Electrically Oriented Antibodies on Transistor for Monitoring Several Copies of Methylated DNA.

An antibody transistor is a promising biosensing platform for the diagnosis and monitoring of various diseases. Nevertheless, the low concentration and short half-life of biomarkers require biodetection at the trace-molecule level, which remains a challenge for existing antibody transistors. Herein, we demonstrate a graphene field-effect transistor (gFET) with electrically oriented antibody probes (EOA-gFET) for monitoring several copies of methylated DNA. The electric field confines the orientation of antibody probes on graphene and diminishes the distance between graphene and methylated DNAs captured by antibodies, generating more induced charges on graphene and amplifying the electric signal. EOA-gFET realizes a limit of detection (LoD) of ∼0.12 copy µL-1, reaching the lowest LoD reported before. EOA-gFET shows a distinguishable signal for liver cancer clinical serum samples within ∼6 min, which proves its potential as a powerful tool for disease screening and diagnosis.

Mixed active metabolites of the SNP-6 series of novel compounds mitigate metabolic dysfunction-associated steatohepatitis and fibrosis: promising results from pre-clinical and clinical trials.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630's potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH. METHODS: SNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers. RESULTS: SNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis. CONCLUSIONS: SNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH. TRIAL REGISTRATION: ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566.

Highly Bionic Neurotransmitter-Communicated Neurons Following Integrate-and-Fire Dynamics.

In biological neural networks, chemical communication follows the reversible integrate-and-fire (I&F) dynamics model, enabling efficient, anti-interference signal transport. However, existing artificial neurons fail to follow the I&F model in chemical communication, causing irreversible potential accumulation and neural system dysfunction. Herein, we develop a supercapacitively gated artificial neuron that mimics the reversible I&F dynamics model. Upon upstream neurotransmitters, an electrochemical reaction occurs on a graphene nanowall (GNW) gate electrode of artificial neurons. Charging and discharging the supercapacitive GNWs mimic membrane potential accumulation and recovery, realizing highly efficient chemical communication upon use of acetylcholine down to 2 × 10-10 M. By combining artificial chemical synapses with axon-hillock circuits, the output of neural spikes is realized. With the same neurotransmitter and I&F dynamics, the artificial neuron establishes chemical communication with other artificial neurons and living cells, holding promise as a basic unit to construct a neural network with compatibility to organisms for artificial intelligence and deep human-machine fusion.

An Efficient CRISPR/Cas Cooperative Shearing Platform for Clinical Diagnostics Applications.

The CRISPR/Cas system is a powerful genome editing tool and possesses widespread applications in molecular diagnostics, therapeutics and genetic engineering. But easy folding of the target sequences causes remarkable deterioration of the recognition and shear efficiency in the case of single Cas-CRISPR RNA (crRNA) duplex. Here, we develop a CRISPR/Cas cooperative shearing (CRISPR-CS) system. Compared with traditional CRISPR/Cas system, two CRISPR/Cas-crRNA duplexes simultaneously recognize different sites in the target sequence, increasing recognition possibility and shearing efficiency. Cooperative shearing cuts more methylene blue-ssDNA reporters on the electrode, enabling unamplified nucleic acid electrochemical assay in less than 5 minutes with a detection limit of 9.5×10-20 M, 2 to 9 orders of magnitude lower than those of other electrochemical assays. The CRISPR-CS platform detects monkeypox, human papilloma virus and amyotrophic lateral sclerosis with an accuracy up to 98.1%, demonstrating the potential application of the efficient cooperative shearing.

Catalytic Hairpin Assembly-Enhanced Graphene Transistor for Ultrasensitive miRNA Detection.

MicroRNAs (miRNAs) have emerged as powerful biomarkers for disease diagnosis and screening. Traditional miRNA analytical techniques are inadequate for point-of-care testing due to their reliance on specialized expertise and instruments. Graphene field-effect transistors (GFETs) offer the prospect of simple and label-free diagnostics. Herein, a GFET biosensor based on tetrahedral DNA nanostructure (TDN)-assisted catalytic hairpin assembly (CHA) reaction (TCHA) has been fabricated and applied to the sensitive and specific detection of miRNA-21. TDN structures are assembled to construct the biosensing interface, facilitating CHA reaction by providing free space and preventing unwanted entanglements, aggregation, and adsorption of probes on the graphene channel. Owing to synergistic effects of TDN-assisted in situ nucleic acid amplification on the sensing surface, as well as inherent signal sensitization of GFETs, the biosensor exhibits ultrasensitive detection of miRNA-21 down to 5.67 × 10-19 M, approximately three orders of magnitude lower than that normally achieved by graphene transistors with channel functionalization of single-stranded DNA probes. In addition, the biosensor demonstrates excellent analytical performance regarding selectivity, stability, and reproducibility. Furthermore, the practicability of the biosensor is verified by analyzing targets in a complex serum environment and cell lysates, showing tremendous potential in bioanalysis and clinical diagnosis.

Artificial Nucleotide Aptamer-Based Field-Effect Transistor for Ultrasensitive Detection of Hepatoma Exosomes.

An aptamer-based field-effect transistor (Apta-FET) is a well-developed assay method with high selectivity and sensitivity. Due to the limited information density that natural nucleotide library holds, the Apta-FET faces fundamental restriction in universality to detect various types of analytes. Herein, we demonstrate a type of Apta-FET sensors based on an artificial nucleotide aptamer (AN-Apta-FET). The introduction of an artificial nucleotide increases the diversity of the potential aptamer structure and expands the analyte category of the Apta-FET. The AN-Apta-FET specifically detects hepatoma exosomes, which traditional Apta-FET fails to discriminate from other tumor-derived exosomes, with a limit of detection down to 242 particles mL-1. The AN-Apta-FET distinguishes serum samples of hepatocellular carcinoma patients within 9 min from those of healthy people, showing the potential as a comprehensive assay tool in future disease diagnosis.

Triple-Probe DNA Framework-Based Transistor for SARS-CoV-2 10-in-1 Pooled Testing.

Accurate and population-scale screening technology is crucial in the control and prevention of COVID-19, such as pooled testing with high overall testing efficiency. Nevertheless, pooled testing faces challenges in sensitivity and specificity due to diluted targets and increased contaminations. Here, we develop a graphene field-effect transistor sensor modified with triple-probe tetrahedral DNA framework (TDF) dimers for 10-in-1 pooled testing of SARS-CoV-2 RNA. The synergy effect of triple probes as well as the special nanostructure achieve a higher binding affinity, faster response, and better specificity. The detectable concentration reaches 0.025-0.05 copy µL-1 in unamplified samples, lower than that of the reverse transcript-polymerase chain reaction. Without a requirement of nucleic-acid amplification, the sensors identify all of the 14 positive cases in 30 nasopharyngeal swabs within an average diagnosis time of 74 s. Unamplified 10-in-1 pooled testing enabled by the triple-probe TDF dimer sensor has great potential in the screening of COVID-19 and other epidemic diseases.

Electrochemical Detection of a Few Copies of Unamplified SARS-CoV-2 Nucleic Acids by a Self-Actuated Molecular System.

The existing electrochemical biosensors lack controllable and intelligent merit to modulate the sensing process upon external stimulus, leading to challenges in analyzing a few copies of biomarkers in unamplified samples. Here, we present a self-actuated molecular-electrochemical system that consists of a tentacle and a trunk modification on a graphene microelectrode. The tentacle that contains a probe and an electrochemical label keeps an upright orientation, which increases recognition efficiency while decreasing the pseudosignal. Once the nucleic acids are recognized, the tentacles nearby along with the labels are spontaneously actuated downward, generating electrochemical responses under square wave voltammetry. Thus, it detects unamplified SARS-CoV-2 RNAs within 1 min down to 4 copies in 80 µL, 2-6 orders of magnitude lower than those of other electrochemical assays. Double-blind testing and 10-in-1 pooled testing of nasopharyngeal samples yield high overall agreement with reverse transcription-polymerase chain reaction results. We fabricate a portable prototype based on this system, showing great potential for future applications.

Ultraprecise Antigen 10-in-1 Pool Testing by Multiantibodies Transistor Assay.

Effective screening of infectious diseases requires a fast, cheap, and population-scale testing. Antigen pool testing can increase the test rate and shorten the screening time, thus being a valuable approach for epidemic prevention and control. However, the overall percent agreement (OPA) with polymerase chain reaction (PCR) is one-half to three-quarters, hampering it from being a comprehensive method, especially pool testing, beyond the gold-standard PCR. Here, a multiantibodies transistor assay is developed for sensitive and highly precise antigen pool testing. The multiantibodies capture SARS-CoV-2 spike S1 proteins with different configurations, resulting in an antigen-binding affinity down to 0.34 fM. The limit of detection reaches 3.5 × 10-17 g mL-1SARS-CoV-2 spike S1 protein in artificial saliva, 4-5 orders of magnitude lower than existing transistor sensors. The testing of 60 nasopharyngeal swabs exhibits ∼100% OPA with PCR within an average diagnoses time of 38.9 s. Owing to its highly precise feature, a portable integrated platform is fabricated, which achieves 10-in-1 pooled screening for high testing throughput. This work solves the long-standing problem of antigen pool testing, enabling it to be a valuable tool in precise diagnoses and population-wide screening of COVID-19 or other epidemics in the future.

Direct SARS-CoV-2 Nucleic Acid Detection by Y-Shaped DNA Dual-Probe Transistor Assay.

Rapid screening of infected individuals from a large population is an effective means in epidemiology, especially to contain outbreaks such as COVID-19. The gold standard assays for COVID-19 diagnostics are mainly based on the reverse transcription polymerase chain reaction, which mismatches the requirements for wide-population screening due to time-consuming nucleic acid extraction and amplification procedures. Here, we report a direct nucleic acid assay by using a graphene field-effect transistor (g-FET) with Y-shaped DNA dual probes (Y-dual probes). The assay relies on Y-dual probes modified on g-FET simultaneously targeting ORF1ab and N genes of SARS-CoV-2 nucleic acid, enabling high a recognition ratio and a limit of detection (0.03 copy µL-1) 1-2 orders of magnitude lower than existing nucleic acid assays. The assay realizes the fastest nucleic acid testing (∼1 min) and achieves direct 5-in-1 pooled testing for the first time. Owing to its rapid, ultrasensitive, easily operated features as well as capability in pooled testing, it holds great promise as a comprehensive tool for population-wide screening of COVID-19 and other epidemics.

Probing energy losses from dye desorption in cobalt complex-based dye-sensitized solar cells.

Self-assembly of organic sensitizer layers in cobalt complex-based DSCs was studied to elucidate its role in reducing the loss of charge recombination. DSCs with various dye loadings were fabricated by dye desorption without the aid of basic solvent. The FT-IR and UV results indicate the deprotonation of the anchoring organic sensitizers, which influences the conduction band of TiO2 remarkably by changing the surface potential. Positive band edge shifts and a decrease of the recombination rate constant are demonstrated to be the main factors affecting energy loss at open circuit. In contrast, absorbed photon conversion efficiency (APCE) analyses illuminate the crucial role of the packing of the anchoring sensitizer in reducing recombination loss at short circuit. This is further supported by numerical simulations, which show that APCE is primarily dependent on the recombination rate constant rather than the band edge shift at short circuit. These results highlight the importance of self-assembly of sensitizers with insulating groups in retarding charge recombination by forming overlapping molecular layers.

Ultra-Fast Single-Nucleotide-Variation Detection Enabled by Argonaute-Mediated Transistor Platform.

"Test-and-go" single-nucleotide variation (SNV) detection within several minutes remains challenging, especially in low-abundance samples, since existing methods face a trade-off between sensitivity and testing speed. Sensitive detection usually relies on complex and time-consuming nucleic acid amplification or sequencing. Here, a graphene field-effect transistor (GFET) platform mediated by Argonaute protein that enables rapid, sensitive, and specific SNV detection is developed. The Argonaute protein provides a nanoscale binding channel to preorganize the DNA probe, accelerating target binding and rapidly recognizing SNVs with single-nucleotide resolution in unamplified tumor-associated microRNA, circulating tumor DNA, virus RNA, and reverse transcribed cDNA when a mismatch occurs in the seed region. An integrated microchip simultaneously detects multiple SNVs in agreement with sequencing results within 5 min, achieving the fastest SNV detection in a "test-and-go" manner without the requirement of nucleic acid extraction, reverse transcription, and amplification.

Supercapacitively Liquid-Solid Dual-State Optoelectronics.

Photo-transduction of solid-state optoelectronics occurs in semiconductors or their interfaces. Considering the confined active area and interfacial capacitance of solid-state materials, solid-state optoelectronics faces inherent limitations in photo-transduction, especially for bionic vision, and the performance is lower than that of living systems. For example, a photoreceptor generates pA-level photocurrent when absorbing a single photon. Here, a liquid-solid dual-state phototransistor is demonstrated, in which photo-transduction and modulation take place at the microporous interface between semiconductors and water, mimicking principles of the photoreceptor. When operating in the water, an orderly stacked photo-harvesting covalent organic framework layer generates supercapacitively photogating modulation of the channel conductivity via a dual-state interface, achieving responsivity of 4.6 × 1010 A W-1 and detectivity of 1.62 × 1016 Jones at room temperature, several orders of magnitude higher than other photodetectors. Such bio-inspired dual-state optoelectronics enables high-contrast scotopic neuromorphic imaging with responsivity greater than photoreceptors, holding promise for constructing optoelectronic systems with performance beyond conventional solid-state optoelectronics.

Rapid and ultrasensitive electromechanical detection of ions, biomolecules and SARS-CoV-2 RNA in unamplified samples.

The detection of samples at ultralow concentrations (one to ten copies in 100 µl) in biofluids is hampered by the orders-of-magnitude higher amounts of 'background' biomolecules. Here we report a molecular system, immobilized on a liquid-gated graphene field-effect transistor and consisting of an aptamer probe bound to a flexible single-stranded DNA cantilever linked to a self-assembled stiff tetrahedral double-stranded DNA structure, for the rapid and ultrasensitive electromechanical detection (down to one to two copies in 100 µl) of unamplified nucleic acids in biofluids, and also of ions, small molecules and proteins, as we show for Hg2+, adenosine 5'-triphosphate and thrombin. We implemented an electromechanical biosensor for the detection of SARS-CoV-2 into an integrated and portable prototype device, and show that it detected SARS-CoV-2 RNA in less than four minutes in all nasopharyngeal samples from 33 patients with COVID-19 (with cycle threshold values of 24.9-41.3) and in none of the 54 COVID-19-negative controls, without the need for RNA extraction or nucleic acid amplification.

Short-wavelength ultraviolet dosimeters based on DNA nanostructure-modified graphene field-effect transistors.

Direct and sensitive short-wavelength ultraviolet (UVC) dosimeters could provide a safer disinfection environment against viruses. We developed direct, quantitative, specific and highly sensitive UVC dosimeters based on DNA nanostructure-modified graphene field-effect transistors. Detectable doses of the dosimeters range from 0.005 to 6 kJ m-2 and such dosimeters have at least 5 times better sensitivity than the current direct UV dosimeters.

Thieno[3,2-b]indole-based hole transporting materials for perovskite solar cells with photovoltages exceeding 1.11 V.

Four new hole transporting materials (HTMs), M107-M110, based on thieno[3,2-b]indole cores have been designed and employed in perovskite solar cells. The perovskite solar cells based on M109 exhibit a leading efficiency of 18.14% with a photovoltage over 1.11 V.

Influence of Nonfused Cores on the Photovoltaic Performance of Linear Triphenylamine-Based Hole-Transporting Materials for Perovskite Solar Cells.

The core plays a crucial role in achieving high performance of linear hole transport materials (HTMs) toward the perovskite solar cells (PSCs). Most studies focused on the development of fused heterocycles as cores for HTMs. Nevertheless, nonfused heterocycles deserve to be studied since they can be easily synthesized. In this work, we reported a series of low-cost triphenylamine HTMs (M101-M106) with different nonfused cores. Results concluded that the introduced core has a significant influence on conductivity, hole mobility, energy level, and solubility of linear HTMs. M103 and M104 with nonfused oligothiophene cores are superior to other HTMs in terms of conductivity, hole mobility, and surface morphology. PSCs based on M104 exhibited the highest power conversion efficiency of 16.50% under AM 1.5 sun, which is comparable to that of spiro-OMeTAD (16.67%) under the same conditions. Importantly, the employment of M104 is highly economical in terms of the cost of synthesis as compared to that of spiro-OMeTAD. This work demonstrated that nonfused heterocycles, such as oligothiophene, are promising cores for high performance of linear HTMs toward PSCs.