Catalytic peptide assemblies Zozulia, O; Dolan, M A; Korendovych, I V
Chemical Society reviews,
05/2018, Volume:
47, Issue:
10
Journal Article
Peer reviewed
Open access
Self-assembly of molecules often results in new emerging properties. Even very short peptides can self-assemble into structures with a variety of physical and structural characteristics. Remarkably, ...many peptide assemblies show high catalytic activity in model reactions reaching efficiencies comparable to those found in natural enzymes by weight. In this review, we discuss different strategies used to rationally develop self-assembled peptide catalysts with natural and unnatural backbones as well as with metal-containing cofactors.
Despite methodological differences between studies, it has been suggested that psychopathy may be associated with a ventromedial prefrontal cortex (VMPFC) deficit and antisocial personality disorder ...(ASPD), as classified in the DSM-IV, with a broader range of deficits in dorsolateral prefrontal cortex (DLPFC) and VMPFC function.
Ninety-six male offenders with ASPD who were assessed using the psychopathy checklist: screening version (PCL:SV) and 49 male right-handed healthy controls (HCs), matched for age and IQ, completed a neuropsychological test battery.
Offenders with ASPD displayed subtle impairments on executive function tasks of planning ability and set shifting and behavioural inhibition compared to HCs. However, among the offenders with ASPD there was no significant association between executive function impairment and scores on the measure of psychopathy.
Psychopathic traits in offenders with ASPD are not associated with greater executive function impairment.
An approach for formally verifying the safety of automated vehicles is proposed. Due to the uniqueness of each traffic situation, we verify safety online, i.e., during the operation of the vehicle. ...The verification is performed by predicting the set of all possible occupancies of the automated vehicle and other traffic participants on the road. In order to capture all possible future scenarios, we apply reachability analysis to consider all possible behaviors of mathematical models considering uncertain inputs (e.g., sensor noise, disturbances) and partially unknown initial states. Safety is guaranteed with respect to the modeled uncertainties and behaviors if the occupancy of the automated vehicle does not intersect that of other traffic participants for all times. The applicability of the approach is demonstrated by test drives with an automated vehicle at the Robotics Institute at Carnegie Mellon University.
Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge ...about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.
In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug ...metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.
The mid-Pliocene Warm Period (mPWP) offers an opportunity to understand a warmer-than-present world and assess the predictive ability of numerical climate models. Environmental reconstruction and ...climate modelling are crucial for understanding the mPWP, and the synergy of these two, often disparate, fields has proven essential in confirming features of the past and in turn building confidence in projections of the future. The continual development of methodologies to better facilitate environmental synthesis and data/model comparison is essential, with recent work demonstrating that time-specific (time-slice) syntheses represent the next logical step in exploring climate change during the mPWP and realizing its potential as a test bed for understanding future climate change.
Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent ...antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify
those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in
and
associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.
There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN), the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the ...utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs) as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05). The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 ± 0.06 decrease in total neurite outgrowth, P = 0.011). The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05), demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN.
Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition has been shown to correlate ...with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.
We use MasterCode to perform a frequentist analysis of the constraints on a phenomenological MSSM model with 11 parameters, the pMSSM11, including constraints from
∼
36
/fb of LHC data at 13 TeV and ...PICO, XENON1T and PandaX-II searches for dark matter scattering, as well as previous accelerator and astrophysical measurements, presenting fits both with and without the
(
g
-
2
)
μ
constraint. The pMSSM11 is specified by the following parameters: 3 gaugino masses
M
1
,
2
,
3
, a common mass for the first-and second-generation squarks
m
q
~
and a distinct third-generation squark mass
m
q
~
3
, a common mass for the first-and second-generation sleptons
m
ℓ
~
and a distinct third-generation slepton mass
m
τ
~
, a common trilinear mixing parameter
A
, the Higgs mixing parameter
μ
, the pseudoscalar Higgs mass
M
A
and
tan
β
. In the fit including
(
g
-
2
)
μ
, a Bino-like
χ
~
1
0
is preferred, whereas a Higgsino-like
χ
~
1
0
is mildly favoured when the
(
g
-
2
)
μ
constraint is dropped. We identify the mechanisms that operate in different regions of the pMSSM11 parameter space to bring the relic density of the lightest neutralino,
χ
~
1
0
, into the range indicated by cosmological data. In the fit including
(
g
-
2
)
μ
, coannihilations with
χ
~
2
0
and the Wino-like
χ
~
1
±
or with nearly-degenerate first- and second-generation sleptons are active, whereas coannihilations with the
χ
~
2
0
and the Higgsino-like
χ
~
1
±
or with first- and second-generation squarks may be important when the
(
g
-
2
)
μ
constraint is dropped. In the two cases, we present
χ
2
functions in two-dimensional mass planes as well as their one-dimensional profile projections and best-fit spectra. Prospects remain for discovering strongly-interacting sparticles at the LHC, in both the scenarios with and without the
(
g
-
2
)
μ
constraint, as well as for discovering electroweakly-interacting sparticles at a future linear
e
+
e
-
collider such as the ILC or CLIC.
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