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Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo , single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.

Till date, humankind has mainly acknowledged the quenching phenomenon of graphene oxide (GO). From a fundamental science standpoint, the unique and dynamic prospects of graphene oxide have been showcased in a brief but concise manner. Worldwide research studies have proven that graphene oxide has tremendous potentiality in showcasing breakthroughs in the fields of both basic science and innovative applications. In this Perspective, the fact that, apart from the very common fluorescence quenching phenomenon, graphene oxide can also enhance fluorescence intensity, promote prototropism, demonstrate aggregation-induced emission, and itself exhibit photoluminescence properties in nonaqueous media has been highlighted. It draws attention to the fact regarding unveiling the unknown properties of graphene oxide that might be useful to scientific communities in upcoming years.

Optical imaging and spectroscopic modalities are of considerable current interest for in vivo cancer detection and image-guided surgery, but the turbid or scattering nature of biomedical tissues has severely limited their abilities to detect buried or occluded tumor lesions. Here we report the development of a dual-modality plasmonic nanostructure based on colloidal gold nanostars (AuNSs) for simultaneous surface-enhanced Raman scattering (SERS) and photoacoustic (PA) detection of tumor phantoms embedded (hidden) in ex vivo animal tissues. By using red blood cell membranes as a naturally derived biomimetic coating, we show that this class of dual-modality contrast agents can provide both Raman spectroscopic and PA signals for the detection and differentiation of hidden solid tumors with greatly improved depths of tissue penetration. Compared to previous polymer-coated AuNSs, the biomimetic coatings are also able to minimize protein adsorption and cellular uptake when exposed to human plasma without compromising their SERS or PA signals. We further show that tumor-targeting peptides (such as cyclic RGD) can be noncovalently inserted for targeting the ανβ 3 -integrin receptors expressed on metastatic cancer cells and tracked via both SERS and PA imaging (PAI). Finally, we demonstrate image-guided resections of tumor-mimicking phantoms comprising metastatic tumor cells buried under layers of skin and fat tissues (6 mm in thickness). Specifically, PAI was used to determine the precise tumor location, while SERS spectroscopic signals were used for tumor identification and differentiation. This work opens the possibility of using these biomimetic dual-modality nanoparticles with superior signal and biological stability for intraoperative cancer detection and resection.

Novel brominated flame retardants (NBFRs) have emerged as chemicals of environmental concern, as they have been widely used as an alternative to polybrominated diphenyl ethers (PBDEs). Considering the similar structural features of NBFRs and PBDEs necessitates a comprehensive investigation to understand the physicochemical relationships of these compounds and their ability to alter biological functions. In this study, we investigated the persistent nature of NBFRs in terms of thyroid-disrupting potential by understanding the structure-stability aspects using density functional theory (DFT)-based reactivity parameters and interactions via molecular docking and molecular dynamics (MD) simulations. The results indicate that the DFT-based stability descriptor (chemical hardness) is associated with the persistent nature of NBFRs. The computed molecular interaction profile revealed prominent interactions between thyroid receptor-β (TR-β) and NBFRs. Stable trajectory and interactions with TR-β were obtained with ATE, p -TBX, PBT, PBEB, and TBBPA-DBPE during 100 ns of MD simulation. The results of these studies have suggested that the presence of a higher number of halogenated atoms increases the stability vis-à-vis the persistence and endocrine disruption potential of NBFRs.

A facile novel approach of introducing dopamine and [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide via dopamine-triggered in situ synthesis into gelatin hydrogels in the presence of ZnSO 4 is presented in this study. Remarkably, the resulting hydrogels showed 99.99 and 100% antibacterial efficiency against Gram-positive and Gram-negative bacteria, respectively, making them the highest performing surfaces in their class. Furthermore, the hydrogels showed adhesive properties, self-healing ability, antifreeze properties, electrical conductivity, fatigue resistance, and mechanical stability from -100 to 80 °C. The added multifunctional performance overcomes several disadvantages of gelatin-based hydrogels such as poor mechanical properties and limited thermostability. Overall, the newly developed hydrogels show significant potential for numerous biomedical applications, such as wearable monitoring sensors and antibacterial coatings.

A major challenge in the "bottom-up" solvothermal synthesis of carbon dots (CDs) is the removal of small-molecule byproducts, noncarbonized polyamides, or other impurities that confound the optical properties. In previously reported benzene diamine-based CDs, the observed fluorescence signal already has been shown to arise from free small molecules, not from nanosized carbonized dots. Here we have unambiguously identified the small-molecule species in the synthesis of CDs starting with several isomers of benzene diamine by directly matching their NMR, mass spectrometry, and optical data with commercially available small organic molecules. By combining dialysis and chromatography, we have sufficiently purified the CD reaction mixtures to measure the CD size by TEM and STM, elemental composition, optical absorption and emission, and single-particle blinking dynamics. The results can be rationalized by electronic structure calculations on small model CDs. Our results conclusively show that the purified benzene diamine-based CDs do not emit red fluorescence, so the quest for full-spectrum fluorescence from isomers of a single precursor molecule remains open.

Real-time guidance through fluorescence imaging improves the surgical outcomes of tumor resections, reducing the chances of leaving positive margins behind. As tumors are heterogeneous, it is imperative to interrogate multiple overexpressed cancer biomarkers with high sensitivity and specificity to improve surgical outcomes. However, for accurate tumor delineation and ratiometric detection of tumor biomarkers, current methods require multiple excitation wavelengths to image multiple biomarkers, which is impractical in a clinical setting. Here, we have developed a biomimetic platform comprising near-infrared fluorescent semiconducting polymer nanoparticles (SPNs) with red blood cell membrane (RBC) coating, capable of targeting two representative cell-surface biomarkers (folate, αυβ3 integrins) using a single excitation wavelength for tumor delineation during surgical interventions. We evaluate our single excitation ratiometric nanoparticles in in vitro tumor cells, ex vivo tumor-mimicking phantoms, and in vivo mouse xenograft tumor models. Favorable biological properties (improved biocompatibility, prolonged blood circulation, reduced liver uptake) are complemented by superior spectral features: (i) specific fluorescence enhancement in tumor regions with high tumor-to-normal tissue (T/NT) ratios in ex vivo samples and (ii) estimation of cell-surface tumor biomarkers with single wavelength excitation providing insights about cancer progression (metastases). Our single excitation, dual output approach has the potential to differentiate between the tumor and healthy regions and simultaneously provide a qualitative indicator of cancer progression, thereby guiding surgeons in the operating room with the resection process.

An efficient method for the construction of hydrocarbazoles bearing three continuous sterically hindered stereocenters, two quaternary and one tertiary, via a highly diastereoselective palladium-catalyzed [4 + 2]-cycloaddition/dearomatization of 3-nitroindoles has been developed. The cycloaddition of 3-nitroindoles occurs at ambient conditions with a 1,4-zwitterionic intermediate, in situ generated from γ-methylidene-δ-valerolactones. The further synthetic utility of this method is demonstrated by the multifaceted transformations possible from the products. The catalytic asymmetric aspect of this transformation has also been explored.

An iridium-catalyzed enantioselective ring-opening of alkenyl oxiranes by unactivated carboxylic acids has been developed. The reaction undergoes at ambient conditions between an in-situ-generated chiral iridium-π-allyl complex and carboxylic acids to provide rapid access to valuable alkenyl diols in high yields. The synthetic utility of this method is demonstrated by the elaboration of the products into various medium and large ring-sized compounds that are part of biologically relevant molecules.

The reliability of molecular mechanics simulations to predict effects of ion binding to proteins depends on their ability to simultaneously describe ion-protein, ion-water, and protein-water interactions. Force fields (FFs) to describe protein-water and ion-water interactions have been constructed carefully and have also been refined routinely to improve accuracy. Descriptions for ion-protein interactions have also been refined, although in an a posteriori manner through the use of "nonbonded-fix (NB-fix)" approaches in which parameters from default Lennard-Jones mixing rules are replaced with those optimized against some reference data. However, even after NB-fix corrections, there remains a significant need for improvement. This is also true for polarizable FFs that include self-consistent inducible moments. Our recent studies on the polarizable AMOEBA FF suggested that the problem associated with modeling ion-protein interactions could be alleviated by recalibrating polarization models of cation-coordinating functional groups so that they respond better to the high electric fields present near ions. Here, we present such a recalibration of carbonyls, carboxylates, and hydroxyls in the AMOEBA protein FF and report that it does improve predictions substantially─mean absolute errors in Na + -protein and K + -protein interaction energies decrease from 8.7 to 5.3 and 9.6 to 6.3 kcal/mol, respectively. Errors are computed with respect to estimates from van der Waals-inclusive density functional theory benchmarked against high-level quantum mechanical calculations and experiments. While recalibration does improve ion-protein interaction energies, they still remain underestimated, suggesting that further improvements can be made in a systematic manner through modifications in classical formalism. Nevertheless, we show that by applying our many-body NB-fix correction to Lennard-Jones components, these errors are further reduced to 2.7 and 2.6 kcal/mol, respectively, for Na + and K + ions. Finally, we show that the recalibrated AMOEBA protein FF retains its intrinsic reliability in predicting protein structure and dynamics in the condensed phase.

Nitrous acid (HONO) is a household pollutant exhibiting adverse health effects and a major source of indoor OH radicals under a variety of lighting conditions. The present study focuses on gas-phase HONO and condensed-phase nitrite and nitrate formation on indoor surface thin films following heterogeneous hydrolysis of NO 2 , in the presence and absence of light, and nitrate (NO 3 - ) photochemistry. These thin films are composed of common building materials including zeolite, kaolinite, painted walls, and cement. Gas-phase HONO is measured using an incoherent broadband cavity-enhanced ultraviolet absorption spectrometer (IBBCEAS), whereby condensed-phase products, adsorbed nitrite and nitrate, are quantified using ion chromatography. All of the surface materials used in this study can store nitrogen oxides as nitrate, but only thin films of zeolite and cement can act as condensed-phase nitrite reservoirs. For both the photo-enhanced heterogeneous hydrolysis of NO 2 and nitrate photochemistry, the amount of HONO produced depends on the material surface. For zeolite and cement, little HONO is produced, whereas HONO is the major product from kaolinite and painted wall surfaces. An important result of this study is that surface interactions of adsorbed nitrite are key to HONO formation, and the stronger the interaction of nitrite with the surface, the less gas-phase HONO produced.

Poloxamer 407 (P-407) composed of a poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) unit has two distinct microenvironments: the interior core formed by the PPG unit and the exterior shell formed by the PEG unit. In this work, we have used two fluorescent molecules coumarin-153 and 8-anilino-1-naphthalene sulfonic acid (ANS) of contrasting natures to characterize and probe the water dynamics in the core and corona regions of the copolymer by means of spectroscopic techniques, namely, absorption, fluorescence, and time-resolved fluorescence emission spectroscopy and Fourier transform infrared (FTIR) spectroscopy. Changes in the surface morphologies were characterized by using microscopic techniques. Further, two classes of osmolytes kosmotropic (betaine and sarcosine) and chaotropic (urea) known to perturb the water structure were added to aqueous solutions of P-407. Our studies reveal that the addition of kosmotropes decreases the critical micelle temperature (CMT) of the copolymer, whereas the chaotropic osmolyte increases the CMT. Steady-state studies reveal that the addition of the osmolytes to the copolymer increases the polarity of the micelle formed and hence results in the red shift in the ANS absorbance maximum. FTIR spectroscopy reveals that kosmotropes interact with the PEG moiety of the copolymer, whereas the chaotrope interacts with both the PEG and PPG moieties of the copolymer. Solvent relaxation studies produced less changes upon the addition of the kosmotropes, whereas a greater change in the relaxation time was observed in the presence of the chaotrope.

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.

Vertically oriented graphene (VG) has attracted attention for years, but the growth mechanism is still not fully revealed. The electric field may play a role, but the direct evidence and exactly what role it plays remains unclear. Here, we conduct a systematic study and find that in plasma-enhanced chemical vapor deposition, the VG growth preferably occurs at spots where the local field is stronger, for example, at GaN nanowire tips. On almost round-shaped nanoparticles, instead of being perpendicular to the substrate, the VG grows along the field direction, that is, perpendicular to the particles' local surfaces. Even more convincingly, the sheath field is screened to different degrees, and a direct correlation between the field strength and the VG growth is observed. Numerical calculation suggests that during the growth, the field helps accumulate charges on graphene, which eventually changes the cohesive graphene layers into separate three-dimensional VG flakes. Furthermore, the field helps attract charged precursors to places sticking out from the substrate and makes them even sharper and turn into VG. Finally, we demonstrate that the VG-covered nanoparticles are benign to human blood leukocytes and could be considered for drug delivery. Our research may serve as a starting point for further vertical two-dimensional material growth mechanism studies.

We disclose for the first time a facile synthetic methodology for the preparation of multicolor carbon dots (CDs) from a single source barring any chromatographic separations. This was achieved via sequential intraparticle cross-linking of surface abundant carboxylic acid groups on the CDs synthesized from a precursor to control their photoluminescence (PL) spectra as well as affect their degree of cellular internalization in cancer cells. The change in PL spectra with sequential cross-linking was projected by theoretical density functional theory (DFT) studies and validated by multiple characterization tools such as X-ray photoelectron spectroscopy (XPS), PL spectroscopy, ninhydrin assay, etc. The variation in cellular internalization of these cross-linked CDs was demonstrated using inhibitor assays, confocal microscopy, and flow cytometry. We supplemented our findings with high-resolution dark-field imaging to visualize and confirm the colocalization of these CDs into distinct intracellular compartments. Finally, to prove the surface-state controlled PL mechanisms of these cross-linked CDs, we fabricated a triple-channel sensor array for the identification of different analytes including metal ions and biologically relevant proteins.

Stimuli-responsive, on-demand release of drugs from drug-eluting depots could transform the treatment of many local diseases, providing intricate control over local dosing. However, conventional on-demand drug release approaches rely on locally implanted drug depots, which become spent over time and cannot be refilled or reused without invasive procedures. New strategies to noninvasively refill drug-eluting depots followed by on-demand release could transform clinical therapy. Here we report an on-demand drug delivery paradigm that combines bioorthogonal click chemistry to locally enrich protodrugs at a prelabeled site and light-triggered drug release at the target tissue. This approach begins with introduction of the targetable depot through local injection of chemically reactive azide groups that anchor to the extracellular matrix. The anchored azide groups then capture blood-circulating protodrugs through bioorthogonal click chemistry. After local capture and retention, active drugs can be released through external light irradiation. In this report, a photoresponsive protodrug was constructed consisting of the chemotherapeutic doxorubicin (Dox), conjugated to dibenzocyclooctyne (DBCO) through a photocleavable ortho-nitrobenzyl linker. The protodrug exhibited excellent on-demand light-triggered Dox release properties and light-mediated in vitro cytotoxicity in U87 glioblastoma cell lines. Furthermore, in a live animal setting, azide depots formed in mice through intradermal injection of activated azide-NHS esters. After i.v. administration, the protodrug was captured by the azide depots with intricate local specificity, which could be increased with multiple refills. Finally, doxorubicin could be released from the depot upon light irradiation. Multiple rounds of depot refilling and light-mediated release of active drug were accomplished, indicating that this system has the potential for multiple rounds of treatment. Taken together, these in vitro and in vivo proof of concept studies establish a novel method for in vivo targeting and on-demand delivery of cytotoxic drugs at target tissues.

Nitrous acid (HONO) is a toxic household pollutant and a major source of indoor OH radicals. The high surface-to-volume ratio and diverse lighting conditions make the indoor photochemistry of HONO complex. This study demonstrates surface uptake of NO 2 and gaseous HNO 3 followed by gas-phase HONO generation on gypsum surfaces, model system for drywall, under reaction conditions appropriate for an indoor air environment. Tens of parts per billion of steady-state HONO are detected under these experimental conditions. Mechanistic insight into this heterogeneous photochemistry is obtained by exploring the roles of material compositions, relative humidities, and light sources. NO 2 and HNO 3 are adsorbed onto drywall surfaces, which can generate HONO under illumination and under dark conditions. Photoenhanced HONO generation is observed for illumination with a solar simulator as well as with the common indoor light sources such as compact fluorescence light and incandescent light bulbs. Incandescent light sources release more HONO and NO 2 near the light source compared to the solar radiation. Overall, HONO production on the gypsum surface increases with the increase of RH up to 70% relative humidity; above that, the gaseous HONO level decreases due to surface loss. Heterogeneous hydrolysis of NO 2 is predicted to be the dominant HONO generation channel, where NO 2 is produced through the photolysis of surface-adsorbed nitrates. This hydrolysis reaction predominantly occurs in the first layer of surface-adsorbed water.

Yersinia pestis is a Gram-negative bacterium that is the causative agent of plague and is widely recognized as a potential biological weapon. Due to the high fatality rate of plague when diagnosis is delayed, the development of rapid, sensitive, specific, and cost-effective methods is needed for its diagnosis. The Y. pestis low calcium response V (LcrV) protein has been identified as a potential microbial biomarker for the diagnosis of plague. In this paper, we present a highly sensitive, paper-based, vertical flow immunoassay (VFI) prototype for the detection of LcrV and the diagnosis of plague. An antigen-capture assay using monoclonal antibodies is employed to capture and detect the LcrV protein, using a colorimetric approach. In addition, the effect of miniaturizing the VFI device is explored based on two different sizes of VFI platforms, denoted as "large VFI" and "mini VFI." Also, a comparative analysis is performed between the VFI platform and a lateral flow immunoassay (LFI) platform to exhibit the improved assay sensitivity suitable for point-of-care (POC) diagnostics. The analytical sensitivity or limit of detection (LOD) in the mini VFI is approximately 0.025 ng/mL, that is, 10 times better than that of the large VFI platform or 80 times over a standard lateral flow configuration. The low LOD of the LcrV VFI appears to be highly suitable for testing clinical samples and potentially diagnosing plague at earlier time points. In addition, optimization of the gold nanoparticle (AuNP) concentration, nanomaterial plasmonic properties, and flow velocity analysis could improve the performance of the VFI. Furthermore, we developed automated image analysis software that shows potential for integrating the diagnostic system into a smartphone. These methods and findings demonstrate that the VFI platform is a highly sensitive device for detecting the LcrV and potentially many other biomarkers.

Abnormal concentrations of a specific protein or the presence of some biomarker proteins may indicate life-threatening diseases. Pattern-based detection of specific analytes using affinity-regulated receptors is one of the potential alternatives to specific antigen-antibody-based detection. In this report, we have schemed a sensor array by using various functionalized two-dimensional (2D)-MoS 2 nanosheets and green fluorescent protein (GFP) as the receptor and the signal transducer, respectively. Two-dimensional MoS 2 has been used as a promising candidate for recognition of the bioanalytes because of its high surface-to-volume ratio compared to those of other nanomaterials. Easy surface tunability of this material provides additional advantages to analyze the target of interest. The optimized 2D-MoS 2 -GFP conjugates are able to discriminate 15 different proteins at 50 nM concentration with a detection limit of 1 nM. Moreover, proteins in the binary mixture and in the presence of serum were discriminated successfully. Ten different proteins in serum media at relevant concentrations were classified successfully with 100% jackknifed classification accuracy, which proves the potentiality of the above system. We have also implemented and discussed the implication of using different machine learning models on the pattern recognition problem associated with array-based sensing., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Additive manufacturing commonly known as 3D printing has numerous applications in several domains including material and biomedical technologies and has emerged as a tool of capabilities by providing fast, highly customized, and cost-effective solutions. However, the impact of the printing materials and chemicals present in the printing fumes has raised concerns about their adverse potential affecting humans and the environment. Thus, it is necessary to understand the properties of the chemicals emitted during additive manufacturing for developing safe and biocompatible fibers having controlled emission of fumes including its sustainable usage. Therefore, in this study, we have developed a computational predictive risk-assessment framework on the comprehensive list of chemicals released during 3D printing using the acrylonitrile butadiene styrene (ABS) filament. Our results showed that the chemicals present in the fumes of the ABS-based fiber used in additive manufacturing have the potential to lead to various toxicity end points such as inhalation toxicity, oral toxicity, carcinogenicity, hepatotoxicity, and teratogenicity. Moreover, because of their absorption, distribution in the body, metabolism, and excretion properties, most of the chemicals exhibited a high absorption level in the intestine and the potential to cross the blood-brain barrier. Furthermore, pathway analysis revealed that signaling like alpha-adrenergic receptor signaling, heterotrimeric G-protein signaling, and Alzheimer's disease-amyloid secretase pathway are significantly overrepresented given the identified target proteins of these chemicals. These findings signify the adversities associated with 3D printing fumes and the necessity for the development of biodegradable and considerably safer fibers for 3D printing technology.

In this work, a nanoscale device architecture is demonstrated for a UV photodetector application on sapphire (0001), incorporating the plasmonic hybrid nanoparticles (HNPs), graphene quantum dots (GQDs), and titanium oxide (TiO 2 ) for the first time. The hybrid GQDs/TiO 2 /HNPs photodetector exhibits the photocurrent of 1.58 × 10 -5 A under the 1.64 mW/mm 2 of 275 nm illumination at 10 V, which is around two order increase from the bare TiO 2 device. The proposed architecture demonstrates a low dark current of ∼1 × 10 -10 A at 10 V and thus the device demonstrates an excellent photo to dark current ratio along with the improved rise and fall time on the order of several hundred millisecond. The enhanced performance of device architecture is attributed to the efficient utilization of localized surface plasmon resonance (LSPR) induced hot carriers as well as scattered photons from the plasmonic HNPs that are fully encapsulated by the photoactive TiO 2 layers. Furthermore, the addition of GQDs on the TiO 2 can offer an additional photon absorption pathway. The proposed hybrid architecture of GQDs/TiO 2 /HNPs demonstrates the integration of the photon absorption and carrier transfer properties of plasmonic HNPs, GQDs, and TiO 2 for an enhanced ultraviolet (UV) photoresponse. The photocurrent enhancement mechanisms of the hybrid device architecture are thoroughly investigated based on the finite-difference time domain (FDTD) simulation along with the energy band analysis. This work demonstrates a great potential of the hybrid device architecture for high-performance UV photodetectors.

Isoniazid is an important first-line antitubercular drug used in the treatment of all major clinical manifestations of tuberculosis, including both pulmonary and cerebral diseases. However, it is associated with significant drawbacks due to its inherent hydrophilic nature, including poor gut permeability and an inability to cross the lipophilic blood-brain barrier, which, in turn, limit its clinical efficacy. We hypothesized that the addition of a hydrophobic moiety to this molecule would help overcome these limitations and improve its bioavailability in the bloodstream. Therefore, we designed a stable, covalently linked lipid-drug conjugate of isoniazid with a short lipid chain of stearoyl chloride. Further, lipid-drug conjugate nanoparticles were synthesized from the bulk lipid-drug conjugate by a cold high-pressure homogenization method enabled by the optimized use of aqueous surfactants. The nanoparticle formulation was characterized systematically using in vitro physicochemical analytical methods, including atomic force microscopy, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, attenuated total reflectance, particle size, ζ-potential, and drug release studies, and the mechanism of drug release kinetics. These investigations revealed that the lipid-drug conjugate nanoparticles were loaded with an appreciable amount of isoniazid conjugate (92.73 ± 6.31% w/w). The prepared lipid-drug conjugate nanoparticles displayed a uniform shape with a smooth surface having a particle size of 124.60 ± 5.56 nm. In vitro drug release studies showed sustained release up to 72 h in a phosphate-buffered solution at pH 7.4. The release profile fitted to various known models of release kinetics revealed that the Higuchi model of diffusion kinetics was the best-fitting model ( R 2 = 0.9929). In addition, confocal studies showed efficient uptake of lipid-drug conjugate nanoparticles by THP-1 macrophages presumably because of increased lipophilicity and anionic surface charge. This was followed by progressive intracellular trafficking into endosomal and lysosomal vesicles and colocalization with intravesicular compartmental proteins associated with mycobacterium tuberculosis pathogenesis, including CD63, LAMP-2, EEA1, and Rab11. The developed lipid-drug conjugate nanoparticles, therefore, displayed significant ability to improve the intracellular delivery of a highly water-soluble drug such as isoniazid., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Fluorescent array-based sensing is an emerging differential sensing platform for sensitive detection of analytes in a complex environment without involving a conventional "lock and key" type-specific interaction. These sensing techniques mainly rely on different optical pattern generation from a sensor array and their pattern recognition to differentiate analytes. Currently emerging, compelling pattern-recognition method, Machine Learning (ML), enables a machine to "learn" a pattern by training without having the recognition method explicitly programmed into it. Thus, ML has an enormous potential to analyze these sensing data better than widely used statistical pattern-recognition methods. Here, an array-based sensor using easy-to-synthesize carbon dots with varied surface functionality is reported, which can differentiate between eight different proteins at 100 nM concentration. The utility of using machine learning algorithms in pattern recognition of fluorescence signals from the array has also been demonstrated. In analyzing the array-based sensing data, Machine Learning algorithms like "Gradient-Boosted Trees" have achieved a 100% prediction efficiency compared to inferior-performing classical statistical method "Linear Discriminant Analysis".

Alkene ozonolysis, an important source of hydroxyl (OH) radicals in the Earth's troposphere, proceeds through unimolecular decay of Criegee intermediates. In this work, infrared activation of the methyl-substituted Criegee intermediate, syn-CH 3 CHOO, in the CH stretch fundamental region (2850-3150 cm -1 ) is shown to result in unimolecular decay to OH radical products. These excitation energies correspond to only half of the transition state barrier height, and thus the resultant 1,4 H atom transfer that leads to OH products occurs exclusively by quantum mechanical tunneling. Infrared action spectra recorded with UV laser-induced fluorescence detection of the OH products reveal the four CH stretch fundamentals and CO stretch overtone predicted to have strong transition strength. The vibrational band origins, relative intensities, and transition types derived from rotational band contour analyses are in good accord with theory. Distinctly different Lorentzian line broadening of the observed features is attributed to mode-specific anharmonic couplings predicted theoretically between spectroscopically bright and nearby dark states. The measured OH product state distribution shows a strong λ-doublet preference arising from pπ orbital alignment, which is indicative of the vinyl hydroperoxide intermediate along the reaction pathway. The unimolecular decay of syn-CH 3 CHOO at ca. 3000 cm -1 is predicted to be quite slow (ca. 10 5 s -1 ) using statistical Rice-Ramsperger-Kassel-Marcus theory with tunneling and much slower than observed at higher energies.

In this investigation, we report the synthesis of biodiesel using benzimidazolium-based brønsted acid ionic liquid (BBAIL) catalyst under the influence of ultrasonication. The prepared BBAIL catalyst was characterized by Fourier transform infrared and NMR spectroscopy techniques, and its acidity was determined by the Hammett method with 4-nitroaniline as the indicator. Ultrasonicator horn (22 kHz, 500 W) was used in this work with an on-off cycle of 50-20 s at 70% amplitude. The highest biodiesel yield of 96% was achieved by ultrasonication when 1:10 molar ratio of castor oil to methyl alcohol was used at 50 °C temperature with 9 mol % of the catalyst in just 90 min, which is about 10 times lesser than the process without ultrasonication. At similar conditions, 96% biodiesel yield was obtained in 14 h without ultrasonication. In summary, ultrasonication proved to be an efficient way to improve biodiesel synthesis in less time and BBAIL showed excellent activity toward the conversion of glycerides to synthesize biodiesel. Other important highlights are easy separation of the catalyst and recyclability up to three cycles with small decrease in its activity., Competing Interests: The authors declare no competing financial interest.

Two-dimensional transition metal dichalcogenides (TMDs), such as MoS 2 , generally exist in two different polymorphic structures, metallic (1T phase) and semiconducting (2H phase). In context of their wide spectrum of applications ranging from electronic to biomedicine, the aspects of ligand conjugation and solution processability are highly significant. In addition, the assessment of their antibacterial property and biocompatibility is equally important to explore their biomedical applications. Here we report a new method for the exfoliation and direct functionalization of 2H-MoS 2 using surfactant molecules with thiol functionality. We found that the exfoliated MoS 2 using thiolated ligands are functionalized with desired functionality and the processing scheme can be extended to other TMDs. Functionalized 2H-MoS 2 exhibits highly enhanced antibacterial efficiency compared to similarly functionalized metallic 1T-MoS 2 against pathogenic bacteria. The newly synthesized functionalized 2H-MoS 2 exhibits better hemocompatibility, which makes it suitable for in vivo applications. This convenient functionalization method opens the door for many other applications of functionalized semiconducting 2H-MoS 2 and other TMDs.

The reaction of ozone with isoprene, one of the most abundant volatile organic compounds in the atmosphere, produces three distinct carbonyl oxide species (RR'COO) known as Criegee intermediates: formaldehyde oxide (CH 2 OO), methyl vinyl ketone oxide (MVK-OO), and methacrolein oxide (MACR-OO). The nature of the substituents (R,R' = H, CH 3 , CH═CH 2 ) and conformations of the Criegee intermediates control their subsequent chemistry in the atmosphere. In particular, unimolecular decay of MVK-OO is predicted to be the major source of hydroxyl radicals (OH) in isoprene ozonolysis. This study reports the initial laboratory synthesis and direct detection of MVK-OO through reaction of a photolytically generated, resonance-stabilized monoiodoalkene radical with O 2 . MVK-OO is characterized utilizing infrared (IR) action spectroscopy, in which IR activation of MVK-OO with two quanta of CH stretch at ca. 6000 cm -1 is coupled with ultraviolet detection of the resultant OH products. MVK-OO is identified by comparison of the experimentally observed IR spectral features with theoretically predicted IR absorption spectra. For syn-MVK-OO, the rate of appearance of OH products agrees with the unimolecular decay rate predicted using statistical theory with tunneling. This validates the hydrogen atom transfer mechanism and computed transition-state barrier (18.0 kcal mol -1 ) leading to OH products. Theoretical calculations reveal an additional roaming pathway between the separating radical fragments, which results in other products. Master equation modeling yields a thermal unimolecular decay rate for syn-MVK-OO of 33 s -1 (298 K, 1 atm). For anti-MVK-OO, theoretical exploration of several unimolecular decay pathways predicts that isomerization to dioxole is the most likely initial step to products.

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Biofouling commonly occurs on carbonaceous capacitive deionization electrodes in the process of treating natural waters. Although previous work reported the effect of electric fields on bacterial mortality for a variety of medical and engineered applications, the effect of electrode surface properties and the magnitude and polarity of applied electric fields on biofilm development has not been comprehensively investigated. This paper studies the formation of a Pseudomonas aeruginosa biofilm on a Papyex graphite (PA) and a carbon aerogel (CA) in the presence and the absence of an electric field. The experiments were conducted using a two-electrode flow cell with a voltage window of ±0.9 V. The CA was less susceptible to biofilm formation compared to the PA due to its lower surface roughness, lower hydrophobicity, and significant antimicrobial properties. For both positive and negative applied potentials, we observed an inverse relationship between biofilm formation and the magnitude of the applied potential. The effect is particularly strong for the CA electrodes and may be a result of cumulative effects between material toxicity and the stress experienced by cells at high applied potentials. Under the applied potentials for both electrodes, high production of endogenous reactive oxygen species (ROS) was indicative of bacterial stress. For both electrodes, the elevated specific ROS activity was lowest for the open circuit potential condition, elevated when cathodically and anodically polarized, and highest for the ±0.9 V cases. These high applied potentials are believed to affect the redox potential across the cell membrane and disrupt redox homeostasis, thereby inhibiting bacterial growth.

In view of the implications of inherent resistance of pathogenic bacteria, especially ESKAPE pathogens toward most of the commercially available antibiotics and the importance of these bacteria-induced biofilm formation leading to chronic infection, it is important to develop new-generation synthetic materials with greater efficacy toward antibacterial property. In addressing this issue, this paper reports a proof-of-principle study to evaluate the potential of functionalized two-dimensional chemically exfoliated MoS 2 (ce-MoS 2 ) toward inhibitory and bactericidal property against two representative ESKAPE pathogenic strain-a Gram-positive Staphylococcus aureus (MRSA) and a Gram-negative Pseudomonas aeruginosa. More significantly, the mechanistic study establishes a different extent of oxidative stress together with rapid membrane depolarization in contact with ce-MoS 2 having ligands of varied charge and hydrophobicity. The implication of our results is discussed in the light of the lack of survivability of planktonic bacteria and biofilm destruction in vitro. A comparison with widely used small molecules and other nanomaterial-based therapeutics conclusively establishes a better efficacy of 2D ce-MoS 2 as a new class of antibiotics.

Dynamics of collisions between structured molecular species quickly become complex as molecules become large. Reactions of methane with halogen and oxygen atoms serve as model systems for polyatomic molecule chemical dynamics, and replacing the atomic reagent with a diatomic radical affords further insights. A new, full-dimensional potential energy surface for collisions between CN + CH4 to form HCN + CH3 is developed and then used to perform quasi-classical simulations of the reaction. Coupled-cluster energies serve as input to an empirical valence bonding (EVB) model, which provides an analytical function for the surface. Efficient sampling permits simulation of velocity-map ion images and exploration of dynamics over a range of collision energies. Reaction populates HCN vibration, and energy partitioning changes with collision energy. The reaction cross-section depends on the orientation of the diatomic CN radical. A two-dimensional extension of the cone of acceptance for an atom in the line-of-centers model appropriately describes its reactivity. The simulation results foster future experiments and diatomic extensions to existing atomic models of chemical collisions and reaction dynamics.

Microbial fuel cells (MFCs) are emerging as a sustainable technology for waste to energy conversion where electrode materials play a vital role on its performance. Platinum (Pt) is the most common material used as cathode catalyst in the MFCs. However, the high cost and low earth abundance associated with Pt prompt the researcher to explore inexpensive catalysts. The present study demonstrates a noble metal-free MFC using a manganese ferrite (MnFe2O4)/polyaniline (PANI)-based electrode material. The MnFe2O4 nanoparticles (NPs) and MnFe2O4 NPs/PANI hybrid composite not only exhibited superior oxygen reduction reaction (ORR) activity for the air cathode but also enhanced anode half-cell potential upon modifying carbon cloth anode in the single-chambered MFC. This is attributed to the improved extracellular electron transfer of exoelectrogens due to Fe(3+) in MnFe2O4 and its capacitive nature. The present work demonstrates for the first time the dual property of MnFe2O4 NPs/PANI, i.e., as cathode catalyst and an anode modifier, thereby promising cost-effective MFCs for practical applications.

Quasi-classical trajectory calculations on a newly constructed and full-dimensionality potential energy surface (PES) examine the dynamics of the reaction of Cl atoms with propene. The PES is an empirical valence bond (EVB) fit to high-level ab initio energies and incorporates deep potential energy wells for the 1-chloropropyl and 2-chloropropyl radicals, a direct H atom abstraction route to HCl + allyl radical (CH2CHCH2(•)) products (Δ(r)H(298K)(⊖) = −63.1 kJ mol(-1)), and a pathway connecting these regions. In total, 94 000 successful reactive trajectories were used to compute distributions of angular scattering and HCl vibrational and rotational level populations. These measures of the reaction dynamics agree satisfactorily with available experimental data. The dominant reaction pathway is direct abstraction of a hydrogen atom from the methyl group of propene occurring in under 500 fs. Less than 10% of trajectories follow an addition–elimination route via the two isomeric chloropropyl radicals. Large amplitude motions of the Cl about the propene molecular framework couple the addition intermediates to the direct abstraction pathway. The EVB method provides a good description of the complicated PES for the Cl + propene reaction despite fitting to a limited number of ab initio points, with the further advantage that dynamics specific to certain mechanisms can be studied in isolation by switching off coupling terms in the EVB matrix connecting different regions of the PES.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

FHA domains are phosphoThr recognition modules found in diverse signaling proteins, including kinase-associated protein phosphatase (KAPP) from Arabidopsis thaliana. The kinase-interacting FHA domain (KI-FHA) of KAPP targets it to function as a negative regulator of some receptor-like kinase (RLK) signaling pathways important in plant development and environmental responses. To aid in the identification of potential binding sites for the KI-FHA domain, we predicted (i) the structure of a representative KAPP-binding RLK, CLAVATA1, and (ii) the functional surfaces of RLK kinase domains using evolutionary trace analysis. We selected phosphopeptides from KAPP-binding Arabidopsis RLKs for in vitro studies of association with KI-FHA from KAPP. Three phosphoThr peptide fragments from the kinase domain of CLV1 or BAK1 were found to bind KI-FHA with KD values of 8-20 microM, by NMR or titration calorimetry. Their affinity is driven by favorable enthalpy and solvation entropy gain. Mutagenesis of these three threonine sites suggests Thr546 in the C-lobe of the BAK1 kinase domain to be a principal but not sole site of KI-FHA binding in vitro. The brassinosteroid receptor BRI1 and KAPP are shown to associate in vivo and in vitro. Further genetic studies indicate that KAPP may be a negative regulator of the BRI1 signaling transduction pathway. 15N-Labeled KI-FHA was titrated with the GST-BRI1 kinase domain and monitored by NMR. BRI1 interacts with the same 3/4, 4/5, 6/7, 8/9, and 10/11 recognition loops of KI-FHA, with similar affinity as the phosphoThr peptides.

A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.