Mechanochromic aromatic hydrocarbons that bear one simple substituent.

Structurally simple aromatic hydrocarbons that possess only one isocyano group show luminescent mechanochromism. The structural isomers of these aromatic hydrocarbons exhibit blue- and red-shifted emission bands upon mechanical stress. Their low molecular weight enables their sublimation under mild conditions.

Establishment of a random forest regression model to estimate the age of bloodstains based on temporal colorimetric analysis.

Bloodstain age estimation is important in forensic science. Although several studies have used spectroscopy to estimate bloodstain ages, this method has not yet been practically applied due to the need for expensive equipment and low reproducibility. Thus, we aimed to develop a bloodstain age estimation model that can be easily performed using a spectrophotometric colorimeter. First, bloodstains were prepared by placing blood obtained from five healthy volunteers on a plastic plate. The bloodstains were kept on conditions with various brightness and temperatures. Then, each bloodstain was dissolved in saline every 24 h to a final concentration of 1%, measured with a spectrophotometric colorimeter, and subjected to machine learning to generate a random forest regression (RFR) model, and finally, the prediction accuracy of the bloodstain age was verified. We also elucidated the mechanism of the color changes utilizing aminoguanidine, which is an inhibitor of Maillard reaction. Finally, we measured the time-dependent color changes of the blood fluids obtained from healthy volunteers and examined if the method could be potentially applied to estimate postmortem interval (PMI). Our results showed that the RFR model estimated the bloodstain age with no substantial assessment, and it was applicable to bloodstains, regardless of the brightness or temperature. The color changes were affected by the addition of aminoguanidine. Furthermore, the method could be applied to blood fluids, suggesting its potential usefulness for PMI estimation. Considering its feasibility, the present method could potentially be introduced to practical forensic sciences in the near future.

Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions.

Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2'-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study.

Functional Molecular Crystals from the Arylation of a Halogenoplatinum Complex: Stimuli Responsiveness, Comproportionation, and π-Bridged Dimerization.

A chloroplatinum complex was arylated to obtain stimuli-responsive molecular crystals. The resulting arylplatinum complex showed polymorph-dependent emission, mechano- and thermochromic luminescence as well as comproportionation and π-bridged dimerization. Simple mixing of structurally similar arylplatinum complexes at room temperature resulted in the transfer of their aryl groups (comproportionation), which allowed their mechanochromic profiles to be tuned. We also found that recrystallization of the complex afforded a dimerized product in which two platinum ions are bridged by aryl groups resulting in a very short (3.0466(10) Å) Pt-Pt distance.

Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy.

Sudden death, or unexpected natural death of a healthy individual, is a serious problem in all nations. Sudden cardiac death (SCD) mainly due to ischemic heart diseases is the top cause of sudden death. However, there are pathophysiological conditions, referred to as sudden arrhythmic death syndrome, in which no apparent lesion can be identified even after complete conventional or ordinary autopsy. While postmortem genetic analyses have accumulated evidence about underlying genetic abnormality in such cases, the precise relationships between genetic background and the phenotype have been largely elusive. In this study, a retrospective investigation of 17 autopsy cases in which lethal arrhythmia was suspected to be the cause of death was carried out. Genetic analysis focusing on 72 genes reported to be associated with cardiac dysfunctions was performed, in combination with detailed histopathological and postmortem imaging examination, and a family study. As a result, in two cases of suspected arrhythmogenic cardiomyopathy (ACM), we found a nonsense variant in PKP2 and frameshift variant in TRPM4 gene. In contrast, the other 15 cases showed no morphological changes in the heart despite the presence of a frameshift variant and several missense variants, leaving the clinical significance of these variants obscure. The findings of the present study suggest that nonsense and frameshift variants could be involved in the morphological abnormality in cases of SCD due to ACM, while missense variants alone rarely contribute to massive structural changes in the heart.

Reversible Transition between Discrete and 1D Infinite Architectures: A Temperature-Responsive Cu(I) Complex with a Flexible Disilane-Bridged Bis(pyridine) Ligand.

A thermoresponsive structural change based on a disilane-bridged bis(pyridine) ligand and CuI is reported. Single-crystal X-ray analysis revealed that there are two polymorphs in the Cu(I) complex: octanuclear copper(I) complex at 20 °C and 1D staircase copper(I) polymer complex at -173 °C. The formation of these polymorphs is due to the flexibility of the ligand. Cu-I bond formation is observed upon cooling the sample from -10 °C to -170 °C. The temperature-induced phase transition progression was clarified by DSC, VT-PXRD, and VT-photoluminescence measurements and indicated a reversible temperature-controlled crystal-to-crystal phase transition. Observation on a VT-stage using a high-speed camera showed crystal cracking during single-crystal to single-crystal transitions between these polymorphic forms.

Study of Polymer Nanofilms Using for High-Throughput Screening in the Development of Transdermal Therapeutic System.

We investigated polymer nanofilm (PNF) for use in high-throughput screening (HTS) to promote the development of transdermal therapeutic systems (TTS). The drug permeability of PNF with a 1 : 1 weight mix ratio of poly(L-lactic acid) (PLLA) and poly(methylhydrosiloxane) (PMHS) (PLLA/PMHS (1/1) PNF) and Strat-M® of the transdermal diffusion test membrane, was evaluated using 12 kinds of drugs with the logarithmic value of n-octanol/water partition coefficients of -4.70 to 3.86. The lag time of PLLA/PMHS (1/1) PNF made via polymer alloying was significantly shorter than that of Strat-M® for 10 drug types, and the formation of a highly diffusible PMHS-rich phase accompanying the formation of a sea-island structure was suggested as a contributing factor. Additionally, a high correlation was confirmed between the measured value for the logarithm of the apparent permeability coefficient of PLLA/PMHS (1/1) PNF and the literature values for the logarithm of the apparent permeability coefficient of human skin (r = 0.929). This study shows that PLLA/PMHS (1/1) PNF can reliably predict drug permeability in human skin and can potentially be used in HTS for developing TTS.

Mechanical deformation and multiple thermal restoration of organic crystals: reversible multi-stage shape-changing effect with luminescence-color changes.

Shape-memory materials can be mechanically deformed and subsequently reverse the deformation upon changing the temperature. Shape-memory materials have attracted considerable attention for basic research and industrial applications, and polymer and alloy shape-memory materials have been well studied; however, it is formidably challenging to develop functional shape-memory materials, such as materials with multi-stage and anisotropic shape changes and shape changes accompanied by changes in color and light emission. Here, we found a reversible multi-stage shape-changing effect after mechanical deformation in a molecular crystal induced by multi-step thermal phase transitions with reversible shape changes and luminescence-color changes. Using single-crystal structure and thermal analyses as well as mechanical property measurements, we found that the reversible multi-stage shape-changing effect was achieved by a combination of a twinning deformation and multi-step thermal phase transitions. The changes in the crystal shape and luminescence suggest novel strategies for imparting known shape-memory materials with additional functionalities.

PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study.

PURPOSE: PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing the delivery of therapeutic molecules. Combinations of chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by increasing tumor oxygenation by improving vascular patency and perfusion, PEGPH20 will also act as a radiosensitization agent. EXPERIMENTAL DESIGN: The effect of PEGPH20 on radiation treatment was analyzed with respect to tumor growth, survival time, p02, local blood volume, and the perfusion/permeability of blood vessels in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (HAS3). RESULTS: Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. In mice that overexpressed HAS3, EPR imaging showed an increase in local pO2 that could be linked to increases in perfusion/permeability and local blood volume immediately after PEGPH20 treatment. Hyperpolarized [1-13C] pyruvate suggested PEGPH20 caused a metabolic shift towards decreased glycolytic flux. These effects were confined to the mice overexpressing HAS3 - no effect of PEGPH20 on survival, radiation treatment, or pO2 was seen in wild type BxPC3 tumors. CONCLUSIONS: PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation. The response of the treatment may potentially be monitored by non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.

Structure-guided design enables development of a hyperpolarized molecular probe for the detection of aminopeptidase N activity in vivo.

Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions, there is a demand for developing exogenous, i.e., artificially designed, DNP-NMR molecular probes; however, complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here, we report Ala-[1-13C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation, calculation, biochemical assessment, and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe, we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived, practical DNP-NMR molecular probes through structure-guided molecular design.

Simple Esterification of [1-13C]-Alpha-Ketoglutarate Enhances Membrane Permeability and Allows for Noninvasive Tracing of Glutamate and Glutamine Production.

Alpha-ketoglutarate (α-KG) is a key metabolite and signaling molecule in cancer cells, but the low permeability of α-KG limits the study of α-KG mediated effects in vivo. Recently, cell-permeable monoester and diester α-KG derivatives have been synthesized for use in vivo, but many of these derivatives are not compatible for use in hyperpolarized carbon-13 nuclear magnetic resonance spectroscopy (HP-13C-MRS). HP-13C-MRS is a powerful technique that has been used to noninvasively trace labeled metabolites in real time. Here, we show that using diethyl-[1-13C]-α-KG as a probe in HP-13C-MRS allows for noninvasive tracing of α-KG metabolism in vivo.

Synthesis of [1-13 C-5-12 C]-alpha-ketoglutarate enables noninvasive detection of 2-hydroxyglutarate.

Isocitrate dehydrogenase 1 (IDH1) mutations that generate the oncometabolite 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG) have been identified in many types of tumors and are an important prognostic factor in gliomas. 2-HG production can be determined by hyperpolarized carbon-13 magnetic resonance spectroscopy (HP-13 C-MRS) using [1-13 C]-α-KG as a probe, but peak contamination from naturally occurring [5-13 C]-α-KG overlaps with the [1-13 C]-2-HG peak. Via a newly developed oxidative-Stetter reaction, [1-13 C-5-12 C]-α-KG was synthesized. α-KG metabolism was measured via HP-13 C-MRS using [1-13 C-5-12 C]-α-KG as a probe. [1-13 C-5-12 C]-α-KG was synthesized in high yields, and successfully eliminated the signal from C5 of α-KG in the HP-13 C-MRS spectra. In HCT116 IDH1 R132H cells, [1-13 C-5-12 C]-α-KG allowed for unimpeded detection of [1-13 C]-2-HG. 12 C-enrichment represents a novel method to circumvent spectral overlap, and [1-13 C-5-12 C]-α-KG shows promise as a probe to study IDH1 mutant tumors and α-KG metabolism.

Real-Time insight into in vivo redox status utilizing hyperpolarized [1-13C] N-acetyl cysteine.

Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized 13C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-13C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized 13C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.

(9-Isocyanoanthracene)gold(I) Complexes Exhibiting Two Modes of Crystal Jumps by Different Structure Change Mechanisms.

The first examples of single crystals exhibiting salient effects by different structure change mechanisms are reported. The crystals of newly prepared aryl(9-isocyanoanthracene)gold(I) complexes jump in response to two different external stimuli: ultraviolet (UV) irradiation and cooling. The photosalient effect is triggered by photodimerization reaction of the anthracene moieties under photoirradiation. By contrast, the thermosalient effect is caused by anisotropic thermal contraction upon cooling without a chemical structure change. By taking advantage of the multiple-jump feature, we also show sequential jumps of crystals by cooling and then UV irradiation for demonstration of the programmed motion of molecular crystals.

Thermosalience in Macrocycle-Based Soft Crystals via Anisotropic Deformation of Disilanyl Architecture.

We describe here the preparation of soft crystals using disilanyl macrocycle C4 possessing four p-phenylenes circularly connected by four flexible disilane bonds. Single crystals of C4 exhibited a reversible thermal single-crystal-to-single-crystal (SCSC) phase transition behavior between two crystal phases accompanied by remarkable mechanical motion (thermosalient effect), as revealed by thermal analyses and X-ray diffraction measurements. Detailed structural analyses implied that flexibility of the parallelogram disilanyl architecture and molecular packing mode via weak intermolecular interactions facilitated a concerted structural transformation (parallel crank motion) of macrocycles in the crystal, thus resulting in the SCSC phase transition accompanied by anisotropic shrinking/elongation of the cells to induce the thermosalient effect. This work explores a new area of organosilicon chemistry and presents the potential utility of disilanyl macrocycles as soft crystals.

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma.

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.

Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma.

Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between 18F-FDG-PET and lactate production, while pO2 was inversely related to lactate production and 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. 18F-FDG uptake negatively correlated with pO2 in the center of the tumor and positively correlated with pO2 on the periphery. In contrast to pO2 and 18F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. SIGNIFICANCE: Novel multimodal molecular imaging techniques reveal the potential of three interrelated imaging biomarkers to profile the tumor microenvironment and interrelationships of hypoxia, glucose uptake, and glycolysis.

Hydrogen bond-directed supramolecular polymorphism leading to soft and hard molecular ordering.

Transformation of metastable supramolecular stacks of hydrogen-bonded rosettes composed of an ester-containing barbiturated naphthalene into crystalline nanosheets occurs through the rearrangement of hydrogen-bonding patterns. The involvement of the ester group in the crystalline hydrogen-bonded pattern is demonstrated, guiding us to a new molecular design that can afford supramolecular polymorphs with soft and hard molecular packing.

Photoluminescent Ferroelastic Molecular Crystals.

Ferroelasticity has been reported for several types of molecular crystals, which show mechanical-stress-induced shape change under twinning and/or spontaneous formation of strain. Aiming to create materials that exhibit both ferroelasticity and light-emission characteristics, we discovered the first examples of ferroelastic luminescent organometallic crystals. Crystals of arylgold(I)(N-heterocyclic carbene)(NHC) complexes bend upon exposure to anisotropic mechanical stress. X-ray diffraction analyses and stress-strain measurements on these ferroelastic crystals confirmed typical ferroelastic behavior, mechanical twinning, and the spontaneous build-up of strain. A comparison with single-crystal structures of related gold-NHC complexes that do not show ferroelasticity shed light on the structural origins of the ferroelastic behavior.

Mixed crystal formation of two gold isocyanide complexes with various ratios for continuous tuning of photophysical properties.

Mixed crystals composed of two distinct gold isocyanide complexes are reported. Characterization of the mixed crystal formation and mixing ratios are performed by single-crystal X-ray diffraction and nuclear magnetic resonance spectroscopy analyses. By changing the mixing ratio, we achieve continuous changes in the emission lifetimes and the emission quantum yields.