Solid-State Quad-Nanopore Array for High-Resolution Single-Molecule Analysis and Discrimination.

The ability to detect and distinguish biomolecules at the single-molecule level is at the forefront of today's biomedicine and analytical chemistry research. Increasing the dwell time of individual biomolecules in the sensing spot can greatly enhance the sensitivity of single-molecule methods. This is particularly important in solid-state nanopore sensing, where the detection of small molecules is often limited by the transit dwell time and insufficient temporal resolution. Here, a quad-nanopore is introduced, a square array of four nanopores (with a space interval of 30-50 nm) to improve the detection sensitivity through electric field manipulation in the access region. It is shown that dwell times of short DNA strands (200 bp) are prolonged in quad-nanopores as compared to single nanopores of the same diameter. The dependence of dwell times on the quad-pore spacing is investigated and it is found that the "retarding effect" increases with decreasing space intervals. Furthermore, ultra-short DNA (50 bp) detection is demonstrated using a 10 nm diameter quad-nanopore array, which is hardly detected by a single nanopore. Finally, the general utility of quad-nanopores has been verified by successful discrimination of two kinds of small molecules, metal-organic cage and bovine serum albumin (BSA).

Metal-Organic Cage as Single-Molecule Carrier for Solid-State Nanopore Analysis.

The ability to detect biomolecules at the single-molecule level is at the forefront of biological research, precision medicine, and early diagnosis. Recently, solid-state nanopore sensors have emerged as a promising technique for label-free and precise diagnosis assay. However, insufficient sensitivity and selectivity for small analytes are a great challenge for clinical diagnosis applications via solid-state nanopores. Here, for the first time, a metal-organic cage, PCC-57, is employed as a carrier to increase the sensitivity and selectivity of solid-state nanopores based on the intrinsic interaction of the nanocage with biomolecules. Firstly, it is found that the carrier itself is undetectable unless bound with the target analytes and used oligonucleotides as linkers to attach PCC-57 and target analytes. Secondly, two small analytes, oligonucleotide conjugated angiopep-2 and polyphosphoric acid, are successfully distinguished using the molecular carrier. Finally, selectivity of nanopore detection is achieved by attaching PCC-57 to oligonucleotide-tailed aptamers, and the human alpha-thrombin sample is successfully detected. It is believed that the highly designable metal-organic cage could serve as a rich carrier repository for a variety of biomolecules, facilitating single-molecule screening of clinically relevant biomolecules based on solid-state nanopores in the future.

Oligonucleotide Discrimination Enabled by Tannic Acid-Coordinated Film-Coated Solid-State Nanopores.

Discrimination of nucleotides serves as the basis for DNA sequencing using solid-state nanopores. However, the translocation of DNA is usually too fast to be detected, not to mention nucleotide discrimination. Here, we utilized polyphenolic TA and Fe3+, an attractive metal-organic thin film, and achieved a fast and robust surface coating for silicon nitride nanopores. The hydrophilic coating layer can greatly reduce the low-frequency noise of an original unstable nanopore, and the nanopore size can be finely tuned in situ at the nanoscale by simply adjusting the relative ratio of Fe3+ and TA monomers. Moreover, the hydrogen bonding interaction formed between the hydroxyl groups provided by TA and the phosphate groups of DNAs significantly increases the residence time of a short double-strand (100 bp) DNA. More importantly, we take advantage of the different strengths of hydrogen bonding interactions between the hydroxyl groups provided by TA and the analytes to discriminate between two oligonucleotide samples (oligodeoxycytidine and oligodeoxyadenosine) with similar sizes and lengths, of which the current signal patterns are significantly different using the coated nanopore. The results shed light on expanding the biochemical functionality of surface coatings on solid-state nanopores for future biomedical applications.

Probing the Effect of Ubiquitinated Histone on Mononucleosomes by Translocation Dynamics Study through Solid-State Nanopores.

Post-translational modifications (PTMs), such as ubiquitination, are critically important in regulating genetic expressions by adjusting the nucleosome stability. A fast and label-free technology inspecting dynamic nucleosome structures can facilitate the interrogation of PTMs effects. Here we leverage the advantages of mechanically stable solid-state nanopores and detect the effect of a ubiquitinated histone on mononucleosomes at the single-molecule level. By comparing the translocation dynamics of natural and cross-linked mononucleosomes, we verified that the nucleosomal DNA unravelled from histones in natural mononucleosomes. Furthermore, we found that a turning point of voltage corresponds to the onset of nucleosome rupture. More importantly, we reveal that ubH2A stabilizes the nucleosome by shifting the turning point to a larger value and investigated the effect of ubiquitination on different histones (ubH2A and ubH2B). These findings open promising possibilities for developing a miniaturized and portable device for the fast screening of PTMs on nucleosomes.

All roads lead to Rome - a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer's disease.

Age-related neurodegenerative disorders such as Alzheimer's disease (AD) have become a critical public health issue due to the significantly extended human lifespan, leading to considerable economic and social burdens. Traditional therapies for AD such as medicine and surgery remain ineffective, impractical, and expensive. Many studies have shown that a variety of bioactive substances released by physical exercise (called "exerkines") help to maintain and improve the normal functions of the brain in terms of cognition, emotion, and psychomotor coordination. Increasing evidence suggests that exerkines may exert beneficial effects in AD as well. This review summarizes the neuroprotective effects of exerkines in AD, focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise. The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages, genders, and health conditions.