Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs
Characterization of Profilin Polymorphism in Pollen with a Focus on Multifunctionality
Profilin, a multigene family involved in actin dynamics, is a multiple partners-interacting protein, as regard of the presence of at least of three binding domains encompassing actin, phosphoinositide lipids, and poly-L-proline interacting patches. In addition, pollen profilins are important allergens in several species like Olea europaea L. (Ole e 2), Betula pendula (Bet v 2), Phleum pratense (Phl p 12), Zea mays (Zea m 12) and Corylus avellana (Cor a 2). In spite of the biological and clinical importance of these molecules, variability in pollen profilin sequences has been poorly pointed out up until now. In this work, a relatively high number of pollen profilin sequences have been cloned, with the aim of carrying out an extensive characterization of their polymorphism among 24 olive cultivars and the above mentioned plant species. Our results indicate a high level of variability in the sequences analyzed. Quantitative intra-specific/varietal polymorphism was higher in comparison to inter-specific/cultivars comparisons. Multi-optional posttranslational modifications, e.g. phosphorylation sites, physicochemical properties, and partners-interacting functional residues have been shown to be affected by profilin polymorphism. As a result of this variability, profilins yielded a clear taxonomic separation between the five plant species. Profilin family multifunctionality might be inferred by natural variation through profilin isovariants generated among olive germplasm, as a result of polymorphism. The high variability might result in both differential profilin properties and differences in the regulation of the interaction with natural partners, affecting the mechanisms underlying the transmission of signals throughout signaling pathways in response to different stress environments. Moreover, elucidating the effect of profilin polymorphism in adaptive responses like actin dynamics, and cellular behavior, represents an exciting research goal for the future
Detection of astrophysical tau neutrino candidates in IceCube
High-energy tau neutrinos are rarely produced in atmospheric cosmic-ray showers or at cosmic particle accelerators, but are expected to emerge during neutrino propagation over cosmic distances due to flavor mixing. When high energy tau neutrinos interact inside the IceCube detector, two spatially separated energy depositions may be resolved, the first from the charged current interaction and the second from the tau lepton decay. We report a novel analysis of 7.5 years of IceCube data that identifies two candidate tau neutrinos among the 60 âHigh-Energy Starting Eventsâ (HESE) collected during that period. The HESE sample offers high purity, all-sky sensitivity, and distinct observational signatures for each neutrino flavor, enabling a new measurement of the flavor composition. The measured astrophysical neutrino flavor composition is consistent with expectations, and an astrophysical tau neutrino flux is indicated at 2.8 significance
Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube
We report the results of a multimessenger search for coincident signals from
the LIGO and Virgo gravitational-wave observatories and the partially completed
IceCube high-energy neutrino detector, including periods of joint operation
between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010
run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79
strings. We find no significant coincident events, and use the search results
to derive upper limits on the rate of joint sources for a range of source
emission parameters. For the optimistic assumption of gravitational-wave
emission energy of \,Mc at \,Hz with \,ms duration, and high-energy neutrino emission of \,erg
comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the
source rate below \,Mpcyr. We also examine
how combining information from gravitational waves and neutrinos will aid
discovery in the advanced gravitational-wave detector era
Measurement of Astrophysical Tau Neutrinos in IceCube's High-Energy Starting Events
We present the results of a search for astrophysical tau neutrinos in 7.5
years of IceCube's high-energy starting event data. At high energies, two
energy depositions stemming from the tau neutrino charged-current interaction
and subsequent tau lepton decay may be resolved. We report the first detection
of two such events, with probabilities of and of being
produced by astrophysical tau neutrinos. The resultant astrophysical neutrino
flavor measurement is consistent with expectations, disfavoring a
no-astrophysical tau neutrino flux scenario with 2.8 significance.Comment: This article is supported by a long-form paper that discusses the
high-energy starting event selection titled: "The IceCube high-energy
starting event sample: Description and flux characterization with 7.5 years
of data.
Searching for VHE gamma-ray emission associated with IceCube neutrino alerts using FACT, H.E.S.S., MAGIC, and VERITAS
The realtime follow-up of neutrino events is a promising approach to search for astrophysical
neutrino sources. It has so far provided compelling evidence for a neutrino point source: the
flaring gamma-ray blazar TXS 0506+056 was observed in coincidence with the high-energy neutrino IceCube-170922A detected by IceCube. The detection of very-high-energy gamma rays (VHE, E > 100 GeV) from this source helped establish the coincidence and constrained the modeling of the blazar emission at the time of the IceCube event. The four major imaging atmospheric Cherenkov telescope arrays (IACTs) - FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program of target-of-opportunity observations of neutrino alerts sent by IceCube. This program has two main components. One are the observations of known gamma-ray sources around which a cluster of candidate neutrino events has been identified by IceCube (Gamma-ray Follow-Up, GFU). The second one is the follow-up of single high-energy neutrino candidate events of potential astrophysical origin such as IceCube-170922A. GFU has been recently upgraded by IceCube in collaboration with the IACT groups. We present here recent results from the IACT follow-up programs of IceCube neutrino alerts and a description of the upgraded IceCube GFU system
A search for time-dependent astrophysical neutrino emission with IceCube data from 2012 to 2017
High-energy neutrinos are unique messengers of the high-energy universe,
tracing the processes of cosmic-ray acceleration. This paper presents analyses
focusing on time-dependent neutrino point-source searches. A scan of the whole
sky, making no prior assumption about source candidates, is performed, looking
for a space and time clustering of high-energy neutrinos in data collected by
the IceCube Neutrino Observatory between 2012 and 2017. No statistically
significant evidence for a time-dependent neutrino signal is found with this
search during this period since all results are consistent with the background
expectation. Within this study period, the blazar 3C 279, showed strong
variability, inducing a very prominent gamma-ray flare observed in 2015 June.
This event motivated a dedicated study of the blazar, which consists of
searching for a time-dependent neutrino signal correlated with the gamma-ray
emission. No evidence for a time-dependent signal is found. Hence, an upper
limit on the neutrino fluence is derived, allowing us to constrain a hadronic
emission model
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