Previous studies of transmembrane protein channels have employed noise analysis to examine their statistical current fluctuations. In general, these explorations determined a substrate-induced amplification in the Gaussian white noise of these systems at a low-frequency regime. This outcome implies a lack of slowly appearing fluctuations in the number and local mobility of diffusing charges in the presence of channel substrates. Such parameters are among the key factors in generating a low-frequency 1/f noise. Here, we show that a protein-selective biological nanopore exhibits a substrate-induced amplification in the 1/f noise. The modular composition of this biological nanopore includes a hydrophilic transmembrane protein pore fused to a water-soluble binding protein on its extramembranous side. In addition, this protein nanopore shows an open substate populated by a high-frequency current noise because of the flickering of an engineered polypeptide adaptor at the tip of the pore. However, the physical association of the protein ligand with the binding domain reversibly switches the protein nanopore from a high-frequency noise substate into a quiet substate. In the absence of the protein ligand, our nanopore shows a low-frequency white noise. Remarkably, in the presence of the protein ligand, an amplified low-frequency 1/f noise was detected in a ligand concentration-dependent fashion. This finding suggests slowly occurring equilibrium fluctuations in the density and local mobility of charge carriers under these conditions. Furthermore, we report that the excess in 1/f noise is generated by reversible switches between the noisy ligand-released substate and the quiet ligand-captured substate. Finally, quantitative aspects of the low-frequency 1/f noise are in accord with theoretical predictions of the current noise analysis of protein channel–ligand interactions.

1/f current noise is ubiquitous in protein pores, porins, and channels. We have previously shown that a protein‐selective biological nanopore with an external protein receptor can function as a 1/f noise generator when a high‐affinity protein ligand is reversibly captured by the receptor. Here, we demonstrate that the binding affinity and concentration of the ligand are key determinants for the nature of current noise. For example, 1/f was absent when a protein ligand was reversibly captured at a much lower concentration than its equilibrium dissociation constant against the receptor. Furthermore, we also analyzed the composite current noise that resulted from mixtures of low‐affinity and high‐affinity ligands against the same receptor. This study highlights the significance of protein recognition events in the current noise fluctuations across biological membranes.

Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocytes (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas, immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome-related pathways are remarkably enriched in the down-regulated genes. Although Nap1l5-mediated gene regulation is correlated with PRC2 and PRC1, Nap1l5 does not directly alter the levels of global histone methylations at K4, K9, K27 or K36. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to promote protein synthesis in cardiomyocyte hypertrophy. This is attributable to a direct regulation of nucleolus hypertrophy and subsequent ribosome assembly. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.

To explore the impact and risk of short sleep duration (sleep duration < 6 h/night) on new-onset cardiovascular and cerebrovascular diseases (CVDs) in people with metabolic syndromes (Mets), this study used the 2011 baseline and 2015 follow-up data from the China Longitudinal Study of Health and Retirement (CHARLS) to conduct a prospective study of people aged ≥ 45 years in China. A total of 5,530 individuals without pre-existing CVDs in baseline were included. Mets were defined according to the harmonized criteria. We applied the Logistic Regression (LR), the Deep Neural Networks (DNN), and the Adaptive Boosting (AdaBoost), to evaluate the association between Mets components, short sleep, and the risk of new-onset CVDs, and the importance of multiple variates for new-onset CVDs. During the 4-year follow-up period, 512 individuals developed CVDs, and short sleep increased the risk of CVD in individuals with Mets. The odds ratio for prevalent CVD in Mets with short sleep group was 3.73 (95%CI 2.95–4.71; P < 0.001) compared to the normal group, and 1.99 (95% CI 1.58–2.51; P < 0.001) compared to the Mets without short sleep group. The DNN method reached the highest precision of 92.24% and f1-score of 95.86%, and the Adaboost method reached the highest recall of 99.92%. Both DNN and Adaboost have better predictive performance than LR and revealed short sleep duration and components of Mets are all the strongest predictors of CVD onset.

to mimic the presence of a negatively charged phosphoryl group. This is useful since intact phosphorylated Cc is difficult to purify by traditional methods. The binding affinity that the mutant Cc has for wild-type CcO and the electron transfer rates between the mutant Cc and wild-type CcO will be determined. Ultimately, this project will provide insight that is needed to settle the current debate over the binding model for Cc and CcO. There are currently two main models proposed; however, they each vary in the role of Cc's S47 residue during Cc and CcO binding. Supported by NIH grants GM20488 and 8P30GM103450.