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Journal: ACS central science


The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

Concepts: Present, Time, Pharmacology, Solubility, Research, Source, Open source, Open research


Photography was employed for the quantitation and differentiation of G- and V-series nerve agent mimics with the use of self-propagating cascades. Fluoride anion and thiols, released from a G-nerve agent mimic (i.e., diisopropyl fluorophosphate) and a V-nerve agent mimic (i.e., demeton-S-methyl), respectively, were used to initiate self-propagating cascades that amplify fluorescence signals exponentially in a ratiometric manner. A homemade LEGO dark-box, a cell phone, and 96-well plates were employed to collect photographs of the fluorescence response to the analytes. The photographic images were digitally processed in the 1931 xyY color space using a watershed and morphological erosion algorithm to generate chromaticity vs concentration calibration curves. We show that the two different amplification routines are selective for their analyte class and thus successfully discriminated the G- and V-series nerve agent mimics. Further, accurate concentrations of the analytes are determined using the chromaticity and LEGO approach given herein, thus demonstrating a simple and on-site constructible/portable device for use in the field.


Recent advances in machine learning have made significant contributions to drug discovery. Deep neural networks in particular have been demonstrated to provide significant boosts in predictive power when inferring the properties and activities of small-molecule compounds (Ma, J. et al. J. Chem. Inf.

Concepts: Machine learning, Learning, Neural network, Artificial neural network, Predictive analytics, Philosophical terminology


Reaction prediction remains one of the major challenges for organic chemistry and is a prerequisite for efficient synthetic planning. It is desirable to develop algorithms that, like humans, “learn” from being exposed to examples of the application of the rules of organic chemistry. We explore the use of neural networks for predicting reaction types, using a new reaction fingerprinting method. We combine this predictor with SMARTS transformations to build a system which, given a set of reagents and reactants, predicts the likely products. We test this method on problems from a popular organic chemistry textbook.

Concepts: Product, Chemical reaction, Chemistry, Organic reaction, Biochemistry, Sodium, Organic chemistry, Forecasting


Secreted and surface-displayed carbohydrates are essential for virulence and viability of many parasites, including for immune system evasion. We have identified the α-Gal trisaccharide epitope on the surface of the protozoan parasites Leishmania infantum and Leishmania amazonensis, the etiological agents of visceral and cutaneous leishmaniasis, respectively, with the latter bearing larger amounts of α-Gal than the former. A polyvalent α-Gal conjugate on the immunogenic Qβ virus-like particle was tested as a vaccine against Leishmania infection in a C57BL/6 α-galactosyltransferase knockout mouse model, which mimics human hosts in producing high titers of anti-α-Gal antibodies. As expected, α-Gal-T knockout mice infected with promastigotes of both Leishmania species showed significantly lower parasite load in the liver and slightly decreased levels in the spleen, compared with wild-type mice. Vaccination with Qβ-α-Gal nanoparticles protected the knockout mice against Leishmania challenge, eliminating the infection and proliferation of parasites in the liver and spleen as probed by qPCR. The α-Gal epitope may therefore be considered as a vaccine candidate to block human cutaneous and visceral leishmaniasis.

Concepts: Immune system, Microbiology, Vaccine, Immunology, Leishmaniasis, Cutaneous leishmaniasis, Leishmania, Knockout mouse


While ∼75% of commercially utilized polymers are semicrystalline, the generally low mechanical modulus of these materials, especially for those possessing a glass transition temperature below room temperature, restricts their use for structural applications. Our focus in this paper is to address this deficiency through the controlled, multiscale assembly of nanoparticles (NPs), in particular by leveraging the kinetics of polymer crystallization. This process yields a multiscale NP structure that is templated by the lamellar semicrystalline polymer morphology and spans NPs engulfed by the growing crystals, NPs ordered into layers in the interlamellar zone [spacing of [Formula: see text] (10-100 nm)], and NPs assembled into fractal objects at the interfibrillar scale, [Formula: see text] (1-10 μm). The relative fraction of NPs in this hierarchy is readily manipulated by the crystallization speed. Adding NPs usually increases the Young’s modulus of the polymer, but the effects of multiscale ordering are nearly an order of magnitude larger than those for a state where the NPs are not ordered, i.e., randomly dispersed in the matrix. Since the material’s fracture toughness remains practically unaffected in this process, this assembly strategy allows us to create high modulus materials that retain the attractive high toughness and low density of polymers.

Concepts: Sol-gel, Liquid, Materials science, Differential scanning calorimetry, Glass, Glass transition, Plasticizer, Physics of glass


Chemiluminescence probes are considered to be among the most sensitive diagnostic tools that provide high signal-to-noise ratio for various applications such as DNA detection and immunoassays. We have developed a new molecular methodology to design and foresee light-emission properties of turn-ON chemiluminescence dioxetane probes suitable for use under physiological conditions. The methodology is based on incorporation of a substituent on the benzoate species obtained during the chemiexcitation pathway of Schaap’s adamantylidene-dioxetane probe. The substituent effect was initially evaluated on the fluorescence emission generated by the benzoate species and then on the chemiluminescence of the dioxetane luminophores. A striking substituent effect on the chemiluminescence efficiency of the probes was obtained when acrylate and acrylonitrile electron-withdrawing groups were installed. The chemiluminescence quantum yield of the best probe was more than 3 orders of magnitude higher than that of a standard, commercially available adamantylidene-dioxetane probe. These are the most powerful chemiluminescence dioxetane probes synthesized to date that are suitable for use under aqueous conditions. One of our probes was capable of providing high-quality chemiluminescence cell images based on endogenous activity of β-galactosidase. This is the first demonstration of cell imaging achieved by a non-luciferin small-molecule probe with direct chemiluminescence mode of emission. We anticipate that the strategy presented here will lead to development of efficient chemiluminescence probes for various applications in the field of sensing and imaging.

Concepts: DNA, Protein, Fluorescence, Spectroscopy, Signal-to-noise ratio, Chemiluminescence, Space probe


Developments in analytical chemistry technologies and portable instrumentation over the past decade have contributed significantly to a variety of applications ranging from point of care testing to industrial process control. In particular, Raman spectroscopy has advanced for analyzing various types of evidence for forensic purposes. Extracting phenotypic information (e.g., sex, race, age, etc.) from body fluid traces is highly desirable for criminal investigations. Identifying the chronological age (CA) of a blood donor can provide significant assistance to detectives. In this proof-of-concept study, Raman spectroscopy and chemometrics have been used to analyze blood from human donors, and differentiate between them based on their CA [i.e., newborns (CA of <1 year), adolescents (CA of 11-13 years), and adults (CA of 43-68 years)]. A support vector machines discriminant analysis (SVMDA) model was constructed, which demonstrated high accuracy in correctly predicting blood donors' age groups where the lowest cross-validated sensitivity and specificity values were 0.96 and 0.97, respectively. Overall, this preliminary study demonstrates the high selectivity of Raman spectroscopy for differentiating between blood donors based on their CA. The demonstrated capability completes our suite of phenotype profiling methodologies including the determination of sex and race. CA determination has particular importance since this characteristic cannot be determined through DNA profiling unlike sex and race. When completed, the developed methodology should allow for phenotype profiling based on dry traces of body fluids immediately at the scene of a crime. The availability of this information within the first few hours since the crime discovery could be invaluable for the investigation.


The iconic helical structure of DNA is stabilized by the solvation environment, where a change in the hydration state can lead to dramatic changes to the DNA structure. X-ray diffraction experiments at cryogenic temperatures have shown crystallographic water molecules in the minor groove of DNA, which has led to the notion of a spine of hydration of DNA. Here, chiral nonlinear vibrational spectroscopy of two DNA sequences shows that not only do such structural water molecules exist in solution at ambient conditions but that they form a chiral superstructure: a chiral spine of hydration. This is the first observation of a chiral water superstructure templated by a biomolecule. While the biological relevance of a chiral spine of hydration is unknown, the method provides a direct way to interrogate the properties of the hydration environment of DNA and water in biological settings without the use of labels.

Concepts: DNA, Oxygen, Diffraction, X-ray, Crystallography, Molecule, X-ray crystallography, DNA structure


Metal-free magnetic resonance imaging (MRI) agents could overcome the established toxicity associated with metal-based agents in some patient populations and enable new modes of functional MRI in vivo. Herein, we report nitroxide-functionalized brush-arm star polymer organic radical contrast agents (BASP-ORCAs) that overcome the low contrast and poor in vivo stability associated with nitroxide-based MRI contrast agents. As a consequence of their unique nanoarchitectures, BASP-ORCAs possess per-nitroxide transverse relaxivities up to ∼44-fold greater than common nitroxides, exceptional stability in highly reducing environments, and low toxicity. These features combine to provide for accumulation of a sufficient concentration of BASP-ORCA in murine subcutaneous tumors up to 20 h following systemic administration such that MRI contrast on par with metal-based agents is observed. BASP-ORCAs are, to our knowledge, the first nitroxide MRI contrast agents capable of tumor imaging over long time periods using clinical high-field (1)H MRI techniques.

Concepts: Oncology, Medical imaging, Brain tumor, Nuclear magnetic resonance, Radiography, Magnetic resonance imaging, Contrast medium, Radiocontrast