Structural mechanisms for binding and activation of a contact-quenched fluorophore by RhoBAST.

The fluorescent light-up aptamer RhoBAST, which binds and activates the fluorophore-quencher conjugate tetramethylrhodamine-dinitroaniline with high affinity, super high brightness, remarkable photostability, and fast exchange kinetics, exhibits excellent performance in super-resolution RNA imaging. Here we determine the co-crystal structure of RhoBAST in complex with tetramethylrhodamine-dinitroaniline to elucidate the molecular basis for ligand binding and fluorescence activation. The structure exhibits an asymmetric "A"-like architecture for RhoBAST with a semi-open binding pocket harboring the xanthene of tetramethylrhodamine at the tip, while the dinitroaniline quencher stacks over the phenyl of tetramethylrhodamine instead of being fully released. Molecular dynamics simulations show highly heterogeneous conformational ensembles with the contact-but-unstacked fluorophore-quencher conformation for both free and bound tetramethylrhodamine-dinitroaniline being predominant. The simulations also show that, upon RNA binding, the fraction of xanthene-dinitroaniline stacked conformation significantly decreases in free tetramethylrhodamine-dinitroaniline. This highlights the importance of releasing dinitroaniline from xanthene tetramethylrhodamine to unquench the RhoBAST-tetramethylrhodamine-dinitroaniline complex. Using SAXS and ITC, we characterized the magnesium dependency of the folding and binding mode of RhoBAST in solution and indicated its strong structural robustness. The structures and binding modes of relevant fluorescent light-up aptamers are compared, providing mechanistic insights for rational design and optimization of this important fluorescent light-up aptamer-ligand system.

The association between the triglyceride-glucose index and in-stent restenosis in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Insulin resistance (IR) can lead to cellular metabolic disorders, activation of oxidative stress, and endothelial dysfunction, contributing to in-stent restenosis (ISR). The triglyceride-glucose index (TyG index), a new indicator reflecting IR, is extensively researched in the cardiovascular field. This study, through a meta-analysis, aimed to utilize a larger combined sample size and thereby enhance the overall test efficacy to explore the TyG index-ISR relationship. METHODS: A thorough search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases to find original papers and their references published between 1990 and January 2024. This search included both prospective and retrospective studies detailing the correlation between the TyG index and ISR in individuals with coronary heart disease (CHD). OUTCOMES: The five included articles comprised 3,912 participants, and the odds ratio (OR) extracted from each study was combined using the Inverse Variance method. Results showed that, in the context of CHD patients, each incremental unit in the TyG index, when treated as a continuous variable, corresponded to a 42% elevation in ISR risk (95% CI 1.26-1.59, I²=13%, p < 0.005). When analyzing the TyG index categorically, the results revealed a higher ISR risk in the highest TyG index group compared to the lowest group (OR: 1.69, 95% CI 1.32-2.17, I²=0). Additionally, in patients with chronic coronary syndrome (CCS), each unit increase in the TyG index, the risk of ISR in patients increased by 37% (95% CI 1.19-1.57, I²=0%, p < 0.005). This correlation was also observable in acute coronary syndrome (ACS) patients (OR:1.48, 95% CI 1.19-1.85, I²=0, p < 0.005). CONCLUSIONS: The TyG index, an economical and precise surrogate for IR, is significantly linked with ISR. Furthermore, this correlation is unaffected by the type of coronary heart disease.

A new agent for contrast-enhanced intravascular ultrasound imaging in vitro: polybutylcyanoacrylate nanoparticles with drug-carrying capacity.

This study prepared and evaluated polymeric polybutylcyanoacrylate (PBCA) nanoparticles (NPs) that can be used as a new agent for contrast-enhanced intravascular ultrasound (IVUS) imaging with drug delivery capacity. The nanoformulation was successfully developed using suspension polymerisation and characterised in terms of size, size distribution, zeta potential, morphology, stability, toxicity effects, imaging effects and drug release study. The results showed that the nanoparticles were round and hollow, with a particle diameter of 215.8 ± 25.3 nm and a zeta potential of -22.2 ± 4.1 mV. In vitro experiments, the nanoparticles were safe, non-toxic, and stable in nature with the capacity to carry and release drug (ant-miR-126). Moreover, the nanoparticles can match the high-frequency probe of commercially IVUS as a contrast agent to improve the resolution of imaging (the mean echo intensity ratio in the vascular wall increased significantly from 10.89 ± 1.10 at baseline, to 24.51 ± 1.91 during injection and 43.70 ± 0.88 after injection, respectively p < .0001). Overall, a new nano agent with drug-carrying capacity was prepared, which can be used in combination with IVUS for simultaneous diagnosis and targeted therapy of coronary atherosclerosis.

Efficacy of rTMS in treating functional impairment in post-stroke patients: a systematic review and meta-analysis.

BACKGROUND: Most stroke patients suffer from an imbalance in blood supply, which causes severe brain damage leading to functional deficits in motor, sensory, swallowing, cognitive, emotional, and speech functions. Repetitive transcranial magnetic stimulation (rTMS) is thought to restore functions impaired during the stroke process and improve the quality of life of stroke patients. However, the efficacy of rTMS in treating post-stroke function impairment varies significantly. Therefore, we conducted a meta-analysis of the number of patients with effective rTMS in treating post-stroke dysfunction. METHODS: The PubMed, Embase, and Cochrane Library databases were searched. Screening and full-text review were performed by three investigators. Single-group rate meta-analysis was performed on the extracted data using a random variable model. Then subgroup analyses were performed at the levels of stroke acuity (acute, chronic, or subacute); post-stroke symptoms (including upper and lower limb motor function, dysphagia, depression, aphasia); rTMS stimulation site (affected side, unaffected side); and whether or not it was a combination therapy. RESULTS: We obtained 8955 search records, and finally 33 studies (2682 patients) were included in the meta-analysis. The overall analysis found that effective strength (ES) of rTMS was 0.53. In addition, we found that the ES of rTMS from acute/subacute/chronic post-stroke was 0.69, 0.45, and 0.52. We also found that the ES of rTMS using high-frequency stimulation was 0.56, while the ES of rTMS using low-frequency stimulation was 0.53. From post-stroke symptoms, we found that the ES of rTMS in sensory aspects, upper limb functional aspects, swallowing function, and aphasia was 0.50, 0.52, 0.51, and 0.54. And from the site of rTMS stimulation, we found that the ES of rTMS applied to the affected side was 0.51, while the ES applied to the unaffected side was 0.54. What's more, we found that the ES of rTMS applied alone was 0.53, while the ES of rTMS applied in conjunction with other therapeutic modalities was 0.53. CONCLUSIONS: By comparing the results of the data, we recommend rTMS as a treatment option for rehabilitation of functional impairment in patients after stroke. We also recommend that rehabilitation physicians or clinicians use combination therapy as one of the options for patients.

Performance of [18F]FDG PET/CT versus FAPI PET/CT for lung cancer assessment: a systematic review and meta-analysis.

PURPOSE: This article aims to compare the diagnostic performance of 18-fluorodeoxyglucose ([18F]FDG) PET/CT and fibroblast activating protein inhibitor (FAPI) PET/CT in the assessment of primary tumors, lymph nodes, and distant metastases in lung cancer patients. METHODS: A systematic search was conducted on the Cochrane Library, Embase, and PubMed/MEDLINE databases from inception until November 1, 2022. Included studies assessed the use of FAPI PET/CT and [18F]FDG PET/CT in patients with lung cancer. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the risk of bias. A random variable model was used to analyze the diagnostic tests of the two imaging modalities. RESULTS: The sensitivity of FAPI PET/CT in detecting primary lung cancer lesions was 0.98 (95% CI: 0.88-1.00), while the sensitivity of [18F]FDG PET/CT was 0.99 (95% CI: 0.74-1.00). For the detection of metastatic lesions (lymph node metastases and distant metastases), FAPI PET/CT had a sensitivity of 0.99 (95% CI: 0.90-1.00), while the sensitivity of [18F]FDG PET/CT was 0.77 (95% CI: 0.66-0.85). However, the specificity of the two imaging modalities could not be assessed due to the lack of sufficient information on pertinent true negatives. CONCLUSION: In the diagnosis of metastatic lung cancer lesions, FAPI PET/CT demonstrated a higher sensitivity compared to [18F]FDG PET/CT. Therefore, FAPI PET/CT may be considered an alternative imaging modality for the assessment of primary lung cancer tumors, lymph node metastases, and distant metastases. CLINICAL RELEVANCE STATEMENT: FAPI may be an alternative to [18F]FDG in the assessment of primary lung cancer tumors, lymph node metastases, and distant metastases, which plays a very important role in treatment. KEY POINTS: • This article is to compare the performance of [18F]FDG PET/CT with FAPI PET/CT in the assessment of primary tumors, lymph nodes, and distant metastases in lung cancer. • However, FAPI PET/CT has a higher sensitivity for the diagnostic assessment of metastatic lung cancer lesions.

Spatiotemporal Excitation Module-based CNN for Diagnosis of Hepatic Malignancy in Four-phase CT Images.

Liver cancer is a part of the common causes of cancer death worldwide, and the accurate diagnosis of hepatic malignancy is important for effective next treatment. In this paper, we propose a convolutional neural network (CNN) based on a spatiotemporal excitation (STE) module for identification of hepatic malignancy in four-phase computed tomography (CT) images. To enhance the display detail of lesion, we expand single-channel CT images into three channels by using the channel expansion method. Our proposed STE module consists of a spatial excitation (SE) module and a temporal interaction (TI) module. The SE module calculates the temporal differences of CT slices at the feature level, which is used to excite shape-sensitive channels of the lesion features. The TI module shifts a portion of the channels in the temporal dimension to exchange information among the current CT slice and adjacent CT slices. Four-phase CT images of 398 patients diagnosed with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are used for experiments and five cross-validations are performed. Our model achieved average accuracy of 85.00% and average AUC of 88.91% for classifying HCC and ICC.Clinical Relevance- The proposed deep learning-based model can perform HCC and ICC recognition tasks based on four-phase CT images, assisting doctors to obtain better diagnostic performance.

On the Ionic Conductivity of Cation Exchange Membranes in Mixed Sulfates Using the Two-Phase Model.

The concentration dependence of the conductivity of ion exchange membranes (IEMs), as well as other transport properties, has been well explained by the contemporary two-phase model (Zabolotsky et al., 1993) considering a gel phase and an inter-gel phase filled with electroneutral solution. Here, this two-phase model has been adopted and first applied in electrolytes containing mixed counter-ions to investigate the correlation between the membrane ionic conductivity and its microstructure. For three representative commercial cation exchange membranes (CEMs), the total membrane conductivity (κT) when in equilibrium with mixed MgSO4 + Na2SO4 and H2SO4 + Na2SO4 electrolytes could be well predicted with the experimental composition of counter-ions in the gel and inter-gel phase, as well as the counter-ion mobility in the gel phase when the membrane is in a single electrolyte. It is found that the volume fraction of the inter-gel phase (f2) has little impact on the predicted results. The accuracy of the model can be largely improved by calculating the inter-gel phase conductivity (κin) with the ionic mobility being the same as that in the external solution (obtained via simulation in the OLI Studio), rather than simply as equivalent to the conductivity of the external solution (κs). Moreover, a nonlinear correlation between the CEMs' conductivities and the counter-ion composition in the gel phase is observed in the mixed MgSO4 + Na2SO4 solution, as well as for the Nafion117 membrane in the presence of sulfuric acid. For CEMs in mixed MgSO4 + Na2SO4 electrolytes, the calculated conductivity values considering the interaction parameter σ, similar to the Kohlrausch's law, are closer to the experimental ones. Overall, this work provides new insights into membrane conductivity with mixed counter-ions and testifies to the applicability of the contemporary two-phase model.

Graphene Enhances the Loading Capacity and Lubrication Performance of Ionic Liquids: A Molecular Dynamics Study.

Ionic liquid (IL) combined with graphene additives have garnered extensive attention in the field of high-performance lubricating materials. However, the ambiguous mechanism of graphene influencing the load-carrying and anti-wear capacity of ILs needs further study. In this work, friction simulation shows that adding graphene causes friction coefficient to reduce by up to 88% compared with pure ILs, but lubrication performance is lost due to the destruction of graphene under high stress. Meanwhile, multilayer graphene has better friction-reducing performance and friction durability as compared to the monolayer structure, which is attributed to the easy-shear property and the reduction in the percentage of high tensile stress sites in multilayer graphene structure. In addition, it was found that excessively thick ILs film would form a three-body abrasive wear structure with graphene, which accelerated the structural destruction of graphene and caused a decline in its tribological properties. It is believed these findings can be valuable for designing of high-performance lubricating oil for practical engineering.

Synthesis of the Isodityrosine Moiety of Seongsanamide A-D and Its Derivatives.

The concise and highly convergent synthesis of the isodityrosine unit of seongsanamide A-D and its derivatives bearing a diaryl ether moiety is described. In this work, the synthetic strategy features palladium-catalyzed C(sp3)-H functionalization and a Cu/ligand-catalyzed coupling reaction. We report a practical protocol for the palladium-catalyzed mono-arylation of ß-methyl C(sp3)-H of an alanine derivative bearing a 2-thiomethylaniline auxiliary. The reaction is compatible with a variety of functional groups, providing practical access to numerous ß-aryl-α-amino acids; these acids can be converted into various tyrosine and dihydroxyphenylalanine (DOPA) derivatives. Then, a CuI/N,N-dimethylglycine-catalyzed arylation of the already synthesized DOPA derivatives with aryl iodides is described for the synthesis of isodityrosine derivatives.

Genetically encoded RNA-based sensors with Pepper fluorogenic aptamer.

Sensors to measure the abundance and signaling of intracellular molecules are crucial for understanding their physiological functions. Although conventional fluorescent protein-based sensors have been designed, RNA-based sensors are promising imaging tools. Numerous RNA-based sensors have been developed. These sensors typically contain RNA G-quadruplex (RG4) motifs and thus may be suboptimal in living cells. Here we describe RNA-based sensors based on Pepper, a fluorogenic RNA without an RG4 motif. With Pepper, we engineered various sensors for metabolites, synthetic compounds, proteins and metal ions in vitro and in living cells. In addition, these sensors show high activation and selectivity, demonstrating their universality and robustness. In the case of sensors responding to S-adenosylmethionine (SAM), a metabolite produced by methionine adenosyltransferase (MATase), we showed that our sensors exhibited positively correlated fluorescence responding to different SAM levels. Importantly, we revealed the SAM biosynthesis pathway and monitored MATase activity and gene expression spatiotemporally in living individual human cells. Additionally, we constructed a ratiometric SAM sensor to determine the inhibition efficacy of a MATase inhibitor in living cells. Together, these sensors comprising Pepper provide a useful platform for imaging diverse cellular targets and their signaling pathway.

Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis).

Mitogen-activated protein kinase (MAPK) cascades are conserved and universal signal transduction modules that play important roles in regulating stress responses in plants. Although MAP3K, MP2K, and MPK family in tea plant (Camellia sinensis) have been investigated, little is known about MPK family genes responding to various abiotic stresses in tea plant. In this study, we performed a comprehensive genome-wide analysis of the tea plant MAPKs (CsMPKs) family gene based on the genomic data of tea plants by bioinformatics-based methods. Here, 21 putative CsMPK genes were identified in the tea plant and divided into 4 subfamilies according to the homologous to Arabidopsis and their phylogenetic relationships. The gene structure and conserved motifs of these CsMPKs in the same group showed high similarity, suggesting that they were highly conserved and might have a similar function. The expression profiles of the CsMPK genes were further investigated by quantitative real-time reverse transcription PCR, indicating that many CsMPK genes were involved in response to cold, drought, heat, or heat combined with drought treatment, suggesting their potential roles in abiotic stress responses in tea plant. These results would provide valuable information for further exploring the functional characterization of CsMPK genes in tea plants.

Autoamputation of the appendix and survival of the amputated part: a rare case report and literature review.

BACKGROUND: Autoamputation of the appendix, i.e., complete separation of a part of the appendix without any surgical intervention, has been rarely documented in the literature in recent years. Herein, we report a case where the amputated part of the appendix was viable after autoamputation and reviewed the related literature. CASE PRESENTATION: A 39-year-old female patient was admitted to our hospital complaining of abdominal pain and subsequently underwent an emergency laparoscopic appendectomy (LA). Intraoperatively, we found an abnormally short appendix protruding from the cecum and a strip-like tissue attached to the mesoappendix, considered a duplex appendix, was resected. Finally, in conjunction with the histopathology findings and the past medical history, the patient was diagnosed with "Pseudo-duplication of the Appendix". CONCLUSIONS: Autoamputation of the appendix resulting in preserved tissue viability and absence of necrosis at both ends, can be termed as "Pseudo-duplication of the Appendix". This condition is very rare in clinical practice and has not been reported in China, to the best of our knowledge. It has been established that the autoamputated appendix can produce chronic inflammation, intestinal fistulae and even cancer, affecting the patient's quality of life. Accordingly, a clear diagnosis and timely management are essential. In this report, we established a novel classification for "Pseudo-duplication of the Appendix", hoping that our report will help surgeons better understand this anatomical anomaly of the appendix, to help during the differential diagnosis process and avoid confusion.

Determination of isoscoparin in mouse blood using UPLC-MS/MS and its pharmacokinetics.

This study developed a UPLC-MS/MS method to detect isoscoparin in mouse blood, determined the pharmacokinetics of isoscoparin in mice after intravenous (5 mg/kg) and intragastric (20 mg/kg) administration, and calculated the absolute bioavailability. A HSS T3 column was used for separation, and the column temperature was set at 40°C. The mobile phases were acetonitrile and 0.1% formic acid, and the gradient elution procedure was used. The blood sample was treated with protein precipitant with acetonitrile-methanol (9:1, v/v). Multiple reaction monitoring mode was used for quantitative analysis in electrospray positive-ion mode. It showed a good linear relationship in the range of 1-4000 ng/mL (r > 0.998); the intra-day and inter-day precision was <12%, and the accuracy was 86-112%. The recovery was >68%, and the matrix effect was 86-90%. The half-life of isoscoparin was relatively short in mice, and the bioavailability was 2.6%. The developed UPLC-MS/MS method was rapid, sensitive, and suitable for the pharmacokinetics of isoscoparin in mice.

Quantum Misuse Attack on Frodo.

Research on the security of lattice-based public-key encryption schemes against misuse attacks is an important part of the cryptographic assessment of the National Institute of Standards and Technology (NIST) post-quantum cryptography (PQC) standardization process. In particular, many NIST-PQC cryptosystems follow the same meta-cryptosystem. At EUROCRYPT 2019, Ba˘etu et al. mounted a classical key recovery under plaintext checking attacks (KR-PCA) and a quantum key recovery under chosen ciphertext attacks (KR-CCA). They analyzed the security of the weak version of nine submissions to NIST. In this paper, we focus on learning with error (LWE)-based FrodoPKE, whose IND-CPA security is tightly related to the hardness of plain LWE problems. We first review the meta-cryptosystem and quantum algorithm for solving quantum LWE problems. Then, we consider the case where the noise follows a discrete Gaussian distribution and recompute the success probability for quantum LWE by using Hoeffding bound. Finally, we give a quantum key recovery algorithm based on LWE under CCA attack and analyze the security of Frodo. Compared with the existing work of Ba˘etu et al., our method reduces the number of queries from 22 to 1 with the same success probability.

Solving HNP with One Bit Leakage: An Asymmetric Lattice Sieving Algorithm.

The Hidden Number Problem (HNP) was introduced by Boneh and Venkastesan to analyze the bit-security of the Diffie-Hellman key exchange scheme. It is often used to mount a side-channel attack on (EC)DSA. The hardness of HNP is mainly determined by the number of nonce leakage bits and the size of the modulus. With the development of lattice reduction algorithms and lattice sieving, the range of practically vulnerable parameters are extended further. However, 1-bit leakage is still believed to be challenging for lattice attacks. In this paper, we proposed an asymmetric lattice sieving algorithm that can solve HNP with 1-bit leakage. The algorithm is composed of a BKZ pre-processing and a sieving step. The novel part of our lattice sieving algorithm is that the lattice used in these two steps have different dimensions. In particular, in the BKZ step we use more samples to derive a better lattice basis, while we just use truncated lattice basis for the lattice sieving step. To verify our algorithm, we use it to solve HNP with 1-bit leakage and 116-bit modulus.

Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration.

Cardiovascular disease is still one of the leading causes of death in the world, and heart transplantation is the current major treatment for end-stage cardiovascular diseases. However, because of the shortage of heart donors, new sources of cardiac regenerative medicine are greatly needed. The prominent development of tissue engineering using bioactive materials has creatively laid a direct promising foundation. Whereas, how to precisely pattern a cardiac structure with complete biological function still requires technological breakthroughs. Recently, the emerging three-dimensional (3D) bioprinting technology for tissue engineering has shown great advantages in generating micro-scale cardiac tissues, which has established its impressive potential as a novel foundation for cardiovascular regeneration. Whether 3D bioprinted hearts can replace traditional heart transplantation as a novel strategy for treating cardiovascular diseases in the future is a frontier issue. In this review article, we emphasize the current knowledge and future perspectives regarding available bioinks, bioprinting strategies and the latest outcome progress in cardiac 3D bioprinting to move this promising medical approach towards potential clinical implementation.

Screening Genes Promoting Exit from Naive Pluripotency Based on Genome-Scale CRISPR-Cas9 Knockout.

Two of the main problems of stem cell and regenerative medicine are the exit of pluripotency and differentiation to functional cells or tissues. The answer to these two problems holds great value in the clinical translation of stem cell as well as regenerative medicine research. Although piling researches have revealed the truth about pluripotency maintenance, the mechanisms underlying pluripotent cell self-renewal, proliferation, and differentiation into specific cell lineages or tissues are yet to be defined. To this end, we took full advantage of a novel technology, namely, the genome-scale CRISPR-Cas9 knockout (GeCKO). As an effective way of introducing targeted loss-of-function mutations at specific sites in the genome, GeCKO is able to screen in an unbiased manner for key genes that promote exit from pluripotency in mouse embryonic stem cells (mESCs) for the first time. In this study, we successfully established a model based on GeCKO to screen the key genes in pluripotency withdrawal. Our strategies included lentiviral package and infection technology, lenti-Cas9 gene knockout technology, shRNA gene knockdown technology, next-generation sequencing, model-based analysis of genome-scale CRISPR-Cas9 knockout (MAGeCK analysis), GO analysis, and other methods. Our findings provide a novel approach for large-scale screening of genes involved in pluripotency exit and offer an entry point for cell fate regulation research.