Molecular Circuits Research Articles

Hydrazine-Modified Topology-Dependent Conductivity of Cyclic NDI as a Molecular Circuit

Hydrazine-Modified Topology-Dependent Conductivity of Cyclic NDI as a Molecular Circuit

A high selective chemosensor for detection of Al3+ based on diarylethene with a hydrazide unit

Al3+ plays an indispensable role in different physiological processes. However, excess Al3+ is destructive to health. Here, a diarylethene-based fluorescent sensor (1O) was synthesized by attaching a hydrazide group to diarylethene moiety through Schiff base structure. In acetonitrile, 1O displayed excellent selectivity and sensitivity to Al3+. The fluorescence intensity increased by 70-fold and accompanied by the color of the solution changed from dark to blue with the addition of Al3+. Further, the potential response mechanism of 1O toward Al3+ was proposed and verified by 1H NMR titrations and mass spectrometry analysis, the stoichiometric ratios of the sensor with Al3+ appeared to be 1:1 with the detection limit of 0.073 μM. In addition, 1O has been successfully applied to the detection of Al3+ in real water samples, and it also has successfully designed as molecular logic circuit and test strips.

Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex.

Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.

Identification of lncRNAs involved in maternal-to-zygotic transition of in vitro-produced porcine embryos by single-cell RNA-seq.

Long non-coding RNAs (lncRNAs) function through multiple tiers of molecular circuits and are vital to gamete maturation and early embryo development. However, in pig early embryos, identification and expression dynamics of lncRNAs remain less studied. Here, we systematically analysed the expression dynamics of lncRNAs based on our previously published single-cell RNA-seq data from pig mature oocytes (GSE160334), and single blastomeres biopsied from pig in vitro fertilized (IVF) and early parthenogenetically activated (PA) embryos (1- to 8-cell stages; GSE164812). With the progression of embryo development, the total number of expressed lncRNAs gradually decreased and showed great variation at each developmental stage for both IVF and PA groups. Consecutive stage pairwise comparison of MII oocytes, 1-cell zygotes, 2-cell, 4-cell and 8-cell IVF embryos identified 151, 245, 1119 and 188 differentially expressed (DE) lncRNAs, including 119, 80, 867, 77 up-regulated and 32, 165, 252, 111 down-regulated, while 289, 437, 895 and 495 DE lncRNAs (141, 89, 768, 97 up-regulated and 148, 348, 127, 398 down-regulated) were identified in PA embryos at the same stages. The DE lncRNAs identified within IVF embryos were much different from that identified within PA embryos, showing embryo type-specific manner. Further cross-comparison between PA and IVF embryos identified 184, 656, 2502 and 266 DE lncRNAs for the 1- to 8-cell embryo stages, respectively. Further GO and KEGG enrichment analysis of DE mRNAs targeted by DELs indicated that different signalling pathways were involved in maternal-only and bi-parental embryo development. Collectively, comparative profiling of lncRNA expression dynamics between pig IVF and PA embryos provides a valuable resource, to investigate further regulatory mechanisms of lncRNAs associated with ZGA and maternal RNA decay during early embryo development.

Evidence of a Synergistic Cross-Talk between the B Cell Receptor (BCR) and Nicotinamide Phosphoribosyl Transferase (NAMPT) in Richter's Syndrome Patient-Derived Xenograft Models: Therapeutic Implications

Background: A rare complication of Chronic Lymphocytic Leukemia (CLL), Richter's Syndrome (RS) represents the transformation of a pre-existing CLL into a Diffuse Large B-cell Lymphoma (DLBCL), generally associated with poor prognosis. Current therapeutic approaches are limited and do not significantly reduce disease progression. For these reasons there is intense investigation to identify potentially druggable molecular circuits, opening the way to innovative combination therapies.Among the several oncogenic signalling pathways that may contribute to disease progression, the B Cell Receptor (BCR) is a main driver and an actionable target. We previously showed that BCR ligation in CLL cells increases expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage NAD pathway starting from nicotinamide, a finding in line with the notion of oncogenic-driven metabolic reprogramming. In this context, increased NAMPT expression leading to heightened NAD+ levels could sustain proliferation through the modulation of the activity of several intracellular enzymes, including sirtuins (NAD-dependent deacetylases).Aim: This work explores the connections between BCR signalling and the NAMPT/NAD/sirtuin axis in RS cells, asking the question of whether BCR and NAMPT can be simultaneously targeted.Methods: RS-PDX cells were freshly purified from tumor masses grown in mice and immediately used for short ex-vivo experiments. For in vivo experiments, NSG mice were injected subcutaneously with RS-PDX cells, which were left to engraft until a palpable mass was evident. Mice were then randomized to receive duvelisib, OT82 or a combination of the two for two consecutive weeks. Control mice were similarly treated with vehicle only. Mice were under a niacin-free diet.Results: By using our 4 RS patient-derived xenografts (PDX) models, we invariably observed high levels of NAMPT expression. High levels of NAMPT expression were also observed in 15 primary RS lymph node biopsies analyzed by RNA sequencing. BCR engagement through αIgM polyclonal antibodies significantly up-regulated NAMPT expression, as determined by qRT-PCR and protein analysis, with a concomitant increase in intracellular NAD+ levels. We then asked whether RS cells are sensitive to NAMPT inhibition, alone or in combination with drugs that target the BCR pathway. As most RS patients would likely have been treated during the preceding CLL phase with a BTK inhibitor, possibly developing resistance, we turned to PI3K inhibitors, which are less commonly used for CLL therapy. As NAMPT inhibitors (NAMPTi) we used both FK866 and OT-82, which are validated small molecules. Results indicated that the combination of the dual PI3K-δ/γ inhibitor duvelisib, with either FK866 or OT-82 induces dramatic apoptosis in all 4 models tested, as confirmed by annexinV/PI staining, by caspase 3 activation and by a significant drop in ATP and NAD+ levels. Importantly, two RS-PDX models (RS9737 and RS1316) were fully resistant to NAMPTi used alone, likely due to high levels of nicotinate phosphoribosyltransferase (NAPRT), which is the rate-limiting enzyme in the NAD salvage pathway that starts from nicotinic acid. However, addition of duvelisib, which was mildly effective when used alone, was followed by marked apoptosis even in these two models.Molecular dissection of the pathway showed that the combination of duvelisib and NAMPTi was followed by complete inhibition of the PI3K pathway, which was only partially blocked by duvelisib alone, even at high doses. The connection between NAMPT and PI3K is represented by cytoplasmic sirtuins, particularly SIRT2, which activate AKT through de-acetylation. Immunoprecipitation and two-dimensional gel electrophoresis showed that in the presence of NAMPTi, the amount of acetylated, i.e., inactive, AKT increased considerably. Consistently, treatment of RS-PDX mice with a combination of duvelisib and OT-82 was followed by significantly higher responses and longer animal survival.Conclusions: These results highlight a crosstalk between BCR signalling and NAMPT/sirtuin axis in RS models, showing the increased efficacy of the dual targeting (i.e., PI3K-δ/γ and NAMPT), and supporting this novel and promising therapeutic strategy for the treatment of RS patients. DisclosuresDeaglio: Heidelberg Pharma: Research Funding; Astra Zeneca: Research Funding.

A spectroscopic probe for hypochlorous acid detection

A spectroscopic probe CMBT was synthesized and characterized. CMBT showed the specific recognition for HClO based on the turn-on blue fluorescence and naked-eye change from pink to colorless. NMR, IR, HRMS-ESI, and spectral analysis suggested that colorimetric and fluorescent change of CMBT to HClO originated from the conversion of CMBT to starting material coumarin-aldehyde 1 caused by the oxidization of HClO, which was responsible for the fluorescence recovery. The detection limit was calculated to be 1.61 μM and 6.58 μM for fluorescence and UV–vis analysis with a range up to 1 mM. HClO's fluorescence detection was successfully achieved in tap and river water samples. The prepared convenient paper test strips showed a distinct color change in varying concentrations of HClO. A multi-input molecular logic circuit was constructed.

Metal-Organic Framework Nanoparticles Power DNAzyme Logic Circuits for Aberrant MicroRNA Imaging.

At the molecular level, a large number of studies exist on the use of dynamic DNA molecular circuits for disease diagnosis and biomedicine. However, how to design programmable molecular circuit devices to autonomously and accurately diagnose multiple low-abundance biomolecules in complex cellular environments remains a challenge. Here, we constructed DNAzyme logic circuits for the analysis and imaging of multiple microRNAs in living cells using Cu/ZIF-8 NPs as a nanocarrier of the logic gate modules and the Cu2+ cofactor of the Cu2+-dependent DNAzyme. The logic gate modules of the logic operation system were adsorbed on the surface of Cu/ZIF-8 NPs via electrostatic interaction. After internalization, pH-responsive Cu/ZIF-8 NPs could efficiently release the logic gate modules and Cu2+, which allowed us to realize multiple logic computations initiated by endogenous miRNA, including one YES logic gate and two binary logic gates (OR and AND) in different living cells. Cu2+-DNAzyme logic circuits could quickly respond to multiple endogenous miRNAs in the complex cell environment, which also provided a new research method for the application of DNA biocomputing circuits in living cells.

FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game.

Fragile X mental retardation protein (FMRP) is an RNA binding protein (RBP) whose absence is essentially associated to Fragile X Syndrome (FXS). As an RNA Binding Protein (RBP), FMRP is able to bind and recognize different RNA structures and the control of specific mRNAs is important for neuronal synaptic plasticity. Perturbations of this pathway have been associated with the autistic spectrum. One of the FMRP partners is the APP mRNA, the main protagonist of Alzheimer’s disease (AD), thereby regulating its protein level and metabolism. Therefore FMRP is associated to two neurodevelopmental and age-related degenerative conditions, respectively FXS and AD. Although these pathologies are characterized by different features, they have been reported to share a number of common molecular and cellular players. The aim of this review is to describe the double-edged sword of FMRP in autism and AD, possibly allowing the elucidation of key shared underlying mechanisms and neuronal circuits. As an RBP, FMRP is able to regulate APP expression promoting the production of amyloid β fragments. Indeed, FXS patients show an increase of amyloid β load, typical of other neurological disorders, such as AD, Down syndrome, Parkinson’s Disease, etc. Beyond APP dysmetabolism, the two neurodegenerative conditions share molecular targets, brain circuits and related cognitive deficits. In this review, we will point out the potential common neuropathological pattern which needs to be addressed and we will hopefully contribute to clarifying the complex phenotype of these two neurorological disorders, in order to pave the way for a novel, common disease-modifying therapy.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Sense and sensibility: of synthetic biology and the redesign of bioreporter circuits.

Sense and sensibility: of synthetic biology and the redesign of bioreporter circuits.

Quantum Circuit Rules for Molecular Electronic Systems: Where Are We Headed Based on the Current Understanding of Quantum Interference, Thermoelectric, and Molecular Spintronics Phenomena?

In this minireview, we discuss important aspects of the various quantum phenomena (such as quantum interference, spin-dependent charge transport, and thermoelectric effects) relevant in single-molecule charge transport and list some of the basic circuit rules devised for different molecular systems. These quantum phenomena, in conjunction with the existing empirical circuit rules, can help in predicting some of the structure-property relationships in molecular circuits. However, a universal circuit law that predicts the charge transport properties of a molecular circuit has not been derived yet. Having such law(s) will help to design and build a complex molecular device leading to exciting unique applications that are not possible with the traditional silicon-based technologies. Based on the existing knowledge in the literature, here we open the discussion on the possible future research directions for deriving unified circuit law(s) to predict the charge transport in complex single-molecule circuits.

Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish

BackgroundZebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.ResultsWe chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validate alx4a as a necessary and sufficient transcription factor for iridophore differentiation and present evidence on alx4a’s potential regulatory role in guanine synthesis pathway.ConclusionsPigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specific alx4a transcription factor.

Hard-Soft Chemistry Design Principles for Predictive Assembly of Single Molecule-Metal Junctions.

The achievement of atomic control over the organic-inorganic interface is key to engineering electronic and spintronic properties of molecular devices. We leverage insights from inorganic chemistry to create hard-soft acid-base (HSAB) theory-derived design principles for incorporation of single molecules onto metal electrodes. A single molecule circuit is assembled via a bond between an organic backbone and an under-coordinated metal atom of the electrode surface, typically Au. Here, we study molecular composition factors affecting the junction assembly of coordination complexes containing transition metals atoms on Au electrodes. We employ hetero- and homobimetallic lantern complexes and systematically change the coordination environment to vary the character of the intramolecular bonds relative to the electrode-molecule interaction. We observe that trends in the robustness and chemical selectivity of single molecule junctions formed with a range of linkers correlate with HSAB principles, which have traditionally been used to guide atomic arrangements in the synthesis of coordination complexes. We find that this similarity between the intermolecular electrode-molecule bonding in a molecular circuit and the intramolecular bonds within a coordination complex has implications for the design of metal-containing complexes compatible with electrical measurements on metal electrodes. Our results here show that HSAB principles determine which intramolecular interactions can be compromised by inter molecule-electrode coordination; in particular on Au electrodes, soft-soft metal-ligand bonding is vulnerable to competition from soft-soft Au-linker bonding in the junction. Neutral donor-acceptor intramolecular bonds can be tuned by the Lewis acidity of the transition metal ion, suggesting future synthetic routes toward incorporation of transition metal atoms into molecular junctions for increased functionality of single molecule devices.

Mutation of the murine Prickle1 (R104Q) causes phenotypes analogous to human symptoms of epilepsy and autism

Epilepsy and autism spectrum disorders (ASD) frequently show comorbidity, suggesting shared or overlapping neurobiological basis underlying these conditions. R104Q is the first mutation in the PRICKLE 1(PK1) gene that was discovered in human patients with progressive myoclonus epilepsy (PME). Subsequently, a number of mutations in the PK1 gene were shown to be associated with either epilepsy, autism, or both, as well as other developmental disorders. Using CRISPR-Cas9-mediated gene editing, we generated a PK1R104Q mouse line. The mutant mice showed reduced density of excitatory synapses in hippocampus and impaired interaction between PK1 and the repressor element 1(RE-1) silencing transcription factor (REST). They also displayed reduced seizure threshold, impaired social interaction, and cognitive functions. Taken together, the PK1R104Q mice display characteristic behavioral features similar to the key symptoms of epilepsy and ASD, providing a useful model for studying the molecular and neural circuit mechanisms underlying the comorbidity of epilepsy and ASD.

A Novel Mechanism of Ataxia Telangiectasia Mutated Mediated Regulation of Chromatin Remodeling in Hypoxic Conditions.

The effects of genotoxic stress can be mediated by activation of the Ataxia Telangiectasia Mutated (ATM) kinase, under both DNA damage-dependent (including ionizing radiation), and independent (including hypoxic stress) conditions. ATM activation is complex, and primarily mediated by the lysine acetyltransferase Tip60. Epigenetic changes can regulate this Tip60-dependent activation of ATM, requiring the interaction of Tip60 with tri-methylated histone 3 lysine 9 (H3K9me3). Under hypoxic stress, the role of Tip60 in DNA damage-independent ATM activation is unknown. However, epigenetic changes dependent on the methyltransferase Suv39H1, which generates H3K9me3, have been implicated. Our results demonstrate severe hypoxic stress (0.1% oxygen) caused ATM auto-phosphorylation and activation (pS1981), H3K9me3, and elevated both Suv39H1 and Tip60 protein levels in FTC133 and HCT116 cell lines. Exploring the mechanism of ATM activation under these hypoxic conditions, siRNA-mediated Suv39H1 depletion prevented H3K9me3 induction, and Tip60 inhibition (by TH1834) blocked ATM auto-phosphorylation. While MDM2 (Mouse double minute 2) can target Suv39H1 for degradation, it can be blocked by sirtuin-1 (Sirt1). Under severe hypoxia MDM2 protein levels were unchanged, and Sirt1 levels depleted. SiRNA-mediated depletion of MDM2 revealed MDM2 dependent regulation of Suv39H1 protein stability under these conditions. We describe a novel molecular circuit regulating the heterochromatic state (H3K9me3 positive) under severe hypoxic conditions, showing that severe hypoxia-induced ATM activation maintains H3K9me3 levels by downregulating MDM2 and preventing MDM2-mediated degradation of Suv39H1. This novel mechanism is a potential anti-cancer therapeutic opportunity, which if exploited could target the hypoxic tumor cells known to drive both tumor progression and treatment resistance.

Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

BackgroundNon-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear.ResultsWe found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue.ConclusionThese findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH.1auxpva_RZCTQ5SP89UX9TVideo abstract

A Cooperative DNA Catalyst

DNA catalysts are fundamental building blocks for diverse molecular information-processing circuits. Allosteric control of DNA catalysts has been developed to activate desired catalytic pathways at desired times. Here we introduce a new type of DNA catalyst that we call a cooperative catalyst: a pair of reversible reactions are employed to drive a catalytic cycle in which two signal species, which can be interpreted as an activator and an input, both exhibit catalytic behavior for output production. We demonstrate the role of a dissociation toehold in controlling the kinetics of the reaction pathway and the significance of a wobble base pair in promoting the robustness of the activator. We show near-complete output production with input and activator concentrations that are 0.1 times the gate concentration. The system involves just a double-stranded gate species and a single-stranded fuel species, as simple as the seesaw DNA catalyst, which has no allosteric control. The simplicity and modularity of the design make the cooperative DNA catalyst an exciting addition to strand-displacement motifs for general-purpose computation and dynamics.

Far infrared irradiation suppresses experimental arthritis in rats by down-regulation of genes involved inflammatory response and autoimmunity

IntroductionFar-infrared radiation (FIR) is widely used in the treatment of various diseases such as insomnia and cardiovascular risk. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which the therapeutic potential of FIR in RA is unclear. ObjectivesTo determine the therapeutic potential and mechanistic actions of FIR in treatment of RA. MethodsAdjuvant-induced arthritis (AIA) rat models were established to assess the therapeutic potency of FIR in RA treatment. The scoring parameters such as arthritis score, swelling of the hind paw, spleen and thymus indices, micro-CT analysis indices were adopted to estimate the beneficial effects of FIR during RA treatment in AIA model. PCR gene expression arrays were used to analyze inflammatory and autoimmune genes expression profiles in rat synovium. The inflammatory and immunity genes profiling was further analyzed through transcription factor prediction using PROMO. A signaling network map of possible molecular circuits connecting the identified differential genes to the RA's pathogenesis was constructed based on extensive literature reviews, and the major signaling pathways were validated by Western blotting. ResultsThirty minutes of FIR treatment significantly improved the symptoms of AIA in rats. Gene expression profiling indicated that 27 out of 370 genes were down-regulated by FIR. AP-1, CEBPα, CEBPβ, c-Fos, GR, HNF-3β, USF-1, and USF-2 were predicted as key transcription factors that regulated the identified differential genes. In addition, MAPK, PI3K-Akt, and NF-κB signaling are the major molecular pathways down-regulated by FIR treatment. ConclusionFIR may provide beneficial effects on the AIA rat model of arthritis by suppression of the MAPK, PI3K-Akt and NF-κB signaling pathways. Therefore, we believe that FIR may provide an alternative non-pharmacological and non-surgical therapeutic approach for the treatment of RA.

Single‐Molecule Doping: Conductance Changed By Transition Metal Centers in Salen Molecules

AbstractThe creation of molecular components for use as electronic devices has made enormous progress. In order to advance the field further toward realistic electronic concepts, methods for the controlled modification of the conducting properties of the molecules contacted by metallic electrodes need to be further developed. Here a comprehensive study of charge transport in a class of molecules that allows modifications by introducing metal centers into organic structures is presented. Single molecules are electrically contacted and characterized in order to understand the role of the metal centers in the conductance mechanism through the molecular junctions. It is shown that the presence of single metal ions modifies the energy levels and the coupling of the molecules to the electrical contacts, and that these modifications lead to systematic variations in the statistical behavior of transport properties of the molecular junctions. A rigorous statistical analysis of thousands of junctions is performed to reveal this correlation. The understanding of the role of the metal ion in the resulting conductance properties is an essential step toward the development of molecular electronic circuits.

Red/Green Tunable-Emission Carbon Nanodots for Smart Visual Precision pH Sensing

The development of novel carbon nanodots (CDs) with excellent optical properties and promising applications is an attractive but a challenging area. Herein, we demonstrate that the fluorescence properties of CDs can be optimized by simple modification of the molecular structure of the carbon source. Significantly, the final optimized CDs 1 exhibit a rare extremely acidic (pH 1-3) sensitivity. A distinguishable red/brown/green fluorescence color change is achieved for visual readout by simply tuning the pH to 1, 2, or 3. The distinguishable color change combined with ratiometric fluorescence changes greatly improves the naked-eye visual resolution up to 0.2 pH units, which is higher than that of commercial precision pH test strips. Furthermore, a smartphone was employed in a portable, low-cost, rapid, and precise pH measurement method, which satisfied the requirement of point-of-care testing. Inspired by the reversible color change of red/brown/green tri-fluorescence on tuning the pH to 1, 2, or 3, a simple yet efficient molecular logic circuit has been designed. Given the unique pH-dependent photoluminescence properties, these CDs have been further applied in the anti-counterfeiting and information encryption field, making the burn after readingencryption technology a reality.