Calmodulin-like protein CML24 interacts with CAMTA2 and WRKY46 to regulate ALMT1-dependent Al resistance in Arabidopsis thaliana.

ALUMINUM-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-mediated malate exudation from roots is critical for aluminium (Al) resistance in Arabidopsis. Its upstream molecular signalling regulation is not yet well understood. The role of CALMODULIN-LIKE24 (CML24) in Al-inhibited root growth and downstream molecular regulation of ALMT1-meditaed Al resistance was investigated. CML24 confers Al resistance demonstrated by an increased root-growth inhibition of the cml24 loss-of-function mutant under Al stress. This occurs mainly through the regulation of the ALMT1-mediated malate exudation from roots. The mutation and overexpression of CML24 leads to an elevated and reduced Al accumulation in the cell wall of roots, respectively. Al stress induced both transcript and protein abundance of CML24 in root tips, especially in the transition zone. CML24 interacts with CALMODULIN BINDING TRANSCRIPTION ACTIVATOR2 (CAMTA2) and promotes its transcriptional activity in the regulation of ALMT1 expression. This results in an enhanced malate exudation from roots and less root-growth inhibition under Al stress. Both CML24 and CAMTA2 interacted with WRKY46 suppressing the transcriptional repression of ALMT1 by WRKY46. The study provides novel insights into understanding of the upstream molecular signalling of the ALMT1-depdendent Al resistance.

Recent Advances in Layered Ti3 C2 Tx MXene for Electrochemical Energy Storage.

Ti3 C2 Tx , a typical representative among the emerging family of 2D layered transition metal carbides and/or nitrides referred to as MXenes, has exhibited multiple advantages including metallic conductivity, a plastic layer structure, small band gaps, and the hydrophilic nature of its functionalized surface. As a result, this 2D material is intensively investigated for application in the energy storage field. The composition, morphology and texture, surface chemistry, and structural configuration of Ti3 C2 Tx directly influence its electrochemical performance, e.g., the use of a well-designed 2D Ti3 C2 Tx as a rechargeable battery anode has significantly enhanced battery performance by providing more chemically active interfaces, shortened ion-diffusion lengths, and improved in-plane carrier/charge-transport kinetics. Some recent progresses of Ti3 C2 Tx MXene are achieved in energy storage. This Review summarizes recent advances in the synthesis and electrochemical energy storage applications of Ti3 C2 Tx MXene including supercapacitors, lithium-ion batteries, sodium-ion batteries, and lithium-sulfur batteries. The current opportunities and future challenges of Ti3 C2 Tx MXene are addressed for energy-storage devices. This Review seeks to provide a rational and in-depth understanding of the relation between the electrochemical performance and the nanostructural/chemical composition of Ti3 C2 Tx , which will promote the further development of 2D MXenes in energy-storage applications.

Vertically Aligned Co9 S8 Nanotube Arrays onto Graphene Papers as High-Performance Flexible Electrodes for Supercapacitors.

Paper-like electrodes are emerging as a new category of advanced electrodes for flexible supercapacitors (SCs). Graphene, a promising two-dimensional material with high conductivity, can be easily processed into papers. Here, we report a rational design of flexible architecture with Co9 S8 nanotube arrays (NAs) grown onto graphene paper (GP) via a facile two-step hydrothermal method. When employed as flexible free-standing electrode for SCs, the proposed architectured Co9 S8 /GPs exhibits superior electrochemical performance with ultrahigh capacitance and outstanding rate capability (469 F g-1 at 10 A g-1 ). These results demonstrate that the new nanostructured Co9 S8 /GPs can be potentially applied in high performance flexible supercapacitors.

The RAE1-STOP1-GL2-RHD6 module regulates the ALMT1-dependent aluminum resistance in Arabidopsis.

Aluminum (Al) toxicity is one of the major constraints for crop production in acid soils, Al-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-dependent malate exudation from roots is essential for Al resistance in Arabidopsis, in which the C2H2-type transcription factor SENSITIVE TO PROTONRHIZOTOXICITY1 (STOP1) play a critical role. In this study, we reveal that the RAE1-GL2-STOP1-RHD6 protein module regulated the ALMT1-mediated Al resistance. GL2, STOP1 and RHD6 directly target the promoter of ALMT1 to suppress or activate its transcriptional expression, respectively, and mutually influence their action on the promoter of ALMT1 by forming a protein complex. STOP1 mediates the expression of RHD6 and RHD6-regulated root growth inhibition, while GL2 and STOP1 suppress each other's expression at the transcriptional and translational level and regulate Al-inhibited root growth. F-box protein RAE1 degrades RHD6 via the 26S proteasome, leading to suppressed activity of the ALMT1 promoter. RHD6 inhibits the transcriptional expression of RAE1 by directly targeting its promoter. Unlike RHD6, RAE1 promotes the GL2 expression at the protein level and GL2 activates the expression of RAE1 at the transcriptional level by directly targeting its promoter. The study provides insights into the transcriptional regulation of ALMT1, revealing its significance in Al resistance and highlighting the crucial role of the STOP1-associated regulatory networks.

Development of a sequential release nanomaterial for co-delivery of hypoxia-induced tirapazamine and HIF-1α siRNA in cancer therapy.

Unlike traditional drug carriers, sequential drug delivery systems can release different drugs in order, with the first released drug providing a prerequisite for the later released drug to maximize its function, thereby achieving stronger anti-tumor effects. Herein we constructed a temporal sequential system designated TPZ@MSN/HIF-1α siRNA@PDA@GOx (MTRPG) in which mesoporous silica nanoparticles were used as cores to load hypoxia induced chemotherapy drug tirapazamine (TPZ) and gene targeted nucleic acid drug HIF-1α siRNA, polydopamine (PDA) as acid -responsive coating as well as to realize photothermal therapy, and glucose oxidase (GOx) as the outermost layer to achieve starvation therapy and construct a deepened hypoxia to activate TPZ. Through in vitro and in vivo experiments, we demonstrated that the first released glucose oxidase catalyzed the oxidation of glucose, achieving starvation treatment while reducing the acidic environment and further exacerbating hypoxia in tumor cells. The reduced acidic conditions enabled the degradation of PDA, resulting in the release of loaded HIF-1α siRNA and TPZ. At the same time, PDA could also exert photothermal therapy under 808 nm near-infrared (808 nm NIR) laser irradiation. The later released hypoxia induced chemotherapy drug TPZ amplifies its anti-tumor activity under intensified hypoxia conditions. Meanwhile, the released HIF-1α siRNA interfered with the up-regulated HIF-1α induced by the deepened hypoxia condition, which caused hypoxia tolerance in tumors, reduced its expression activity, and achieved synergistic killing of tumor cells with chemotherapy. This work provides an effective multimodal synergistic therapy strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.

Nanoparticles loaded withß-Lapachone and Fe3+exhibit enhanced chemodynamic therapy by producing H2O2through cascaded amplification.

The rapid, irreversible change of active Fe2+to inactive Fe3+after the Fenton reaction occurring reduces the chemodynamic therapeutic (CDT) effect. Therefore, manipulation of the tumor microenvironment to provide sufficient hydrogen peroxide (H2O2) while maintaining metal ion catalyst activity is critical for effective CDT. Here,ß-Lapachone (LPC) was loaded by mesoporous silica nanoparticles (MSNs) and coated with polydopamine (PDA) to further chelate Fe3+and link aptamer AS1411, and a pH-controlled released, chemotherapy-photothermal therapy (PTT)-enhanced CDT-small molecule therapy combination drug delivery system with passive and active tumor targeting was engineered (designated asß-LPC@MSN@PDA/Fe3+-AS1411, LMPFA). The results showed that LFMPA nanoparticles massively accumulated in tumor tissues to achieve tumor targeting through AS1411 mediating and enhanced permeability and retention (EPR) effect. Subsequently, PDA released Fe3+and LPC through acid response to exhibited CDT and chemotherapeutic therapy. Meanwhile, the photothermal effect of PDA promoted the release of LPC from the pores of MSN. LPC exerted chemotherapy effect and cyclically producing of H2O2by the catalysis of NQO1, which enhanced the CDT activated by Fe3+. In addition, while serving as a targeted ligand, AS1411 could also exhibit a small molecule therapeutic effect by binding to nucleoli of tumor cells. This unique nano delivery system achieved the combination of chemotherapy, PTT, enhanced CDT and small molecule therapy, and fought against malignant tumors synergistically through multi-target and multi-dimension.

Multilayer nanodrug delivery system with spatiotemporal drug release improves tumor microenvironment for synergistic anticancer therapy.

The inflammatory response is one of the general symptoms that accompany tumorigenesis, the pro-inflammatory factors cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin-2 (PGE-2) in the inflammatory environment surrounding tumors possess promoting tumor development, metastasis and angiogenesis effects. In addition, the hypoxic environment of tumors severely limits the effectiveness of photodynamic therapy (PDT). In this study, a universal extracellular-intracellular 'on-demand' release nanomedicine DOX@PDA-ICG@MnO2@GN-CEL was developed for the combined fight against malignant tumors using a spatiotemporal controlled gelatin coated polydopamine (PDA@GN) as the carrier and loaded with the chemotherapeutic drug doxorubicin (DOX), the photosensitizer indocyanine green (ICG), the PDT enhancer MnO2and the anti-inflammatory drug celecoxib (CEL) individually. Our results showed that DOX@PDA-ICG@MnO2@GN-CEL could release CEL extracellularly by matrix metalloproteinase-2 response and inhibit the COX-2/PGE-2 pathway, reduce chemotherapy resistance and attenuate the concurrent inflammation. After entering the tumor cells, the remaining DOX@PDA-ICG@MnO2released DOX, ICG and MnO2intracellularly through PDA acid response. MnO2promoted the degradation of endogenous H2O2to generate oxygen under acidic conditions to alleviate the tumor hypoxic environment, enhance PDT triggered by ICG. PDA and ICG exhibited photothermal therapy synergistically, and DOX exerted chemotherapy with reduced chemotherapy resistance. The dual responsive drug release switch enabled the chemotherapeutic, photothermal, photodynamic and anti-inflammatory drugs precisely acted on different sites of tumor tissues and realized a promising multimodal combination therapy.

Progressive enhanced photodynamic therapy and enhanced chemotherapy fighting against malignant tumors with sequential drug release.

During the process of malignant tumor treatment, photodynamic therapy (PDT) exerts poor efficacy due to the hypoxic environment of the tumor cells, and long-time chemotherapy reduces the sensitivity of tumor cells to chemotherapy drugs due to the presence of drug-resistant proteins on the cell membranes for drug outward transportation. Therefore, we reported a nano platform based on mesoporous silica coated with polydopamine (MSN@PDA) loading PDT enhancer MnO2, photosensitizer indocyanine green (ICG) and chemotherapeutic drug doxorubicin (DOX) (designated as DMPIM) to achieve a sequential release of different drugs to enhance treatment of malignant tumors. MSN was first synthesized by a template method, then DOX was loaded into the mesoporous channels of MSN, and locked by the PDA coating. Next, ICG was modified by π-π stacking on PDA, and finally, MnO2layer was accumulated on the surface of DOX@MSN@PDA- ICG@MnO2, achieving orthogonal loading and sequential release of different drugs. DMPIM first generated oxygen (O2) through the reaction between MnO2and H2O2after entering tumor cells, alleviating the hypoxic environment of tumors and enhancing the PDT effect of sequentially released ICG. Afterwards, ICG reacted with O2in tumor tissue to produce reactive oxygen species, promoting lysosomal escape of drugs and inactivation of p-glycoprotein (p-gp) on tumor cell membranes. DOX loaded in the MSN channels exhibited a delay of approximately 8 h after ICG release to exert the enhanced chemotherapy effect. The drug delivery system achieved effective sequential release and multimodal combination therapy, which achieved ideal therapeutic effects on malignant tumors. This work offers a route to a sequential drug release for advancing the treatment of malignant tumors.

Electrochemiluminescence biosensor based on conducting poly(5-formylindole) for sensitive detection of Ramos cells.

A signal-on electrochemiluminescence (ECL) biosensor devoted to the detection of Ramos cells was fabricated based on a novel conducting polymer, poly(5-formylindole) (P5FIn), which was synthesized electrochemically by direct anodic oxidation of 5-formylindole (5FIn). This ECL platform was presented by covalently coupling the 18-mer amino-substituted oligonucleotide (ODN) probes with aldehyde groups that are strongly reactive toward a variety of nucleophiles on the surface of solid substrates. The specific identification and high-affinity between aptamers and target cells, gold nanoparticles (AuNPs) enhanced ECL nanoprobes, along with P5FIn induced ECL quenching contributed greatly to the sensitivity and selectivity. The ECL signals were logarithmically linear with the concentration of Ramos cells in a wide determination range from 500 to 1.0 × 10(5) cells mL(-1), and the corresponding detection limit was 300 cells mL(-1).

[Raman and infrared spectrograms of organic borate intercalated hydrotalcite].

The pattern of X-ray diffraction, the Raman and infrared spectra of organic borate intercalated hydrotalcite were discussed. The well crystallized zinc-aluminum layered double hydroxides (Zn-Al LDHs) intercalated by carbonate ions and borate ions were respectively prepared by co-precipitation method. Patterns of X-ray diffraction showed that the (003) reflection of borate-LDHs was sharp and symmetric and shifted to lower angle than that of carbonate-LDHs. The gallery height of borate-LDHs increased from 0. 28 nm to 0.42 nm after intercalation, indicating that interlayered carbonate ions were substituted by borate anions. The Raman and IR spectra showed that specific bands of carbonate ions in the borate-LDHs disappeared, but with the presence of B3O3(OH)4- X B4O5(OH)4(2-) and B(OH)4- in the interlayer galleries. The hydroxide interlayer anions had a significant influence on the band positions in Raman and infrared spectra of modes related to the hydroxyl group. Our results indicate that single phase and pure borate-pillared LDHs can be obtained using tributyl orthoborate as intercalating agents, and the change in the structure and nature of hydrotalcite can be detected precisely by Raman spectroscopy.

Non-interference delivery of Ce6 and DOX in NIR light-responsive liposomes for synergetic cervical cancer therapy.

Multi-model combination treatment of malignant tumors can make up for the shortcomings of single treatment through multi-target and multi-path to achieve more ideal tumor treatment effect. However, the mutual interference of different drugs in the delivery processin vivoand the difficulty of effective drug accumulation in tumor cells are the bottlenecks of combined therapy. To this project, light-responsive liposomes loading doxorubicin (DOX) and chlorin e6 (Ce6) (DOX-Ce6-Lip) without mutual interference were engineered by thin film hydration method. This kind of nano-drug delivery system increased the drugs concentration accumulated in tumor sites through enhanced permeability and retention effect, and reduced the toxic and side effects of drugs on normal tissuesin vivo. In addition, after entering the tumor cells, Ce6 produced a large number of reactive oxygen species under 660 nm NIR laser irradiation, which further oxidized the unsaturated fatty acid chain in the liposomes and caused the collapse of the liposomes, thus realizing the stimulus-responsive release of Ce6 and DOX. The concentrations of DOX and Ce6 in the tumor cells rapidly reached the peak and achieved a more effective combination of chemotherapy and photodynamic therapy (PDT). Consequently, DOX-Ce6-Lip followed by 660 nm NIR irradiation achieved an efficient tumor growth inhibition of 71.90 ± 3.14%, indicating the versatile potential of chemotherapy and PDT. In conclusion, this study provides a delivery scheme for drugs with different solubilities and an effectively combined anti-tumor therapy method.

A systematic review of primary gastric diffuse large B-cell lymphoma: Clinical diagnosis, staging, treatment and prognostic factors.

Primary gastric lymphoma (PGL) is a rare clinical entity accounting for the majority of extra-nodal non-Hodgkin lymphoma (EN-NHL). The most common histological subtype is the primary gastric diffuse large B-cell lymphoma (PG-DLBCL) with a media age of 50-60 years old, mostly in male. Pathogenesis is often related to some bacterial infection such as Helicobacter pylori (H. pylori) infection. However, due to various available staging system, there is still no consensus on the staging of PG-DLBCL. The international prognostic index (IPI) is the most valuable used for the stratification of almost all subtype of NHL and as well as for PG-DLBCL. As for treatment strategies, surgery, chemotherapy, radiation therapy and antibiotic therapy in various combinations have been applied in clinical treatment. There are a few well-known prognostic factors and some of them may constitute prognostic models. Due to the increasing incidence of this neoplasm, it is necessary for clinicians to make deep insight of the diagnosis, staging, treatment and prognostic factors of PG-DLBCL.

Clinical prognosis and bioinformatic analysis of primary thyroid lymphoma.

ABSTRACT: Primary thyroid lymphoma (PTL) is a rare malignant disease with the most common histological type of diffuse large B-cell lymphoma (DLBCL). Hashimoto's thyroiditis (HT) is closely related to the pathogenesis of PTL. The present study is to explore the clinical prognosis of PTL and analyze the gene correlations between PTL and HT.Thirty-nine patients diagnosed with PTL between 2010 and 2018 in our institute were retrospectively reviewed and clinical features were evaluated on PTL survival. Then, overlapping differentially expressed genes (DEGs) between PTL and HT were evaluated for gene ontology, pathways enrichment, protein-protein interaction network analysis. Furthermore, we used gene expression profiling interactive analysis to evaluate the differential expression of these hub genes.In this analysis, International Prognostic Index (IPI) score ≥3 and high ß2-MG (>3 mg/L) were associated with worse prognosis in PTL. Notably, a total of 15 both upregulated DEGs in DLBCL and HT were identified and 10 hub genes with a high degree of connectivity were picked out. Among these 10 hub genes, IL6, IL10, CXCL10, and CXCR3 were higher expressed in DLBCL than the normal tissue but have no significant prognosis of DLBCL.High IPI score and high ß2-MG level have a poor prognosis in PTL. Besides, IL6, IL10, CXCL10, and CXCR3 are associated with both DLBCL and HT and may be used for the early diagnosis of PTL.

Identification of Methicillin-Resistant Staphylococcus Aureus From Methicillin-Sensitive Staphylococcus Aureus and Molecular Characterization in Quanzhou, China.

To distinguish Methicillin-Resistant Staphylococcus aureus (MRSA) from Methicillin-Sensitive Staphylococcus aureus (MSSA) in the protein sequences level, test the susceptibility to antibiotic of all Staphylococcus aureus isolates from Quanzhou hospitals, define the virulence factor and molecular characteristics of the MRSA isolates. MRSA and MSSA Pfam protein sequences were used to extract feature vectors of 188D, n-gram and 400D. Weka software was applied to classify the two Staphylococcus aureus and performance effect was evaluated. Antibiotic susceptibility testing of the 81 Staphylococcus aureus was performed by the Mérieux Microbial Analysis Instrument. The 65 MRSA isolates were characterized by Panton-Valentine leukocidin (PVL), X polymorphic region of Protein A (spa), multilocus sequence typing test (MLST), staphylococcus chromosomal cassette mec (SCCmec) typing. After comparing the results of Weka six classifiers, the highest correctly classified rates were 91.94, 70.16, and 62.90% from 188D, n-gram and 400D, respectively. Antimicrobial susceptibility test of the 81 Staphylococcus aureus: Penicillin-resistant rate was 100%. No resistance to teicoplanin, linezolid, and vancomycin. The resistance rate of the MRSA isolates to clindamycin, erythromycin and tetracycline was higher than that of the MSSAs. Among the 65 MRSA isolates, the positive rate of PVL gene was 47.7% (31/65). Seventeen sequence types (STs) were identified among the 65 isolates, and ST59 was the most prevalent. SCCmec type III and IV were observed at 24.6 and 72.3%, respectively. Two isolates did not be typed. Twenty-one spa types were identified, spa t437 (34/65, 52.3%) was the most predominant type. MRSA major clone type of molecular typing was CC59-ST59-spa t437-IV (28/65, 43.1%). Overall, 188D feature vectors can be applied to successfully distinguish MRSA from MSSA. In Quanzhou, the detection rate of PVL virulence factor was high, suggesting a high pathogenic risk of MRSA infection. The cross-infection of CA-MRSA and HA-MRSA was presented, the molecular characteristics were increasingly blurred, HA-MRSA with typical CA-MRSA molecular characteristics has become an important cause of healthcare-related infections. CC59-ST59-spa t437-IV was the main clone type in Quanzhou, which was rare in other parts of mainland China.

Primary Gastric Diffuse Large B-Cell Lymphoma: Prognostic Factors in the Immuno-Oncology Therapeutics Era

Objective: This study aimed to explore the prognostic factors for primary gastric diffuse large B-cell lymphoma (PG-DLBCL). Materials and Methods: This retrospective study analyzed 72 PG-DLBCL patients between January 2012 and December 2017 in the Shanxi Cancer Hospital of Shanxi Medical University to identify the different prognostic factors in PG-DLBCL. The clinical features, treatment, and follow-up information were analyzed. Results: The low CD4:CD8 ratio group (median subsequent overall survival [OS]: 36.06 months; 95% confidence interval [CI]: 25.73-46.40) showed a significant decrease in subsequent OS compared to the normal group among PG-DLBCL patients who were newly diagnosed and did not receive rituximab (median OS: 52.58 months; 95% CI: 44.18-60.97; p=0.029). Event-free survival status 24 months after the date of diagnosis (EFS24) also decreased significantly in the low CD4:CD8 group (median EFS24: 16.27 months; 95% CI: 13.09-19.45) compared to the normal group (median EFS24: 20.34 months; 95% CI: 17.05-23.63; p=0.014). Multivariate analysis showed that low CD4:CD8 at diagnosis was an independent poor prognostic factor for subsequent OS and EFS24. Conclusion: Our data suggest that identifying prognostic factors, especially host immunity, may provide useful information for assessing prognosis or clinical management.

MiR-93-5p Promotes Cell Proliferation through Down-Regulating PPARGC1A in Hepatocellular Carcinoma Cells by Bioinformatics Analysis and Experimental Verification.

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, formerly known as PGC-1a) is a transcriptional coactivator and metabolic regulator. Previous studies are mainly focused on the association between PPARGC1A and hepatoma. However, the regulatory mechanism remains unknown. A microRNA associated with cancer (oncomiR), miR-93-5p, has recently been found to play an essential role in tumorigenesis and progression of various carcinomas, including liver cancer. Therefore, this paper aims to explore the regulatory mechanism underlying these two proteins in hepatoma cells. Firstly, an integrative analysis was performed with miRNA-mRNA modules on microarray and The Cancer Genome Atlas (TCGA) data and obtained the core regulatory network and miR-93-5p/PPARGC1A pair. Then, a series of experiments were conducted in hepatoma cells with the results including miR-93-5p upregulated and promoted cell proliferation. Thirdly, the inverse correlation between miR-93-5p and PPARGC1A expression was validated. Finally, we inferred that miR-93-5p plays an essential role in inhibiting PPARGC1A expression by directly targeting the 3'-untranslated region (UTR) of its mRNA. In conclusion, these results suggested that miR-93-5p overexpression contributes to hepatoma development by inhibiting PPARGC1A. It is anticipated to be a promising therapeutic strategy for patients with liver cancer in the future.

Superior Cathode Performance of Nitrogen-Doped Graphene Frameworks for Lithium Ion Batteries.

Development of alternative cathode materials is of highly desirable for sustainable and cost-efficient lithium-ion batteries (LIBs) in energy storage fields. In this study, for the first time, we report tunable nitrogen-doped graphene with active functional groups for cathode utilization of LIBs. When employed as cathode materials, the functionalized graphene frameworks with a nitrogen content of 9.26 at% retain a reversible capacity of 344 mAh g-1 after 200 cycles at a current density of 50 mA g-1. More surprisingly, when conducted at a high current density of 1 A g-1, this cathode delivers a high reversible capacity of 146 mAh g-1 after 1000 cycles. Our current research demonstrates the effective significance of nitrogen doping on enhancing cathode performance of functionalized graphene for LIBs.

Simple Label-Free Femtomolar DNA Detection Based on a Nanostructure Composite Material: MWNT-Doped Poly(indole-6-carboxylic acid).

A nanostructure composite material consisting of poly(indole-6-carboxylic acid) (PICA) and carboxylic groups ended multiwall carbon nanotubes (MWNTs) was directly electrosynthesized from indole-6-carboxylic acid (ICA) monomer and MWNTs in one step, in which MWNTs was also used as supporting electrolytes. And a simple electrochemical sensor for recognition of target DNA related to hepatitis B virus (HBV) was directly fabricated by means of this composite material. The corresponding detection limit is 2.0 fmol L-1. This interesting conducting polymer with a very large surface area will provide new insights into how a biosensor is designed.