HimGNN: a novel hierarchical molecular graph representation learning framework for property prediction.

Accurate prediction of molecular properties is an important topic in drug discovery. Recent works have developed various representation schemes for molecular structures to capture different chemical information in molecules. The atom and motif can be viewed as hierarchical molecular structures that are widely used for learning molecular representations to predict chemical properties. Previous works have attempted to exploit both atom and motif to address the problem of information loss in single representation learning for various tasks. To further fuse such hierarchical information, the correspondence between learned chemical features from different molecular structures should be considered. Herein, we propose a novel framework for molecular property prediction, called hierarchical molecular graph neural networks (HimGNN). HimGNN learns hierarchical topology representations by applying graph neural networks on atom- and motif-based graphs. In order to boost the representational power of the motif feature, we design a Transformer-based local augmentation module to enrich motif features by introducing heterogeneous atom information in motif representation learning. Besides, we focus on the molecular hierarchical relationship and propose a simple yet effective rescaling module, called contextual self-rescaling, that adaptively recalibrates molecular representations by explicitly modelling interdependencies between atom and motif features. Extensive computational experiments demonstrate that HimGNN can achieve promising performances over state-of-the-art baselines on both classification and regression tasks in molecular property prediction.

High-Affinity Aptamers for In Vitro and In Vivo Cocaine Sensing.

The ability to quantify cocaine in biological fluids is crucial for both the diagnosis of intoxication and overdose in the clinic as well as investigation of the drug's pharmacological and toxicological effects in the laboratory. To this end, we have performed high-stringency in vitro selection to generate DNA aptamers that bind cocaine with nanomolar affinity and clinically relevant specificity, thus representing a dramatic improvement over the current-generation, micromolar-affinity, low-specificity cocaine aptamers. Using these novel aptamers, we then developed two sensors for cocaine detection. The first, an in vitro fluorescent sensor, successfully detects cocaine at clinically relevant levels in 50% human serum without responding significantly to other drugs of abuse, endogenous substances, or a diverse range of therapeutic agents. The second, an electrochemical aptamer-based sensor, supports the real-time, seconds-resolved measurement of cocaine concentrations in vivo in the circulation of live animals. We believe the aptamers and sensors developed here could prove valuable for both point-of-care and on-site clinical cocaine detection as well as fundamental studies of cocaine neuropharmacology.

Codeposition Enhances the Performance of Electrochemical Aptamer-Based Sensors.

Electrochemical aptamer-based (EAB) sensors, a minimally invasive means of performing high-frequency, real-time measurement of drugs and biomarkers in situ in the body, have traditionally been fabricated by depositing their target-recognizing aptamer onto an interrogating gold electrode using a "sequential" two-step method involving deposition of the thiol-modified oligonucleotide (typically for 1 h) followed by incubation in mercaptohexanol solution (typically overnight) to complete the formation of a stable, self-assembled monolayer. Here we use EAB sensors targeting vancomycin, tryptophan, and phenylalanine to show that "codeposition", a less commonly employed EAB fabrication method in which the thiol-modified aptamer and the mercaptohexanol diluent are deposited on the electrode simultaneously and for as little as 1 h, improves the signal gain (relative change in signal upon the addition of high concentrations of the target) of the vancomycin and tryptophan sensors without significantly reducing their stability. In contrast, the gain of the phenylalanine sensor is effectively identical irrespective of the fabrication approach employed. This sensor, however, appears to employ binding-induced displacement of the redox reporter rather than binding-induced folding as its signal transduction mechanism, suggesting in turn a mechanism for the improvement observed for the other two sensors. Codeposition thus not only provides a more convenient means of fabricating EAB sensors but also can improve their performance.

Recent advances in biological molecule detection based on a three-dimensional graphene structure.

Graphene has become an attractive material in the field of electrochemical detection owing to its unique electrical properties. Although the simple stacking structures of two-dimensional (2D) graphene sheets can provide excellent detection properties, a macroscopic three-dimensional (3D) structure needs to be constructed to enhance its functional properties. Graphene with a 3D structure has elegant functions, unlike graphene with a 2D structure. These properties include a large specific surface area, easy loading of nanomaterials with electrocatalytic and redox functions, and so on. Herein, we outline the preparation methods (self-assembly, chemical vapor deposition, templates, and 3D printing) for 3D graphene structures for obtaining excellent detection performance and applications in detecting biological molecules, bacteria, and cells. Furthermore, this review focuses on the improvement of the detection performance and enhancement of the applicability of graphene-based electrochemical sensors. We hope that this article will provide a reference for the future development of electrochemical sensors based on 3D graphene composites.

PERSISTENT SUBRETINAL FLUID AFTER VITRECTOMY FOR MACULAR HOLE-ASSOCIATED RETINAL DETACHMENT.

PURPOSE: To evaluate the incidence, associated factors, and outcome of persistent subretinal fluid (SRF) after vitrectomy for macular hole-associated retinal detachment (MHRD). METHODS: A total of 158 eyes from 156 patients with MHRD who achieved macular hole closure after primary vitrectomy were included in the analysis; persistent SRF was defined as the presence of SRF for more than 1 month after first surgery. Preoperative and postoperative parameters were analyzed for their relationship with SRF development. RESULTS: Persistent SRF was observed in 19 eyes (12.0% of 158) postoperatively. Seven eyes (36.8% of 19) with persistent SRF eventually displayed complete absorption during follow-up. Univariate analysis revealed that eyes with persistent SRF were statistically associated with internal limiting membrane inverted flap, duration of symptoms, tamponade (perfluoropropane/silicone oil: 14/5 vs. 35/104, P < 0.001), and MHRD subtype (Type 1/Type 2/Type 3: 15/4/0 vs. 60/40/39, P = 0.003). In multivariate analysis, only internal limiting membrane inverted flap (odds ratio, 15.778, 95% confidence interval, 3.170-78.523; P = 0.001) was positively associated with persistent SRF. There were no significant differences in best-corrected visual acuity improvement ( P = 0.425) between the SRF involved foveal and without involved foveal groups and no significant differences between the SRF complete absorption and incomplete absorption groups. CONCLUSION: Absorption of persistent SRF may be more difficult in MHRD eyes than in ordinary rhegmatogenous retinal detachment eyes. The internal limiting membrane inverted flap in MHRD was associated with a greater likelihood of persistent SRF. The location and incomplete absorption of persistent SRF did not seem to be associated with the final visual outcome.

Using Spectroscopy to Guide the Adaptation of Aptamers into Electrochemical Aptamer-Based Sensors.

Electrochemical aptamer-based (EAB) sensors utilize the binding-induced conformational change of an electrode-attached, redox-reporter-modified aptamer to transduce target recognition into an easily measurable electrochemical output. Because this signal transduction mechanism is single-step and rapidly reversible, EAB sensors support high-frequency, real-time molecular measurements, and because it recapitulates the reagentless, conformation-linked signaling seen in vivo among naturally occurring receptors, EAB sensors are selective enough to work in the complex, time-varying environments found in the living body. The fabrication of EAB sensors, however, requires that their target-recognizing aptamer be modified such that (1) it undergoes the necessary binding-induced conformational change and (2) that the thermodynamics of this "conformational switch" are tuned to ensure that they reflect an acceptable trade-off between affinity and signal gain. That is, even if an "as-selected" aptamer achieves useful affinity and specificity, it may fail when adapted to the EAB platform because it lacks the binding-induced conformational change required to support EAB signaling. In this paper we reveal the spectroscopy-guided approaches we use to modify aptamers such that they support the necessary binding-induced conformational change. Specifically, using newly reported aptamers, we demonstrate the systematic design of EAB sensors achieving clinically and physiologically relevant specificity, limits of detection, and dynamic range against the targets methotrexate and tryptophan.

Ursolic acid alleviates steroid-induced avascular necrosis of the femoral head in mouse by inhibiting apoptosis and rescuing osteogenic differentiation.

Steroid-induced avascular necrosis of femoral head (SANFH) is a common disorder worldwide with high disability. Overdose of glucocorticoid (GC) is the most common non-traumatic cause of SANFH. Up until now, there are limited therapeutic strategies for curing SANFH, and the mechanisms underlying SANFH progression remain unclear. Nevertheless, Osteogenic dysfunction is considered to be one of the crucial pathobiological mechanisms in the development of SANFH, which involves mouse bone marrow mesenchymal stem cells (BMSCs) apoptosis and osteogenic differentiation disorder. Ursolic acid (UA), an important component of the Chinese medicine formula Yougui Yin, has a wide range of pharmacological properties such as anti-tumor, anti-inflammatory and bone remodeling. Due to the positive effect of Yougui Yin on bone remodeling, the purpose of this study was to investigate the effects of UA on dexamethasone (DEX)-induced SANFH in vitro and vivo. In vitro, we demonstrated that UA can promote mouse BMSCs proliferation and resist DEX-induced apoptosis by CCK8, Western blotting, TUNEL and so on. In addition, vitro experiments such as ALP and Alizarin red staining assay showed that UA had a beneficial effect on the osteogenic differentiation of mouse BMSCs. In vivo, the results of H&E staining, immunohistochemistry staining, Elisa and micro-CT analysis showed that UA had a bone repair-promoting effect in SANFH model. Moreover, the results of Western blot and TUNEL experiments showed that UA could delay the disease progression of SANFH in mice by inhibiting apoptosis. Overall, our study suggests that UA is a potential compound for the treatment of SANFH.

Lymphadenectomy and optimal excise lymph nodes count for early-stage primary fallopian tube cancer: a SEER-based study.

BACKGROUNDS: There is still no consensus on the significance of Lymphadenectomy (LD) and the number of lymph nodes that need to be excised (ELNs) for adequate LD in patients with early-stage primary fallopian tube cancer (PFTC). Our endeavor is geared towards deepening comprehension of LD in early-stage PFTC and identify the optimal cut-off of ELNs. METHODS: This SEER-based study analyzed the clinical data of patients with early-stage PFTC between 2000 and 2018. X-tile was employed to confirm the optimal cut-off of ELNs. The survival data between groups were analyzed by the Kaplan-Meier estimates, Log-rank test and Cox proportional hazards model. RESULTS: There was significant improvement in both mean cancer-specific survival (CSS, p < 0.001) and overall survival (OS, p < 0.001) in LD group. Regardless of matched or not, LD was identified as an independent protective factor of CSS and OS. The optimal 3-year CSS-based cutoff of ELNs was 11 (p = 0.026) as determined by X-tile. Both the mean CSS (p = 0.001) and mean OS (p = 0.002) in adequate LD group (ELNs > 11, n = 574) were significantly longer than these in inadequate LD group (ELNs ≤ 11, n = 738). Adequate LD, FIGO stage, tumor grade and histology were significant prognostic factors for CSS and OS. CONCLUSION: LD is an independent protective prognostic factor of patients with early-stage PFTC. The association between ELNs > 11 and an improved prognosis is evident. Future studies are needed to further clarify the results above.

Stable, Bright, and Long-Fluorescence-Lifetime Dyes for Deep-Near-Infrared Bioimaging.

Near-infrared (NIR) fluorophores absorbing maximally in the region beyond 800 nm, i.e., deep-NIR spectral region, are actively sought for biomedical applications. Ideal dyes are bright, nontoxic, photostable, biocompatible, and easily derivatized to introduce functionalities (e.g., for bioconjugation or aqueous solubility). The rational design of such fluorophores remains a major challenge. Silicon-substituted rhodamines have been successful for bioimaging applications in the red spectral region. The longer-wavelength silicon-substituted congeners for the deep-NIR spectral region are unknown to date. We successfully prepared four silicon-substituted bis-benzannulated rhodamine dyes (ESi5a-ESi5d), with an efficient five-step cascade on a gram-scale. Because of the extensive overlapping of their HOMO-LUMO orbitals, ESi5a-ESi5d are highly absorbing (λabs ≈ 865 nm and ε > 105 cm-1 M-1). By restraining both the rotational freedom via annulation and the vibrational freedom via silicon-imparted strain, the fluorochromic scaffold of ESi5 is highly rigid, resulting in an unusually long fluorescence lifetime (τ > 700 ps in CH2Cl2) and a high fluorescence quantum yield (ϕ = 0.14 in CH2Cl2). Their half-lives toward photobleaching are 2 orders of magnitude longer than the current standard (ICG in serum). They are stable in the presence of biorelevant concentration of nucleophiles or reactive oxygen species. They are minimally toxic and readily metabolized. Upon tail vein injection of ESi5a (as an example), the vasculature of a nude mouse was imaged with a high signal-to-background ratio. ESi5 dyes have broad potentials for bioimaging in the deep-NIR spectral region.

Extraction-Dominated Temperature Degradation of Population Inversion in Terahertz Quantum Cascade Lasers.

Degraded population inversion (PI) at elevated temperature, regarded as an important temperature degradation factor in terahertz quantum cascade lasers (THz QCL), has hindered the widespread use of these devices. Herein, the mechanism of the temperature degradation of PI is investigated microscopically. It is demonstrated that the limited extraction efficiency of the extraction system dominates the decrease of PI at elevated temperatures. To be specific, the increased temperature brings about intense thermally activated longitudinal optical phonon scattering, leading to large amounts of electrons scattering to lower level state. In this case, the resonant-phonon extraction system is incapable of depleting all the electrons from lower level states. So even though the resonant-tunneling injection seems efficient enough to compensate the electron runoff at the upper state, the electron density at lower level state increases and the overall PI turns out lower. In addition, it is found that strong electron-ionized donor separation at high temperature can induce level misalignment, which can stagger the optimal conditions of injection and extraction. Also, the extraction efficiency gets lower as the extraction system requires accurate coupling between several energy levels.

Fine modulation of the energy band strategy to control the carrier confinement capability of digital alloys.

In this paper, a strategy to finely modulate the energy band structure to control the carrier confinement capability of digital alloys (DA) is proposed. Strain analysis shows that As and Sb atoms are exchanged within the AlAsSb DA. The bottom of the corrected potential well is low on the left and high on the right in the growth direction, resulting in a higher band offset of the AlSb potential barrier layer on the left side of the potential well than on the right side. The modulation of the band leads to a higher probability of electron tunneling in DA under the action of an electric field opposite to the growth direction. Conversely, it is difficult for the electrons to tunnel into the lower energy level potential wells. TheI-Vcurve of DA shows that the current value under positive bias is significantly smaller than the value under negative bias when the voltage is higher. The measured results correspond perfectly with the modified energy band model, which verifies the feasibility of energy band modulation. This is important for the structural design of DA and the reduction of dark current in optoelectronic devices.

Chemiluminescent magnetic nanoparticles with good catalytic activity and rapid separation capability and sensitive sensing for H2O2.

It is of considerable importance to develop chemiluminescent functionalized nanomaterials (CF-NMs) with good catalytic activity, high chemiluminescence (CL) efficiency and good stability, and rapid magnetic separation capability, achieving excellent performance in CL biosensing. In this study, N-(4-aminobutyl)-N-ethylisoluminol (ABEI)-functionalized CuFe2O4 magnetic nanomaterial (ABEI/CuFe2O4) with high catalytic activity was synthesized by virtue of a solvothermal and post-functionalization method. ABEI/CuFe2O4 showed outstanding CL properties, superior to ABEI-CuFe2O4 in liquid phase. This reveals that the immobilization of ABEI on the surface of CuFe2O4 exhibits unique heterogeneous catalytic property. The catalytic ability of CuFe2O4 was better than that of CoFe2O4, ZnFe2O4, MnFe2O4, and NiFe2O4. It is suggested that the peroxide-like activity as well as Cu2+ and Cu0 enriched on the surface of ABEI/CuFe2O4 opened up a dual route for synergistic catalysis of H2O2. ABEI/CuFe2O4 also demonstrated good superparamagnetism and magnetic separation could be carried out in 2 min, which is advantageous for the separation and purification of ABEI/CuFe2O4 during the synthetic procedures and bioassays. Owing to the sensitive response of ABEI/CuFe2O4 to H2O2, an enzyme-free sensor was developed for the detection of H2O2 with a wide linear range over 5 orders of magnitude of H2O2 concentrations and a low detection limit of 5.6 nM. The as-developed sensor is sensitive, stable, and convenient. This work provides a new family member of nanomaterials with good magnetism and CL activity as well as good stability. The developed ABEI/CuFe2O4 shows great prospects in biocatalysis, bioassays, biosensing, and bioimaging, etc.

Characterization of Phenolic Plant Exudates by Nuclear Magnetic Resonance Spectroscopy.

The class of plant exudates that contain the phenol functionality, termed phenolics, is defined, surveyed, and characterized by solid-state 13C NMR spectroscopy and by solution-state 1H NMR spectroscopy. Materials in this group are identified by the phenolic 13C resonance (from the ipso carbon of ArOH) at δ 145-160 (δ 160-167 for ArOR). The resonance patterns define several subclasses based on the collective similarity of their 13C spectra, specifically, aloetics from the genus Aloe, guaiacs from the genus Guaiacum and other eurosid and conifer genera, xanthics from the genus Garcinia, and kinos from the genus Eucalyptus and many other genera. Phenolic exudates often are mixed with terpenoid materials (the building block of exudates known as resins) and carbohydrates (the building block of exudates known as gums) to form hybrid subgroups such as guaiac gums, guaiac resins, and kino resins. There are numerous phenolic exudates not affiliated with any of these groups, both as pure phenolics and as hybrids (phenolic resins, phenolic gum resins, and phenolic waxes).

A Heteromeric Carboxylic Acid Based Single-Crystalline Crosslinked Organic Framework.

The development of large pore single-crystalline covalently linked organic frameworks is critical in revealing the detailed structure-property relationship with substrates. One emergent approach is to photo-crosslink hydrogen-bonded molecular crystals. Introducing complementary hydrogen-bonded carboxylic acid building blocks is promising to construct large pore networks, but these molecules often form interpenetrated networks or non-porous solids. Herein, we introduced heteromeric carboxylic acid dimers to construct a non-interpenetrated molecular crystal. Crosslinking this crystal precursor with dithiols afforded a large pore single-crystalline hydrogen-bonded crosslinked organic framework HC OF-101. X-ray diffraction analysis revealed HC OF-101 as an interlayer connected hexagonal network, which possesses flexible linkages and large porous channels to host a hydrazone photoswitch. Multicycle Z/E-isomerization of the hydrazone took place reversibly within HC OF-101, showcasing the potential use of HC OF-101 for optical information storage.

Structural changes from heating amber and copal as observed by nuclear magnetic resonance spectroscopy.

Structural changes caused by heating of fossilized (amber) and semifossilized (copal) resins have been examined by nuclear magnetic resonance spectroscopy. A set of 28 samples was constituted to include different geographical sources, degrees of maturation, colors, and structural groupings. The onset of structural alterations was determined by observation of the lowest temperature at which spectral changes occurred. Both proton spectra in solution and carbon-13? spectra in the solid state then were recorded of cooled samples after heating for 12 hr at temperature increments, until liquification of the sample began. The spectra of both nuclides exhibit loss of a few peaks, broadening of most peaks, and enhancement of the unsaturated or aromatic region at the expense of saturated resonances. Such changes are irreversible and lead to a harder and less soluble material on cooling. The changes parallel those that occur with maturation of fossil resins or materials that lead to coal.

Hierarchical-Coassembly-Enabled 3D-Printing of Homogeneous and Heterogeneous Covalent Organic Frameworks.

Covalent organic frameworks (COFs) are crystalline polymers with permanent porosity. They are usually synthesized as micrometer-sized powders or two-dimensional thin films and membranes for applications in molecular storage, separation, and catalysis. In this work, we report a general method to integrate COFs with imine or ß-ketoenamine linkages into three-dimensional (3D)-printing materials. A 3D-printing template, Pluronic F127, was introduced to coassemble with imine polymers in an aqueous environment. By limitation of the degree of imine polycondensation during COF formation, the amorphous imine polymer and F127 form coassembled 3D-printable hydrogels with suitable shear thinning and rapid self-healing properties. After the removal of F127 followed by an amorphous-to-crystalline transformation, three ß-ketoenamine- and imine-based COFs were fabricated into 3D monoliths possessing high crystallinity, hierarchical pores with high surface areas, good structural integrity, and robust mechanical stability. Moreover, when multiple COF precursor inks were employed for 3D printing, heterogeneous dual-component COF monoliths were fabricated with high spatial precision. This method not only enables the development of COFs with sophisticated 3D macrostructure but also facilitates the heterogeneous integration of COFs into devices with interconnected interfaces at the molecular level.

Topochemical Synthesis of Single-Crystalline Hydrogen-Bonded Cross-Linked Organic Frameworks and Their Guest-Induced Elastic Expansion.

Covalently linked single-crystalline porous organic materials are highly desired for structure-property analysis; however, periodically polymerizing organic entities into high dimensional networks is challenging. Here, we report a series of topologically divergent single-crystalline hydrogen-bonded cross-linked organic frameworks (HCOFs) with visible guest-induced elastic expansions, which mutually integrate high structural order and high flexibility into one framework. These HCOFs are synthesized by photo-cross-linking molecular crystals with alkyldithiols of different chain lengths. Their detailed structural information was revealed by single-crystal X-ray analysis and experimental investigations of HCOFs and their corresponding single-crystalline analogues. Upon guest adsorption, HCOF-2 crystals composed of a 3D self-entangled polymer network undergo anisotropic expansion to more than twice their original size, while the 2D-bilayer HCOF-3 crystals exhibit visible, layered sorption bands and form delaminated sheets along the plane of its 2D layers. The dynamic expansion of HCOF networks creates guest-induced porosity with over 473% greater volume than their permanent voids, as calculated from their record-breaking aqueous iodine adsorption capacities. Temperature-gated DMSO sorption investigations illustrated that the flexible nature of cross-linkers in HCOFs provides positive entropy from the coexistence of multiple conformations to allow for elastic expansion and contraction of the frameworks.

Highly Selective, Naked-Eye, and Trace Discrimination between Perfect-Match and Mismatch Sequences Using a Plasmonic Nanoplatform.

A plasmonic nanoplatform to perform an enzyme-free, naked-eye, and trace discrimination of single-base mutation from fully matched sequence is reported. The nanoplatform showed great potential to enhance catalytic hairpin assembly (CHA) amplification efficiency and biocatalytic activity of hemin/G-quadruplex (DNAzyme). When human immunodeficiency virus (HIV) DNA biomarker was used as the model analyst, a naked-eye detection with high selectivity and high sensitivity down to 10-17 M in whole serum was achieved by observing red-to-blue color change. Single-base mismatch and two-base mismatch were detected at the low concentrations of 10-11 and 10-8 M, respectively. The naked-eye detection based on the enzyme-free plasmonic nanoplatform is expected to have potential applications ranging from quick detection and early diagnostics to point-of-care research.

Hierarchical Co-Assembly Enhanced Direct Ink Writing.

Integrating intelligent molecular systems into 3D printing materials and transforming their molecular functions to the macroscale with controlled superstructures will unleash great potential for the development of smart materials. Compared to macromolecular 3D printing materials, self-assembled small-molecule-based 3D printing materials are very rare owing to the difficulties of facilitating 3D printability as well as preserving their molecular functions macroscopically. Herein, we report a general approach for the integration of functional small molecules into 3D printing materials for direct ink writing through the introduction of a supramolecular template. A variety of inorganic and organic small-molecule-based inks were 3D-printed, and their superstructures were refined by post-printing hierarchical co-assembly. Through spatial and temporal control of individual molecular events from the nano- to the macroscale, fine-tuned macroscale features were successfully installed in the monoliths.

Supported Tetrahedral Oxo-Sn Catalyst: Single Site, Two Modes of Catalysis.

Mild calcination in ozone of a (POSS)-Sn-(POSS) complex grafted on silica generated a heterogenized catalyst that mostly retained the tetrahedral coordination of its homogeneous precursor, as evidenced by spectroscopic characterizations using EXAFS, NMR, UV-vis, and DRIFT. The Sn centers are accessible and uniform and can be quantified by stoichiometric pyridine poisoning. This Sn-catalyst is active in hydride transfer reactions as a typical solid Lewis acid. However, the Sn centers can also create Brønsted acidity with alcohol by binding the alcohol strongly as alkoxide and transferring the hydroxyl H to the neighboring Sn-O-Si bond. The resulting acidic silanol is active in epoxide ring opening and acetalization reactions.