Light-Induced Self-Assembled Polydiacetylene/Carbon Dot Functional "Honeycomb".

The design of functional supramolecular assemblies from individual molecular building blocks is a fundamental challenge in chemistry and material science. We report on the fabrication of "honeycomb" films by light-induced coassembly of diacetylene derivatives and carbon dots. Specifically, modulating noncovalent interactions between the carbon dots, macrocyclic diacetylene, and anthraquinone diacetylene facilitates formation of thin films exhibiting a long-range, uniform pore structure. We show that light irradiation at distinct wavelengths plays a key role in the assembly process and generation of unique macro-porous morphology, by both initiating interactions between the carbon dots and the anthraquinone moieties and giving rise to the topotactic polymerization of the polydiacetylene network. We further demonstrate utilization of the macro-porous film as a photocatalytic platform for water pollutant degradation and as potential supercapacitor electrodes, both applications taking advantage of the high surface area, hydrophobicity, and pore structure of the film.

Functional redundancy and formin-independent localization of tropomyosin isoforms in Saccharomyces cerevisiae.

Tropomyosin is an actin binding protein which protects actin filaments from cofilin-mediated disassembly. Distinct tropomyosin isoforms have long been hypothesized to differentially sort to subcellular actin networks and impart distinct functionalities. Nevertheless, a mechanistic understanding of the interplay between Tpm isoforms and their functional contributions to actin dynamics has been lacking. In this study, we present acetylation-mimic engineered mNeonGreen-Tpm fusion proteins that exhibit complete functionality as a sole copy, surpassing limitations of existing probes and enabling real-time dynamic tracking of Tpm-actin filaments in vivo. Using these functional Tpm fusion proteins, we find that both Tpm1 and Tpm2 indiscriminately bind to actin filaments nucleated by either formin isoform- Bnr1 and Bni1 in vivo, in contrast to the long-held paradigm of Tpm-formin pairing. We also show that Tpm2 can protect and organize functional actin cables in absence of Tpm1. Overall, our work supports a concentration-dependent and formin-independent model of Tpm-actin binding and demonstrates for the first time, the functional redundancy of the paralog Tpm2 in actin cable maintenance in S. cerevisiae.

Controlling the counterintuitive optical repulsive thrust of nano dimers with counter propagating type waves and background medium.

This work focuses on the utilization of counter-propagating plane waves for optical manipulation, which provides a unique approach to control the behavior of Rayleigh and Dipolar nanoparticles immersed in a homogeneous or heterogeneous medium. Our study presents an interesting finding of a repulsive force between plasmonic-chiral heterodimers where the particles move away from each other in both near and far field regions. Interestingly, this repulsive thrust supports the wave like nature of light for the case of homogeneous background but particle type nature of light for heterogenous background. At first, we have investigated the theory underlying the optical trapping of the chiral particle and the impact of this phenomenon on the overall repulsive behavior of the heterodimers placed in air (homogeneous) background. After that, our proposed set-up has further been investigated putting in air-water interface (heterogenous background) and by varying light angle only a little bit. Our observation for this interface case is suggesting the transfer of Minkowski momentum of photon to each optically pulled Rayleigh or dipolar particle of the dimer set, which ultimately causes a broad-band giant repulsive thrust of the dimers. However, in absence of the other particle in the cluster, a single half-immersed particle does not experience the pulling force for the broad-band spectrum. The 'common' reason of the observed repulsive thrust of the dimers for both the aforementioned cases has been attributed to "modified" longitudinal Optical Binding Force (OBF). Technically, this work may open a new way to control the repulsion and attraction between the nanoparticles both in near and far field regions by utilizing the background and the counter-propagating waves. We also believe that this work manifests a possible simple set-up, which will support to observe a background dependent wave 'or' particle nature of light experimentally.

Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy.

Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.

Rapid eye movement sleep loss associated cytomorphometric changes and neurodegeneration.

Rapid eye movement sleep (REMS) is essential for leading normal healthy living at least in higher-order mammals, including humans. In this review, we briefly survey the available literature for evidence linking cytomorphometric changes in the brain due to loss of REMS. As a mechanism of action, we add evidence that REMS loss elevates noradrenaline (NA) levels in the brain, which affects neuronal cytomorphology. These changes may be a compensatory mechanism as the changes return to normal after the subjects recover from the loss of REMS or if during REMS deprivation, the subjects are treated with NA-adrenoceptor antagonist prazosin (PRZ). We had proposed earlier that one of the fundamental functions of REMS is to maintain the level of NA in the brain. We elaborate on this idea to propose that if REMS loss continues without recovery, the sustained level of NA breaks down neurophysiologically active compensatory mechanism/s starting with changes in the neuronal cytomorphology, followed by their degeneration, leading to acute and chronic pathological conditions. Identification of neuronal cytomorphological changes could prove to be of significance for predicting future neuronal (brain) damage as well as an indicator for REMS health. Although current brain imaging techniques may not enable us to visualize changes in neuronal cytomorphology, given the rapid technological progress including use of artificial intelligence, we are optimistic that it may be a reality soon. Finally, we propose that maintenance of optimum REMS must be considered a criterion for leading a healthy life.

Mechanism of Tumor-Platelet Communications in Cancer.

BACKGROUND: Thrombosis is one of the main complications in cancer patients often leading to mortality. However, the mechanisms underlying platelet hyperactivation are poorly understood. METHODS: Murine and human platelets were isolated and treated with small extracellular vesicles (sEVs) from various cancer cell lines. The effects of these cancer-sEVs on platelets were evaluated both in vitro and in vivo using various approaches, including the detection of cancer-sEV-specific markers in murine platelets and patient samples, measurement of platelet activation and thrombosis assays. Signaling events induced by cancer-sEVs and leading to platelet activation were identified, and the use of blocking antibodies to prevent thrombosis was demonstrated. RESULTS: We demonstrate that platelets very effectively take up sEVs from aggressive cancer cells. The process of uptake is fast, proceeds effectively in circulation in mice, and is mediated by the abundant sEV membrane protein-CD63. The uptake of cancer-sEVs leads to the accumulation of cancer cell-specific RNA in platelets in vitro and in vivo. The human prostate cancer-sEV-specific RNA marker PCA3 is detected in platelets of ~70% of prostate cancer patients. This was markedly reduced after prostatectomy. In vitro studies showed that platelet uptake of cancer-sEVs induces strong platelet activation in a CD63-RPTPα (receptor-like protein tyrosine phosphatase alpha)-dependent manner. In contrast to physiological agonists ADP and thrombin, cancer-sEVs activate platelets via a noncanonical mechanism. Intravital studies demonstrated accelerated thrombosis both in murine tumor models and in mice that received intravenous injections of cancer-sEVs. The prothrombotic effects of cancer-sEVs were rescued by blocking CD63. CONCLUSIONS: Tumors communicate with platelets by means of sEVs, which deliver cancer markers and activate platelets in a CD63-dependent manner leading to thrombosis. This emphasizes the diagnostic and prognostic value of platelet-associated cancer markers and identifies new pathways for intervention.

Organic Supercapacitors as the Next Generation Energy Storage Device: Emergence, Opportunity, and Challenges.

Harnessing new materials for developing high-energy storage devices set off research in the field of organic supercapacitors. Various attractive properties like high energy density, lower device weight, excellent cycling stability, and impressive pseudocapacitive nature make organic supercapacitors suitable candidates for high-end storage device applications. This review highlights the overall progress and future of organic supercapacitors. Sustainable energy production and storage depend on low cost, large supercapacitor packs with high energy density. Organic supercapacitors with high pseudocapacitance, lightweight form factor, and higher device potential are alternatives to other energy storage devices. There are many recent ongoing research works that focus on organic electrolytes along with the material aspect of organic supercapacitors. This review summarizes the current research status and the chemistry behind the storage mechanism in organic supercapacitors to overcome the challenges and achieve superior performance for future opportunities.

Design and evaluation of neutralizing and fusion inhibitory peptides to Crimean-Congo hemorrhagic fever virus.

Crimean-Congo hemorrhagic fever (CCHF) is a medically relevant tick-borne viral disease caused by the Bunyavirus, Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is endemic to Asia, the Middle East, South-eastern Europe, and Africa and is transmitted in enzootic cycles among ticks, mammals, and birds. Human infections are mostly subclinical or limited to mild febrile illness. Severe disease may develop, resulting in multi-organ failure, hemorrhagic manifestations, and case-fatality rates up to 30%. Despite the widespread distribution and life-threatening potential, no treatments have been approved for CCHF. Antiviral inhibitory peptides, which antagonize viral entry, are licensed for clinical use in certain viral infections and have been experimentally designed against human pathogenic bunyaviruses, with in vitro and in vivo efficacies. We designed inhibitory peptides against CCHFV with and without conjugation to various polyethylene glycol and sterol groups. These additions have been shown to enhance both cellular uptake and antiviral activity. Peptides were evaluated against pseudotyped and wild-type CCHFV via neutralization tests, Nairovirus fusion assays, and cytotoxicity profiling. Four peptides neutralized CCHFV with two of these peptides shown to inhibit viral fusion. This work represents the development of experimental countermeasures for CCHF, describes a nairovirus immunofluorescence fusion assay, and illustrates the utility of pseudotyped CCHFV for the screening of entry antagonists at low containment settings for CCHF.

Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein.

Measles virus (MeV) infection remains a significant public health threat despite ongoing global efforts to increase vaccine coverage. As eradication of MeV stalls, and vulnerable populations expand, effective antivirals against MeV are in high demand. Here, we describe the development of an antiviral peptide that targets the MeV fusion (F) protein. This antiviral peptide construct is composed of a carbobenzoxy-d-Phe-l-Phe-Gly (fusion inhibitor peptide; FIP) conjugated to a lipidated MeV F C-terminal heptad repeat (HRC) domain derivative. Initial in vitro testing showed high antiviral potency and specific targeting of MeV F-associated cell plasma membranes, with minimal cytotoxicity. The FIP and HRC-derived peptide conjugates showed synergistic antiviral activities when administered individually. However, their chemical conjugation resulted in markedly increased antiviral potency. In vitro mechanistic experiments revealed that the FIP-HRC lipid conjugate exerted its antiviral activity predominantly through stabilization of the prefusion F, while HRC-derived peptides alone act predominantly on the F protein after its activation. Coupled with in vivo experiments showing effective prevention of MeV infection in cotton rats, FIP-HRC lipid conjugates show promise as potential MeV antivirals via specific targeting and stabilization of the prefusion MeV F structure.

Circulating CD36 is increased in hyperlipidemic mice: Cellular sources and triggers of release.

CD36 is a multifunctional transmembrane glycoprotein abundantly expressed in several cell types. Recent studies have identified CD36 in circulation (cCD36) in several chronic inflammatory diseases, including type 2 diabetes and chronic kidney disease, and proposed cCD36 to be a biomarker of disease activity. Whether cCD36 is present in hyperlipidemia, a condition characterized by oxidative stress and low-grade inflammation, is not known. In addition, the cellular origin of cCD36 and triggers of CD36 release have not been elucidated. We now demonstrate that plasma cCD36 level is increased in hyperlipidemic ApoE-/- and Ldlr-/- mice. Using several cell-specific CD36 knockout mice, we showed that multiple cell types contribute to cCD36 generation in hyperlipidemic conditions, with a particularly strong contribution from endothelial cells. In vitro studies have demonstrated that oxidized phospholipids, ligands for CD36 (oxPCCD36), which are known to accumulate in circulation in hyperlipidemia, induce a robust release of CD36 from several cell types. In vivo studies have demonstrated CD36 release into the circulation of WT mice in response to tail-vein injection of oxPCCD36. These findings document the presence of cCD36 in hyperlipidemia and identify a link between cCD36 and oxidized phospholipids generated under oxidative stress and low-grade inflammation associated with hyperlipidemia.

Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets.

Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.

Hierarchical cage-frame type nanostructure of CeO2 for bio sensing applications: from glucose to protein detection.

Self-assembled hierarchical nanostructures are slowly superseding their conventional counterparts for use in biosensors. These morphologies show high surface area with tunable porosity and packing density. Modulating the interfacial interactions and subsequent particle assembly occurring at the water-and-oil interface in inverse miniemulsions, are amongst the best strategies to stabilize various type of hollow nanostructures. The paper presents a successful protocol to obtain CeO2 hollow structures based biosensors that are useful for glucose to protein sensing. The fabricated glucose sensor is able to deliver high sensitivity (0.495 µA cm-2 nM-1), low detection limit (6.46 nM) and wide linear range (0 nM to 600 nM). CeO2 based bioelectrode can also be considered as a suitable candidate for protein sensors. It can detect protein concentrations varying from 0 to 30 µM, which is similar or higher than most reports in the literature. The limit of detection (LOD) for protein was ∼0.04 µM. Therefore, the hollow CeO2 electrodes, with excellent reproducibility, stability and repeatability, open a new area of application for cage-frame type particles.

Hierarchical NaFePO4 nanostructures in combination with an optimized carbon-based electrode to achieve advanced aqueous Na-ion supercapacitors.

Recent trends in sodium-ion-based energy storage devices have shown the potential use of hollow structures as an electrode material to improve the performance of these storage systems. It is shown that, in addition to the use of hierarchical structures, the choice of the complementary carbon electrode determines the final performance of Na-ion-based devices. Here, we present simple synthesis strategies to prepare different structured carbonaceous materials that can be upscaled to an industrial level. Individual carbon materials deliver specific capacitance ranges from 120 to 220 F g-1 at a current density of 1 A g-1 (with excellent capacity retention). These structures, when combined with hollow NaFePO4 microspheres to fabricate an aqueous supercapacitor, show as high as a 1.7 V working potential window and can deliver a maximum energy density of 25.29 W h kg-1 capacity retention. These values are much higher than those reported by NaFePO4 solid particles and randomly chosen carbon structure-based supercapacitors.

Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets.

Containment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed a dimeric lipopeptide fusion inhibitor that blocks this critical first step of infection for emerging coronaviruses and document that it completely prevents SARS-CoV-2 infection in ferrets. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and non-toxic and thus readily translate into a safe and effective intranasal prophylactic approach to reduce transmission of SARS-CoV-2. ONE-SENTENCE SUMMARY: A dimeric form of a SARS-CoV-2-derived lipopeptide is a potent inhibitor of fusion and infection in vitro and transmission in vivo .

Gas identification with graphene plasmons.

Identification of gas molecules plays a key role a wide range of applications extending from healthcare to security. However, the most widely used gas nano-sensors are based on electrical approaches or refractive index sensing, which typically are unable to identify molecular species. Here, we report label-free identification of gas molecules SO2, NO2, N2O, and NO by detecting their rotational-vibrational modes using graphene plasmon. The detected signal corresponds to a gas molecule layer adsorbed on the graphene surface with a concentration of 800 zeptomole per µm2, which is made possible by the strong field confinement of graphene plasmons and high physisorption of gas molecules on the graphene nanoribbons. We further demonstrate a fast response time (<1 min) of our devices, which enables real-time monitoring of gaseous chemical reactions. The demonstration and understanding of gas molecule identification using graphene plasmonic nanostructures open the door to various emerging applications, including in-breath diagnostics and monitoring of volatile organic compounds.

Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route.

A clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatment in vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV.IMPORTANCE Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.

A Y-Shaped Three-Arm Structure for Probing Bivalent Interactions between Protein Receptor-Ligand Using AFM and SPR.

The goal of this research was to develop linkage chemistry for the study of bivalent interactions between a receptor and its ligand using atomic force microscopy (AFM) and surface plasmon resonance (SPR). We conceived a three-arm structure composed of flexible chains connected to a large rigid core with orthogonal functional groups at their ends for formation and attachment (or immobilization) of bivalent ligands. To demonstrate the principle, we chose the well-known biotin-streptavidin interaction as a model system. On the basis of a crystal structure of the biotin-streptavidin complex, we designed and synthesized a bisbiotin ligand to have a Y shape with two biotin motifs on its arms for binding and a functional group on its stem for immobilization or attachment, referred to as y-bisbiotin. First, we found that the y-bisbiotin ligand stabilized the streptavidin more than its monobiotin counterpart did in solution, which indicates that the bivalent interaction was synergistic. The y-bisbiotin was attached to AFM tips through a click reaction for the force measurement experiments, which showed that unbinding the bisbiotin from streptavidin needed twice the force of unbinding a monobiotin. For the SPR study, we added a ω-thiolated alkyl chain to y-bisbiotin for its incorporation into a monolayer. The SPR data indicated that the streptavidin dissociated from a mixed monolayer bearing y-bisbiotin much slower than from the one bearing monobiotin. This work demonstrates unique chemistry for the study of bivalent interactions using AFM and SPR.

Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling.

Three Akt isoforms, encoded by 3 separate genes, are expressed in mammals. While the roles of Akt1 and Akt2 in metabolism are well established, it is not yet known whether Akt3 plays a role in metabolic diseases. We now report that Akt3 protects mice from high-fat diet-induced obesity by suppressing an alternative pathway of adipogenesis via with no lysine protein kinase-1 (WNK1) and serum/glucocorticoid-inducible kinase 1 (SGK1). We demonstrate that Akt3 specifically phosphorylates WNK1 at T58 and promotes its degradation via the ubiquitin-proteasome pathway. A lack of Akt3 in adipocytes increases the WNK1 protein level, leading to activation of SGK1. SGK1, in turn, promotes adipogenesis by phosphorylating and inhibiting transcription factor FOXO1 and, subsequently, activating the transcription of PPARγ in adipocytes. Akt3-deficient mice have an increased number of adipocytes and, when fed a high-fat diet, display increased weight gain, white adipose tissue expansion, and impaired glucose homeostasis. Pharmacological blockade of SGK1 in high-fat diet-fed Akt3-deficient mice suppressed adipogenesis, prevented excessive weight gain and adiposity, and ameliorated metabolic parameters. Thus, Akt3/WNK1/SGK1 represents a potentially novel signaling pathway controlling the development of obesity.

TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia.

RATIONALE: Platelet hyperreactivity, which is common in many pathological conditions, is associated with increased atherothrombotic risk. The mechanisms leading to platelet hyperreactivity are complex and not yet fully understood. OBJECTIVE: Platelet hyperreactivity and accelerated thrombosis, specifically in dyslipidemia, have been mechanistically linked to the accumulation in the circulation of a specific group of oxidized phospholipids (oxPCCD36) that are ligands for the platelet pattern recognition receptor CD36. In the current article, we tested whether the platelet innate immune system contributes to responses to oxPCCD36 and accelerated thrombosis observed in hyperlipidemia. METHODS AND RESULTS: Using in vitro approaches, as well as platelets from mice with genetic deletion of MyD88 (myeloid differentiation factor 88) or TLRs (Toll-like receptors), we demonstrate that TLR2 and TLR6 are required for the activation of human and murine platelets by oxPCCD36. oxPCCD36 induce formation of CD36/TLR2/TLR6 complex in platelets and activate downstream signaling via TIRAP (Toll-interleukin 1 receptor domain containing adaptor protein)-MyD88-IRAK (interleukin-1 receptor-associated kinase)1/4-TRAF6 (TNF receptor-associated factor 6), leading to integrin activation via the SFK (Src family kinase)-Syk (spleen tyrosine kinase)-PLCγ2 (phospholipase Cγ2) pathway. Intravital thrombosis studies using ApoE-/- mice with genetic deficiency of TLR2 or TLR6 have demonstrated that oxPCCD36 contribute to accelerated thrombosis specifically in the setting of hyperlipidemia. CONCLUSIONS: Our studies reveal that TLR2 plays a key role in platelet hyperreactivity and the prothrombotic state in the setting of hyperlipidemia by sensing a wide range of endogenous lipid peroxidation ligands and activating innate immune signaling cascade in platelets.

Universal Readers Based on Hydrogen Bonding or π-π Stacking for Identification of DNA Nucleotides in Electron Tunnel Junctions.

A reader molecule, which recognizes all the naturally occurring nucleobases in an electron tunnel junction, is required for sequencing DNA by a recognition tunneling (RT) technique, referred to as a universal reader. In the present study, we have designed a series of heterocyclic carboxamides based on hydrogen bonding and a large-sized pyrene ring based on a π-π stacking interaction as universal reader candidates. Each of these compounds was synthesized to bear a thiolated linker for attachment to metal electrodes and examined for their interactions with naturally occurring DNA nucleosides and nucleotides by 1H NMR, ESI-MS, computational calculations, and surface plasmon resonance. RT measurements were carried out in a scanning tunnel microscope. All of these molecules generated electrical signals with DNA nucleotides in tunneling junctions under physiological conditions (phosphate buffered aqueous solution, pH 7.4). Using a support vector machine as a tool for data analysis, we found that these candidates distinguished among naturally occurring DNA nucleotides with the accuracy of pyrene (by π-π stacking interactions) > azole carboxamides (by hydrogen-bonding interactions). In addition, the pyrene reader operated efficiently in a larger tunnel junction. However, the azole carboxamide could read abasic (AP) monophosphate, a product from spontaneous base hydrolysis or an intermediate of base excision repair. Thus, we envision that sequencing DNA using both π-π stacking and hydrogen-bonding-based universal readers in parallel should generate more comprehensive genome sequences than sequencing based on either reader molecule alone.