Advancing Brain Research through Surface-Enhanced Raman Spectroscopy (SERS): Current Applications and Future Prospects.

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as a potent analytical technique with significant potential in the field of brain research. This review explores the applications and innovations of SERS in understanding the pathophysiological basis and diagnosis of brain disorders. SERS holds significant advantages over conventional Raman spectroscopy, particularly in terms of sensitivity and stability. The integration of label-free SERS presents promising opportunities for the rapid, reliable, and non-invasive diagnosis of brain-associated diseases, particularly when combined with advanced computational methods such as machine learning. SERS has potential to deepen our understanding of brain diseases, enhancing diagnosis, monitoring, and therapeutic interventions. Such advancements could significantly enhance the accuracy of clinical diagnosis and further our understanding of brain-related processes and diseases. This review assesses the utility of SERS in diagnosing and understanding the pathophysiological basis of brain disorders such as Alzheimer's and Parkinson's diseases, stroke, and brain cancer. Recent technological advances in SERS instrumentation and techniques are discussed, including innovations in nanoparticle design, substrate materials, and imaging technologies. We also explore prospects and emerging trends, offering insights into new technologies, while also addressing various challenges and limitations associated with SERS in brain research.

Optimal control of the coronavirus pandemic with both pharmaceutical and non-pharmaceutical interventions.

Coronaviruses are types of viruses that are widely spread in humans, birds, and other mammals, leading to hepatic, respiratory, neurologic, and enteric diseases. The disease is presently a pandemic with great medical, economical, and political impacts, and it is mostly spread through physical contact. To extinct the virus, keeping physical distance and taking vaccine are key. In this study, a dynamical transmission compartment model for coronavirus (COVID-19) is designed and rigorously analyzed using Routh-Hurwitz condition for the stability analysis. A global dynamics of mathematical formulation was investigated with the help of a constructed Lyapunov function. We further examined parameter sensitivities (local and global) to identify terms with greater impact or influence on the dynamics of the disease. Our approach is data driven to test the efficacy of the proposed model. The formulation was incorporated with available confirmed cases from January 22, 2020, to December 20, 2021, and parameterized using real-time series data that were collected on a daily basis for the first 705 days for fourteen countries, out of which the model was simulated using four selected countries: USA, Italy, South Africa, and Nigeria. A least square technique was adopted for the estimation of parameters. The simulated solutions of the model were analyzed using MAPLE-18 with Runge-Kutta-Felberg method (RKF45 solver). The model entrenched parameters analysis revealed that there are both disease-free and endemic equilibrium points. The solutions depicted that the free equilibrium point for COVID-19 is asymptotic locally stable, when the epidemiological reproduction number condition ( R 0 < 1 ) . The simulation results unveiled that the pandemic can be controlled if other control measures, such as face mask wearing in public areas and washing of hands, are combined with high level of compliance to physical distancing. Furthermore, an autonomous derivative equation for the five-dimensional deterministic was done with two control terms and constant rates for the pharmaceutical and non-pharmaceutical strategies. The Lagrangian and Hamilton were formulated to study the model optimal control existence, using Pontryagin's Maximum Principle describing the optimal control terms. The designed objective functional reduced the intervention costs and infections. We concluded that the COVID-19 curve can be flattened through strict compliance to both pharmaceutical and non-pharmaceutical strategies. The more the compliance level to physical distance and taking of vaccine, the earlier the curve is flattened and the earlier the economy will be bounce-back.

3D hierarchically porous magnetic molybdenum trioxide@gold nanospheres as a nanogap-enhanced Raman scattering biosensor for SARS-CoV-2.

The global pandemic of COVID-19 is an example of how quickly a disease-causing virus can take root and threaten our civilization. Nowadays, ultrasensitive and rapid detection of contagious pathogens is in high demand. Here, we present a novel hierarchically porous 3-dimensional magnetic molybdenum trioxide-polydopamine-gold functionalized nanosphere (3D mag-MoO3-PDA@Au NS) composed of plasmonic, semiconductor, and magnetic nanoparticles as a multifunctional nanosculptured hybrid. Based on the synthesized 3D mag-MoO3-PDA@Au NS, a universal "plug and play" biosensor for pathogens is proposed. Specifically, a magnetically-induced nanogap-enhanced Raman scattering (MINERS) detection platform was developed using the 3D nanostructure. Through a magnetic actuation process, the MINERS system overcomes Raman signal stability and reproducibility challenges for the ultrasensitive detection of SARS-CoV-2 spike protein over a wide dynamic range up to a detection limit of 10-15 g mL-1. The proposed MINERS platform will facilitate the broader use of Raman spectroscopy as a powerful analytical detection tool in diverse fields.

Sulfur-doped carbon dots@polydopamine-functionalized magnetic silver nanocubes for dual-modality detection of norovirus.

Synergistic dual-mode optical platforms are up-and-coming detection tools in the diagnosis and management of infectious diseases. Here, novel dual-modality fluorescence (FL) and surface-enhanced Raman scattering (SERS) techniques have been integrated into a single probe for the rapid and ultrasensitive detection of norovirus (NoV). The developed FL-SER-based biosensor relies on the dual-signal enhancements of newly synthesized sulfur-doped agar-derived carbon dots (S-agCDs). The antigen-antibody immunoreaction results in forming a core-satellite immunocomplex between anti-NoV antibody-conjugated S-agCDs and polydopamine-functionalized magnetic silver nanocubes [poly (dop)-MNPs-Ag NCs]. By deploying an immunomagnetic enrichment protocol and performing the SERS modality on a single-layer graphene substrate, norovirus-like particles (NoV-LPs) were detected across a wide range of 1 fg mL-1 - 10 ng mL-1 with an excellent limit of detection of 0.1 fg mL-1. The combined advantage of the dual-signaling properties of the biosensor was demonstrated using FL confocal imaging for "hotspots" tracking prior to SERS detection of clinical NoV in fecal specimen down to ⁓10 RNA copies mL-1. The proposed dual-modality biosensor's performance increases the prospect of a rapid and low-cost sensitive NoV detection and surveillance option for public health.

Molybdenum Trioxide Quantum Dot-Encapsulated Nanogels for Virus Detection by Surface-Enhanced Raman Scattering on a 2D Substrate.

The use of nanogels (NGs) to modulate surface-enhanced Raman scattering (SERS) activities is introduced as an innovative strategy to address certain critical issues with SERS-based immunoassays. This includes the chemical deformation of SERS nanotags, as well as their nonspecific interactions and effective "hotspots" formation. Herein, the polymeric cocoon and stimuli-responsive properties of NGs were used to encapsulate SERS nanotags containing plasmonic molybdenum trioxide quantum dots (MoO3-QDs). The pH-controlled release of the encapsulated nanotags and their subsequent localization by maleimide-functionalized magnetic nanoparticles facilitated the creation of "hotspots" regions with catalyzed SERS activities. This approach resulted in developing a biosensing platform for the ultrasensitive immunoassays of hepatitis E virus (HEV) or norovirus (NoV). The immunoassays were optimized using the corresponding virus-like particles to attain limits of detection of 6.5 and 8.2 fg/mL for HEV-LPs and NoV-LPs, respectively. The SERS-based technique achieved a signal enhancement factor of up to ∼108 due to the combined electromagnetic and chemical mechanisms of the employed dual-SERS substrate of MoO3-QDs/2D hexagonal boron nitride nanosheets. The highlight and validation of the developed SERS-based immunoassays was the detection of NoV in infected patients' fecal specimen and clinical HEV G7 subtype. Importantly, this system can be used to maintain the stability of SERS nanotags and improve their reliability in immunoassays.

Fluorescent and electrochemical dual-mode detection of Chikungunya virus E1 protein using fluorophore-embedded and redox probe-encapsulated liposomes.

The critical goal of sensitive virus detection should apply in the early stage of infection, which may increase the probable survival rate. To achieve the low detection limit for the early stage where a small number of viruses are present in the sample, proper amplified signals from a sensor can make readable and reliable detection. In this work, a new model of fluorescent and electrochemical dual-mode detection system has been developed to detect virus, taking recombinant Chikungunya virus E1 protein (CHIK-VP) as an example. The hydrophobic quantum dots (QDs) embedded in the lipid bilayer of liposome and methylene blue (MB) encapsulated in the inner core of liposomes played a role of dual-signaling modulator. After CHIK-VP addition, the nanocomposites and APTES-coated Fe3O4 nanoparticles (Fe3O4 NPs) were conjugated with antibodies to form a sandwich structure and separated from the medium magnetically. The nanoconjugates have been burst out by chloroform as surfactant, and both the QDs and MB are released from the liposome and were then monitored through changes in the fluorescence and electrochemical signals, respectively. These two fluorometric and electrochemical signals alteration quantified the CHIK-VP in the range of femtogram to nanogram per milliliter level with a LOD of 32 fg mL-1, making this liposomal system a potential matrix in a virus detection platform. Graphical abstract.

Molybdenum Trioxide Nanocubes Aligned on a Graphene Oxide Substrate for the Detection of Norovirus by Surface-Enhanced Raman Scattering.

A novel biosensing system based on graphene-mediated surface-enhanced Raman scattering (G-SERS) using plasmonic/magnetic molybdenum trioxide nanocubes (mag-MoO3 NCs) has been designed to detect norovirus (NoV) via a dual SERS nanotag/substrate platform. A novel magnetic derivative of MoO3 NCs served as the SERS nanotag and the immunomagnetic separation material of the biosensor. Single-layer graphene oxide (SLGO) was adopted as the 2D SERS substrate/capture platform and acted as the signal reporter, with the ability to accommodate an additional Raman molecule as a coreporter. The developed SERS-based immunoassay achieved a signal amplification of up to ∼109-fold resulting from the combined electromagnetic and chemical mechanisms of the dual SERS nanotag/substrate system. The developed biosensor was employed for the detection of NoV in human fecal samples collected from infected patients by capturing the virus with the aid of NoV-specific antibody-functionalized magnetic MoO3 NCs. This approach enabled rapid signal amplification for NoV detection with this biosensing technology. The biosensor was tested and optimized using NoV-like particles within a broad linear range from 10 fg/mL to 100 ng/mL and a limit of detection (LOD) of ∼5.2 fg/mL. The practical applicability of the developed biosensor to detect clinical NoV subtypes in human fecal samples was demonstrated by effective detection with an LOD of ∼60 RNA copies/mL, which is ∼103-fold lower than that of a commercial enzyme-linked immunosorbent assay kit for NoV.

Plasmonic/magnetic molybdenum trioxide and graphitic carbon nitride quantum dots-based fluoroimmunosensing system for influenza virus.

A novel magnetic/plasmonic-assisted fluoro-immunoassay system is developed for the detection of influenza virus using magnetic-derivatized plasmonic molybdenum trioxide quantum dots (MP-MoO3 QDs) as the plasmonic/magnetic agent and fluorescent graphitic carbon nitride quantum dots (gCNQDs) as the monitoring probe. Specific antibody against influenza A virus was conjugated onto the surface of MP-MoO3 QDs and gCNQDs, respectively. In the presence of influenza A virus (as the test virus), a core-satellite immunocomplex is formed between the antibody-conjugated nanomaterials (Ab-MP-MoO3 QDs and Ab-gCNQDs) and their interaction resulted in the modulation and gradual enhancement of the fluorescence intensity of the detection probe with the influenza virus concentration-dependent increase. In addition, PL change without influenza A virus was not observed. Limits of detection of 0.25 and 0.9 pg/mL were achieved for Influenza virus A/New Caledonia (20/99/IVR/116) (H1N1) detection in deionized water and human serum, respectively. Clinically isolated influenza virus A/Yokohama (110/2009) (H3N2) was detected in the range of 45 - 25,000 PFU/mL, with a limit of detection ca 45 PFU/mL (as opposed to a minimum of 5000 PFU/mL for a commercial test kit). This developed biosensor provides a robust, sensitive as well as a selective platform for influenza virus detection.

Fluoroimmunoassay of influenza virus using sulfur-doped graphitic carbon nitride quantum dots coupled with Ag2S nanocrystals.

Novel sulfur-doped graphitic carbon nitride quantum dots (S-gCNQDs) are synthesized using a single-source precursor in a one-step solvothermal process. The S-gCNQDs with a size of ~ 5-nm displayed a strong green intrinsic fluorescence at 512 nm when excited at 400 nm, with a quantum yield of ~ 33% in aqueous solution. The prepared S-gCNQDs and Ag2S nanocrystals were applied as innovative functional materials to fabricate a biosensor for virus detection based on the conjugation of specific anti-human influenza A monoclonal antibody to the S-gCNQDs and Ag2S NCs, respectively. In the presence of the influenza A virus, an interaction between the S-gCNQDs/Ag2S-labeled antibody resulted in the formation of a nanosandwich structure, which is accompanied by the fluorescence enhancement of the S-gCNQDs. The change in fluorescence intensity linearly correlats with the concentration of the influenza A virus (H1N1) in the 10 fg/mL to 1.0 ng/mL range, with a limit of detection of 5.5 fg/mL. The assay was applied to the assay of clinically isolated influenza A virus (H3N2/Yokohama) mixed with human serum. The obtained limit of detection was 100 PFU/mL within the detection range of 102- 5 × 104 PFU/mL for the H3N2 virus. Graphical abstract.

Tannic acid-derivatized graphitic carbon nitride quantum dots as an "on-off-on" fluorescent nanoprobe for ascorbic acid via copper(II) mediation.

A microwave-assisted hydrothermal route was employed to prepare fluorescent tannic acid (TA)-derivatized graphitic carbon nitride quantum dots. The resulting dots display blue fluorescence (best measured at excitation/emission wavelengths of 350/452 nm) with a quantum yield as high as ~44%. The incorporated TA imparts a fluorescence switching behavior in that very low concentrations of Cu(II) can quench the fluorescence, while (AA) can restore it. It is presumed that AA causes Cu(II) to be transformed to Cu(I). Based on these findings, a fluorometric method was designed for AA detection. The probe allows AA to be detected with a 50 pM limit of detection and a linear analytical range that extends from 0.1 to 200 nM of AA. Real and spiked samples were successfully assayed by the probe to demonstrate its analytical applicability. Graphical abstract Schematic presentation of fluorescent graphitic carbon nitride quantum dots functionalized with tannic acid. Their fluorescence is quenched by Cu2+ and recovered by ascorbic acid (AA). This is exploited in an assay with a picomolar detection limit.

Microwave-assisted synthesis of thymine-functionalized graphitic carbon nitride quantum dots as a fluorescent nanoprobe for mercury(II).

A microwave-assisted hydrothermal method was employed to prepare thymine-modified graphitic carbon nitride quantum dots (T-gCNQDs) which are shown to be a novel fluorescent nanoprobe for Hg(II). They exhibit excellent optical properties (blue emission with a fluorescence quantum yield of 46%) and water solubility. The incorporation of thymine into the gCNQDs results in an enhancement in photoluminescence properties. It is found that fluorescence, best measured at excitation/emission wavelengths of 350/445 nm, is much more strongly quenched by Hg(II) compared to the thymine-free nanoprobe. The quenching is highly selective even in the presence other metal ions. This is ascribed to the formation of T-Hg(II)-T base complexes. Fluorescence drops linearly in the 1.0 to 500 nM Hg(II) concentration range, and the limit of detection is 0.15 nM. The method was applied to the determination of Hg(II) in spiked samples of tap and pond water. Recoveries were found to be >95%, thus demonstrating the practical applicability of the assay. Graphical abstract A microwave-assisted hydrothermal route was employed to prepare thymine-functionalized graphitic carbon nitride QDs (T-gCNQDs). A selective fluorescence quenching mechanism occurred between T-gCNQDs and Hg(II) due to thymine functionalization. T-gCNQDs was utilized to detect Hg(II) in real samples.

In situ one-pot synthesis of graphitic carbon nitride quantum dots and its 2,2,6,6-tetramethyl(piperidin-1-yl)oxyl derivatives as fluorescent nanosensors for ascorbic acid.

Graphitic carbon nitride quantum dots (gCNQDs) when alone or containing embedded 4-amino-2,2,6,6-tetramethyl(piperidin-1-yl)oxyl) (4-AT) (gCNQDs-4-AT(embedded)) were synthesized via low temperature in situ one-pot process from diaminomaleonitrile (DAMN). The blue emission of both gCNQDs and gCNQDs-4-AT were excitation wavelength-dependent with very high fluorescence quantum yields of 43 and 51%, respectively. Further, the gCNQDs were covalently linked to 4-AT via an amide bond to give (gCNQDs-4-AT (linked)). gCNQDs were also non-covalently linked to 2,2,6,6-etramethyl(piperidin-1-yl)oxyl (TEMPO, not containing amino groups) derivatized zinc phthalocyanine (ZnPc) to form gCNQDs-TEMPO-ZnPc(π-π). The TEMPO-derivatized gCNQDs (gCNQDs-4-AT(embedded)), gCNQDs-4-AT(linked), or gCNQDs-TEMPO-ZnPc(π-π) were found to be highly sensitive and selective fluorescent probes for ascorbic acid (AA) detection with limits of detection (LOD) in the nanomolar range. Hence, 4-AT (or TEMPO) functionality introduced into the gCNQDs (or ZnPc) afforded the derivation of selective and sensitive AA probes. Real samples were evaluated by the designed probes and satisfactory recoveries further confirmed the analytical applicability of the gCNQDs-based probes.

Graphene quantum dots decorated with maleimide and zinc tetramaleimido-phthalocyanine: Application in the design of "OFF-ON" fluorescence sensors for biothiols.

The fabrication of maleimide-derivatized graphene quantum dots (M-GQDs) and zinc phthalocyanine (2) as novel sensor probes for the selective detection of biothiols (cysteine, homocysteine or glutathione) through the rapid and specific Michael addition reaction between biothiols and the maleimide-derivatized probes is presented in this study. GQDs directly functionalized with maleimide units (M-GQDs) were synthesized and deployed for biothiols recognition following the principle of Michael addition. M-GQDs probe was found to be highly sensitive and selective towards biothiols detection in the nanomolar range in aqueous solution and at physiological pH (7.0). On the other hand, non-covalent interaction between pristine GQDs and novel zinc tetramaleimido-derivatized phthalocyanine resulted in the quenching of the pristine GQDs fluorescence emission which was switched back to the "ON" mode by Michael addition mechanism in the presence of biothiols. Tested relevant biomolecules did not interfere in the quantitative recognition of the biothiols. The probes showed to be highly sensitive, specific and selective for biothiols sensing in simulated real samples.

Nonlinear Interactions of Zinc Phthalocyanine-Graphene Quantum Dots Nanocomposites: Investigation of Effects of Surface Functionalization with Heteroatoms.

This study reports the development of functional optical limiting materials composed of pristine graphene (GQDs), nitrogen-doped (NGQDs) and sulfur-nitrogen co-doped (SNGQDs) graphene quantum dots covalently linked to mono-amino substituted zinc phthalocyanine (Pc). Open aperture Z-scan technique was employed to monitor the behaviour of the conjugates under tightly focussed Gaussian laser beam using a mode-locked Nd:YAG laser delivering 10 nanosecond (FWHM) pulses at 532 nm wavelength. Nonlinear effect due to reverse saturable absorption was the predominant mechanism; and was attributed to the moderately enhanced triplet population. The major factor(s) responsible for the enhanced nonlinearities in the Pc-NGQDs and Pc-SNGQDs was fully described and attributed to the surface defects caused by the presence of heteroatoms of N and S.

Graphene quantum dots coordinated to mercaptopyridine-substituted phthalocyanines: Characterization and application as fluorescence "turn ON" nanoprobes.

This study reports on the design of novel nanoconjugates of graphene quantum dots (GQDs) and tetra or octa-mercaptopyridine-substituted zinc and aluminium phthalocyanines (Pcs) deployed as fluorescence "turn ON" nanoprobes. The phthalocyanines were separately adsorbed onto the planar structure of graphene quantum dots (GQDs) via π-π stacking interaction to form GQDs-mercaptopyridine Pcs nanoconjugates. The quaternized Pc complexes could also interact with the GQDs through electrostatic attraction due to the positive charges on the Pcs ring substituents and the negative charges on the surface of GQDs. The fluorescence emission of the GQDs was quenched upon coordination to the respective Pcs. However, the fluorescence emission was "turned ON" in the presence of Hg2+ employed as a test analyte. The mechanism of the "turn ON" of the GQDs emission in the nanoconjugates is ascribed to the strong affinity of Hg2+ to bind with the bridging sulfur on the Pcs periphery thereby disrupting the π-π stacking interaction between the GQDs and the Pcs with a consequent "turn ON" of the coordinated GQDs' fluorescence.

Graphene Quantum Dots Functionalized with 4-Amino-2, 2, 6, 6-Tetramethylpiperidine-N-Oxide as Fluorescence "Turn-ON" Nanosensors.

In this study, we report on the fabrication of simple and rapid graphene quantum dots (GQDs)-based fluorescence "turn-ON" nanoprobes for sensitive and selective detection of ascorbic acid (AA). Pristine GQDs and S and N co-doped-GQDs (SN-GQDs) were functionalized with 4-amino-2,2,6,6-tetramethylpiperidine-N-oxide (4-amino-TEMPO, a nitroxide free radical). The nitroxide free radicals efficiently quenched the fluorescence of the GQDs and upon interaction of the nanoconjugates with ascorbic acid, the quenched fluorescence was restored. The linear ranges recorded were 0.5-5.7 µM and 0.1-5.5 µM for GQDs-4-amino-TEMPO and SN-GQDs-4amino-TEMPO nanoprobes, respectively. Limits of detection were found to be 60 nM and 84 nM for SN-GQDS-4-amino-TEMPO and GQDs-4-amino-TEMPO for AA detection, respectively. This novel fluorescence "turn-ON" technique showed to be highly rapid and selective towards AA detection.

Interaction of Graphene Quantum Dots with 4-Acetamido-2,2,6,6-Tetramethylpiperidine-Oxyl Free Radicals: A Spectroscopic and Fluorimetric Study.

We report on the interaction of graphene quantum dots (GQDs) with 4-acetamido-2,2,6,6-tetramethylpiperidine-oxyl (4-acetamido-TEMPO) free radicals. The GQDs were N and S, N doped. The fluorescence quantum yields were higher for the doped GQDs compared to the undoped. The interaction is assessed by spectrofluorimetric, steady state/time resolved fluorescence and electron paramagnetic resonance (EPR) techniques. Fluorescence quenching was observed upon the addition of 4-acetamido-TEMPO to the GQDs. Photo-induced electron transfer (PET) mechanism was suggested as the plausible mechanism involved in the fluorescence quenching in which 4-acetamido-TEMPO acted as the electron acceptor.