Accurate low temperature charge transport measurements in combination with high-precision x-ray diffraction experiments have allowed detection of the symmetry lowering in the single domain ...Tm0.19Yb0.81B12 crystals that belong to the family of dodecaborides with metal-insulator transition. Based on the fine structure analysis we discover the formation of dynamic charge stripes within the semiconducting matrix of Tm0.19Yb0.81B12. The charge dynamics in these conducting nano-size channels is characterized by broad-band optical spectroscopy that allowed estimating the frequency (~2.4 × 1011 Hz) of quantum motion of the charge carriers. It is suggested that cooperative Jahn-Teller effect in the boron sublattice is a cause of the large-amplitude rattling modes of the Tm and Yb ions responsible for the 'modulation' of the conduction band along one of the directions through the variation of 5d-2p hybridization of electron states.
The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic ...infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite's biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Safety assessment is an essential component of the regulatory acceptance of industrial chemicals. Previously, we have developed a model to predict the skin sensitization potential of chemicals for ...two assays, the human patch test and murine local lymph node assay, and implemented this model in a web portal. Here, we report on the substantially revised and expanded freely available web tool, Pred-Skin version 3.0. This up-to-date version of Pred-Skin incorporates multiple quantitative structure–activity relationship (QSAR) models developed with in vitro, in chemico, and mice and human in vivo data, integrated into a consensus naïve Bayes model that predicts human effects. Individual QSAR models were generated using skin sensitization data derived from human repeat insult patch tests, human maximization tests, and mouse local lymph node assays. In addition, data for three validated alternative methods, the direct peptide reactivity assay, KeratinoSens, and the human cell line activation test, were employed as well. Models were developed using open-source tools and rigorously validated according to the best practices of QSAR modeling. Predictions obtained from these models were then used to build a naïve Bayes model for predicting human skin sensitization with the following external prediction accuracy: correct classification rate (89%), sensitivity (94%), positive predicted value (91%), specificity (84%), and negative predicted value (89%). As an additional assessment of model performance, we identified 11 cosmetic ingredients known to cause skin sensitization but were not included in our training set, and nine of them were accurately predicted as sensitizers by our models. Pred-Skin can be used as a reliable alternative to animal tests for predicting human skin sensitization.
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IJS, KILJ, NUK, PNG, UL, UM
Modern chemical toxicology is facing a growing need to Reduce, Refine, and Replace animal tests (Russell 1959) for hazard identification. The most common type of animal assays for acute toxicity ...assessment of chemicals used as pesticides, pharmaceuticals, or in cosmetic products is known as a "6-pack" battery of tests, including three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) end points.
We compiled, curated, and integrated, to the best of our knowledge, the largest publicly available data sets and developed an ensemble of quantitative structure-activity relationship (QSAR) models for all six end points. All models were validated according to the Organisation for Economic Co-operation and Development (OECD) QSAR principles, using data on compounds not included in the training sets.
In addition to high internal accuracy assessed by cross-validation, all models demonstrated an external correct classification rate ranging from 70% to 77%. We established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for 6-pack assays.
We developed STopTox, a comprehensive collection of computational models that can be used as an alternative to
6-pack tests for predicting the toxicity hazard of small organic molecules. Models were established following the best practices for the development and validation of QSAR models. Scientists and regulators can use the STopTox portal to identify putative toxicants or nontoxicants in chemical libraries of interest. https://doi.org/10.1289/EHP9341.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
6.
Defining clinical outcome pathways Korn, Daniel; Thieme, Andrew J.; Alves, Vinicius M. ...
Drug discovery today,
June 2022, 2022-Jun, 2022-06-00, 20220601, Volume:
27, Issue:
6
Journal Article
Peer reviewed
Open access
•We define the concept of Clinical Outcome Pathways (COP).•COPs is a chain of key events: Initiating-Intermediate-Clinical Outcome.•COPs will deepen our understanding of the biological pathways of ...drug action.•COP concept could accelerate drug discovery and repurposing.
Here, we propose a broad concept of ‘Clinical Outcome Pathways’ (COPs), which are defined as a series of key molecular and cellular events that underlie therapeutic effects of drug molecules. We formalize COPs as a chain of the following events: molecular initiating event (MIE) → intermediate event(s) → clinical outcome. We illustrate the concept with COP examples both for primary and alternative (i.e., drug repurposing) therapeutic applications. We also describe the elucidation of COPs for several drugs of interest using the publicly accessible Reasoning Over Biomedical Objects linked in Knowledge-Oriented Pathways (ROBOKOP) biomedical knowledge graph-mining tool. We propose that broader use of COP uncovered with the help of biomedical knowledge graph mining will likely accelerate drug discovery and repurposing efforts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The results of studying the thermal conductivity of hot-pressed AlB
12
–AlN ceramic composites with different AlN concentrations were presented. The thermal conductivity coefficient was measured for ...composite specimens at room temperature and approximated for AlB
12
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
In the United States, a pre-market regulatory submission for any medical device that comes into contact with either a patient or the clinical practitioner must include an adequate toxicity ...evaluation of chemical substances that can be released from the device during its intended use. These substances, also referred to as extractables and leachables, must be evaluated for their potential to induce sensitization/allergenicity, which traditionally has been done in animal assays such as the guinea pig maximization test (GPMT). However, advances in basic and applied science are continuously presenting opportunities to employ new approach methodologies, including computational methods which, when qualified, could replace animal testing methods to support regulatory submissions. Herein, we developed a new computational tool for rapid and accurate prediction of the GPMT outcome that we have named PreS/MD (predictor of sensitization for medical devices). To enable model development, we (1) collected, curated, and integrated the largest publicly available dataset for GPMT results; (2) succeeded in developing externally predictive (balanced accuracy of 70%–74% as evaluated by both 5-fold external cross-validation and testing of novel compounds) quantitative structure-activity relationships (QSAR) models for GPMT using machine learning algorithms, including deep learning; and (3) developed a publicly accessible web portal integrating PreS/MD models that can predict GPMT outcomes for any molecule of interest. We expect that PreS/MD will be used by both industry and regulatory scientists in medical device safety assessments and help replace, reduce, or refine the use of animals in toxicity testing. PreS/MD is freely available at https://presmd.mml.unc.edu/.
The broad-band reflection spectra of YB
6
and YbB
6
hexaborides with Jahn–Teller instability of the boron cage have been measured at room temperature. An optical conductivity analysis has revealed, ...along with the Drude electronic components, heavily overdamped collective modes, which are notable in YB
6
for high dielectric contributions, Δε = 2000–5700. The fraction of nonequilibrium charge carriers in YB
6
, which is at the boundary of structural instability in the hexaboride family, reaches 85–90%, whereas this fraction in doped YbB
6
semiconductor is not higher than 25%. It has been shown that unlike the predictions of the topological Kondo insulator model, the surface “metallization” in Yb
2+
B
6
crystals can be explained by additional doping of a surface layer with Yb
3+
ions.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
By measuring room temperature infrared (40–35000 cm
–1
) reflectivity of metallic LuB12 single crystals with different isotopic compositions (
nat
B,
10
B,
11
B), we find that to model the spectrum ...we had to introduce, additionally to Drude free-carrier component, a broad excitation with unusually large dielectric contribution (Δε = 8000 ± 4000), which is characterized by a non-Lorentzian lineshape. It is suggested that the origin of the excitation is connected with cooperative dynamics of Jahn–Teller active B
12
molecules producing quasilocal vibrations (rattling modes) of caged lutetium ions. The coupling of the Lu
3+
rattling motions with the charge carriers of conduction band is proposed to be the reason of strongly damped character of the excitation.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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