RNA adapts its flexibility to efficiently fold and resist unfolding.

Recent studies have demonstrated that the mechanisms through which biopolymers like RNA interconvert between multiple folded structures are critical for their cellular functions. A major obstacle to elucidating these mechanisms is the lack of experimental approaches that can resolve these interconversions between functionally relevant biomolecular structures. Here, using a nano-electronic device with microsecond time resolution, we dissect the complete set of structural rearrangements executed by an ultra-stable RNA, the UUCG stem-loop, at the single-molecule level. We show that the stem-loop samples at least four conformations along two folding pathways leading to two distinct folded structures, only one of which has been previously observed. By modulating its flexibility, the stem-loop can adaptively select between these pathways, enabling it to both fold rapidly and resist unfolding. This paradigm of stabilization through compensatory changes in flexibility broadens our understanding of stable RNA structures and is expected to serve as a general strategy employed by all biopolymers.

Characterizing the Conformational Free-Energy Landscape of RNA Stem-Loops Using Single-Molecule Field-Effect Transistors.

We have developed and used single-molecule field-effect transistors (smFETs) to characterize the conformational free-energy landscape of RNA stem-loops. Stem-loops are one of the most common RNA structural motifs and serve as building blocks for the formation of complex RNA structures. Given their prevalence and integral role in RNA folding, the kinetics of stem-loop (un)folding has been extensively characterized using both experimental and computational approaches. Interestingly, these studies have reported vastly disparate timescales of (un)folding, which has been interpreted as evidence that (un)folding of even simple stem-loops occurs on a highly rugged conformational energy landscape. Because smFETs do not rely on fluorophore reporters of conformation or mechanical (un)folding forces, they provide a unique approach that has allowed us to directly monitor tens of thousands of (un)folding events of individual stem-loops at a 200 µs time resolution. Our results show that under our experimental conditions, stem-loops (un)fold over a 1-200 ms timescale during which they transition between ensembles of unfolded and folded conformations, the latter of which is composed of at least two sub-populations. The 1-200 ms timescale of (un)folding we observe here indicates that smFETs report on complete (un)folding trajectories in which unfolded conformations of the RNA spend long periods of time wandering the free-energy landscape before sampling one of several misfolded conformations or the natively folded conformation. Our findings highlight the extremely rugged landscape on which even the simplest RNA structural elements fold and demonstrate that smFETs are a unique and powerful approach for characterizing the conformational free-energy of RNA.

Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.

Plasma tau/amyloid-ß1-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer's disease.

One of the hallmarks of Alzheimer's disease is abnormal deposition of tau proteins in the brain. Although plasma tau has been proposed as a potential biomarker for Alzheimer's disease, a direct link to brain deposition of tau is limited. Here, we estimated the amount of in vivo tau deposition in the brain by PET imaging and measured plasma levels of total tau (t-tau), phosphorylated tau (p-tau, T181) and amyloid-ß1-42. We found significant correlations of plasma p-tau, t-tau, p-tau/amyloid-ß1-42, and t-tau/amyloid-ß1-42 with brain tau deposition in cross-sectional and longitudinal manners. In particular, t-tau/amyloid-ß1-42 in plasma was highly predictive of brain tau deposition, exhibiting 80% sensitivity and 91% specificity. Interestingly, the brain regions where plasma t-tau/amyloid-ß1-42 correlated with brain tau were similar to the typical deposition sites of neurofibrillary tangles in Alzheimer's disease. Furthermore, the longitudinal changes in cerebral amyloid deposition, brain glucose metabolism, and hippocampal volume change were also highly associated with plasma t-tau/amyloid-ß1-42. These results indicate that combination of plasma tau and amyloid-ß1-42 levels might be potential biomarkers for predicting brain tau pathology and neurodegeneration.

Thermo and flex multi-functional array ionic sensor for a human adaptive device.

Recently, electronic skin that mimics human skin in measuring tactile stimuli, temperature, and humidity and having a self-healing function was developed. Furthermore, with the advances in the field of artificial intelligence and health monitoring, various materials and methods have been studied for e-skin. The limitations to work on actual human skin include device flexibility and large-area applications through array structures, and many studies are underway to overcome these problems. Polymeric materials containing ionic liquids can be used to easily fabricate devices in the solid state. They are highly sensitive to both pressure and temperature, making them suitable for multi-sensing devices. Resistive and capacitive sensors have the advantage of having a simple structure, which makes them easy to fabricate. In a single device, both types work well. For resistive sensors, the temperature sensitivity (1.1/°C) is relatively high. Conversely, capacitive sensors have a low temperature sensitivity (0.3/°C). However, they have the advantage of being uniformly variable under each condition and having a smaller error range. In the array structure, independent flex and thermo sensors are arranged repeatedly. The resistive type shows changes in temperature and bending, but in the capacitive type, it is difficult to obtain results from the pixels due to parasitic capacitance.

Ultrasensitive, Low-Power Oxide Transistor-Based Mechanotransducer with Microstructured, Deformable Ionic Dielectrics.

The development of a highly sensitive artificial mechanotransducer that mimics the tactile sensing features of human skin has been a big challenge in electronic skin research. Here, we demonstrate an ultrasensitive, low-power oxide transistor-based mechanotransducer modulated by microstructured, deformable ionic dielectrics, which is consistently sensitive to a wide range of pressures from 1 to 50 kPa. To this end, we designed a viscoporoelastic and ionic thermoplastic polyurethane (i-TPU) with micropyramidal feature as a pressure-sensitive gate dielectric for the indium-gallium-zinc-oxide (IGZO) transistor-based mechanotransducer, which leads to an unprecedented sensitivity of 43.6 kPa-1, which is 23 times higher than that of a capacitive mechanotransducer. This is because the pressure-induced ion accumulation at the interface of the i-TPU dielectric and IGZO semiconductor effectively modulates the conducting channel, which contributed to the enhanced current level under pressure. We believe that the ionic transistor-type mechanotransducer suggested by us will be an effective way to perceive external tactile stimuli over a wide pressure range even under low power (<4 V), which might be one of the candidates to directly emulate the tactile sensing capability of human skin.