Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Nucleotide excision repair (NER) counteracts the onset of cancer and aging by removing helix-distorting DNA lesions via a "cut-and-patch"-type reaction. The regulatory mechanisms that drive NER through its successive damage recognition, verification, incision, and gap restoration reaction steps remain elusive. Here, we show that the RAD5-related translocase HLTF facilitates repair through active eviction of incised damaged DNA together with associated repair proteins. Our data show a dual-incision-dependent recruitment of HLTF to the NER incision complex, which is mediated by HLTF's HIRAN domain that binds 3'-OH single-stranded DNA ends. HLTF's translocase motor subsequently promotes the dissociation of the stably damage-bound incision complex together with the incised oligonucleotide, allowing for an efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

R-loop-derived cytoplasmic RNA-DNA hybrids activate an immune response.

R-loops are RNA-DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2-4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA-DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA-DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. 5-7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. 8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. 9) and in BRCA1-mutated cancer cells10. These findings establish RNA-DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.

Nanoribbon Yarn with Versatile Inorganic Materials.

Nanomaterial-based yarns have been actively developed owing to their advantageous features, namely, high surface-area-to-volume ratios, flexibility, and unusual material characteristics such as anisotropy in electrical/thermal conductivity. The superior properties of the nanomaterials can be directly imparted and scaled-up to macro-sized structures. However, most nanomaterial-based yarns have thus far, been fabricated with only organic materials such as polymers, graphene, and carbon nanotubes. This paper presents a novel fabrication method for fully inorganic nanoribbon yarn, expanding its applicability by bundling highly aligned and suspended nanoribbons made from various inorganic materials (e.g., Au, Pd, Ni, Al, Pt, WO3, SnO2, NiO, In2O3, and CuO). The process involves depositing the target inorganic material on a nanoline mold, followed by suspension through plasma etching of the nanoline mold, and twisting using a custom-built yarning machine. Nanoribbon yarn structures of various functional inorganic materials are utilized for chemical sensors (Pd-based H2 and metal oxides (MOx)-based green gas sensors) and green energy transducers (water splitting electrodes/triboelectric nanogenerators). This method is expected to provide a comprehensive fabrication strategy for versatile inorganic nanomaterials-based yarns.

TREX1 degrades the 3' end of the small DNA oligonucleotide products of nucleotide excision repair in human cells.

The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3' of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders.

Weighted Domain Adaptation Using the Graph-Structured Dataset Representation for Machinery Fault Diagnosis under Varying Operating Conditions.

Data-driven fault diagnosis has received significant attention in the era of big data. Most data-driven methods have been developed under the assumption that both training and test data come from identical data distributions. However, in real-world industrial scenarios, data distribution often changes due to varying operating conditions, leading to a degradation of diagnostic performance. Although several domain adaptation methods have shown their feasibility, existing methods have overlooked metadata from the manufacturing process and treated all domains uniformly. To address these limitations, this article proposes a weighted domain adaptation method using a graph-structured dataset representation. Our framework involves encoding a collection of datasets into the proposed graph structure, which captures relations between datasets based on metadata and raw data simultaneously. Then, transferability scores of candidate source datasets for a target are estimated using the constructed graph and a graph embedding model. Finally, the fault diagnosis model is established with a voting ensemble of the base classifiers trained on candidate source datasets and their estimated transferability scores. For validation, two case studies on rotor machinery, specifically tool wear and bearing fault detection, were conducted. The experimental results demonstrate the effectiveness and superiority of the proposed method over other existing domain adaptation methods.

How Can Insulin Resistance Cause Alzheimer's Disease?

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.

Effects of Radix Polygalae on Cognitive Decline and Depression in Estradiol Depletion Mouse Model of Menopause.

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Enhancement of refractive index sensing for an infrared plasmonic metamaterial absorber with a nanogap.

An infrared plasmonic metamaterial absorber with a nanogap was numerically and experimentally investigated as a refractive index sensor. We experimentally demonstrated large enhancements of both sensitivity (approximately 1091 nm/refractive index unit) and figure of merit (FOM*; approximately 273) owing to the nanogap formation in the metamaterial absorber to achieve perfect absorption (99%). The refractive index sensing platform was fabricated by producible nanoimprint lithography and isotropic dry etching processes to have a large area and low cost while providing a practical solution for high-performance plasmonic biosensors.

Preparation of multilayer periodic nanopatterned WO3-based photoanode by reverse nanoimprinting for water splitting.

Photoelectrochemical (PEC) water splitting has been studied extensively as an environmentally friendly technology for hydrogen production using solar energy. WO3is considered a promising semiconducting material for photoanodes due to its high electron mobility, good hole diffusion length, and chemical stability. Periodic nanostructures of WO3have been investigated for enhancing the PEC performance of WO3-based photoanodes. In this study, facile fabrication of periodic nanostructures of WO3was achieved using reverse nanoimprint lithography, and the multilayer stacking of nanopatterned WO3film was also confirmed. The multilayer nanopatterned WO3films were used as photoanodes for PEC water splitting. The performance of the fabricated photoanode in PEC was 2 times higher than that of planar WO3film due to its higher light absorbance and lower charge transfer resistance.

Multi-Domain Convolutional Neural Networks for Lower-Limb Motor Imagery Using Dry vs. Wet Electrodes.

Motor imagery (MI) brain-computer interfaces (BCIs) have been used for a wide variety of applications due to their intuitive matching between the user's intentions and the performance of tasks. Applying dry electroencephalography (EEG) electrodes to MI BCI applications can resolve many constraints and achieve practicality. In this study, we propose a multi-domain convolutional neural networks (MD-CNN) model that learns subject-specific and electrode-dependent EEG features using a multi-domain structure to improve the classification accuracy of dry electrode MI BCIs. The proposed MD-CNN model is composed of learning layers for three domain representations (time, spatial, and phase). We first evaluated the proposed MD-CNN model using a public dataset to confirm 78.96% classification accuracy for multi-class classification (chance level accuracy: 30%). After that, 10 healthy subjects participated and performed three classes of MI tasks related to lower-limb movement (gait, sitting down, and resting) over two sessions (dry and wet electrodes). Consequently, the proposed MD-CNN model achieved the highest classification accuracy (dry: 58.44%; wet: 58.66%; chance level accuracy: 43.33%) with a three-class classifier and the lowest difference in accuracy between the two electrode types (0.22%, d = 0.0292) compared with the conventional classifiers (FBCSP, EEGNet, ShallowConvNet, and DeepConvNet) that used only a single domain. We expect that the proposed MD-CNN model could be applied for developing robust MI BCI systems with dry electrodes.

Developing a Motor Imagery-Based Real-Time Asynchronous Hybrid BCI Controller for a Lower-Limb Exoskeleton.

This study aimed to develop an intuitive gait-related motor imagery (MI)-based hybrid brain-computer interface (BCI) controller for a lower-limb exoskeleton and investigate the feasibility of the controller under a practical scenario including stand-up, gait-forward, and sit-down. A filter bank common spatial pattern (FBCSP) and mutual information-based best individual feature (MIBIF) selection were used in the study to decode MI electroencephalogram (EEG) signals and extract a feature matrix as an input to the support vector machine (SVM) classifier. A successive eye-blink switch was sequentially combined with the EEG decoder in operating the lower-limb exoskeleton. Ten subjects demonstrated more than 80% accuracy in both offline (training) and online. All subjects successfully completed a gait task by wearing the lower-limb exoskeleton through the developed real-time BCI controller. The BCI controller achieved a time ratio of 1.45 compared with a manual smartwatch controller. The developed system can potentially be benefit people with neurological disorders who may have difficulties operating manual control.

Dual nanotransfer printing for complementary plasmonic biosensors.

One of the main challenges in the widespread utilization of localized plasmon resonance-based biosensors is the fabrication of large-area and low-cost plasmonic nanostructures. In this work, we fabricated large-area and low-cost complementary plasmonic biosensors such as nanohole and nanodisk arrays using dual nanotransfer printing (NTP) with a single metal deposition and a single reusable mold. The suspended nanohole arrays and the suspended nanodisk arrays were fabricated using the subsequent dry etching process. We confirmed a maximum enhancement in bulk sensitivity in experiments and simulations by controlling the vertical and lateral etching depths of the dielectric layer underneath the gold (Au) nanohole and nanodisk arrays. Furthermore, we show that the surface sensitivity evaluated by atomic layer deposition of aluminum oxide increased because appropriate vertical and lateral etching depths allow the target analyte to access the additional near-field formed at the bottom of the Au nanostructure. The dual NTP method provides a practical solution for the realization of large-area and low-cost label-free plasmonic biosensing systems, with a reduction in complexity and cost of the fabrication process of complementary plasmonic structures and metasurfaces.

Development of an inverse distance weighted active infrared stealth scheme using the repulsive particle swarm optimization algorithm.

Treatments for detection by infrared (IR) signals are higher than for other signals such as radar or sonar because an object detected by the IR sensor cannot easily recognize its detection status. Recently, research for actively reducing IR signal has been conducted to control the IR signal by adjusting the surface temperature of the object. In this paper, we propose an active IR stealth algorithm to synchronize IR signals from the object and the background around the object. The proposed method includes the repulsive particle swarm optimization statistical optimization algorithm to estimate the IR stealth surface temperature, which will result in a synchronization between the IR signals from the object and the surrounding background by setting the inverse distance weighted contrast radiant intensity (CRI) equal to zero. We tested the IR stealth performance in mid wavelength infrared (MWIR) and long wavelength infrared (LWIR) bands for a test plate located at three different positions on a forest scene to verify the proposed method. Our results show that the inverse distance weighted active IR stealth technique proposed in this study is proved to be an effective method for reducing the contrast radiant intensity between the object and background up to 32% as compared to the previous method using the CRI determined as the simple signal difference between the object and the background.

An Integrated Approach for Analysis of the DNA Damage Response in Mammalian Cells: NUCLEOTIDE EXCISION REPAIR, DNA DAMAGE CHECKPOINT, AND APOPTOSIS.

DNA damage by UV and UV-mimetic agents elicits a set of inter-related responses in mammalian cells, including DNA repair, DNA damage checkpoints, and apoptosis. Conventionally, these responses are analyzed separately using different methodologies. Here we describe a unified approach that is capable of quantifying all three responses in parallel using lysates from the same population of cells. We show that a highly sensitive in vivo excision repair assay is capable of detecting nucleotide excision repair of a wide spectrum of DNA lesions (UV damage, chemical carcinogens, and chemotherapeutic drugs) within minutes of damage induction. This method therefore allows for a real-time measure of nucleotide excision repair activity that can be monitored in conjunction with other components of the DNA damage response, including DNA damage checkpoint and apoptotic signaling. This approach therefore provides a convenient and reliable platform for simultaneously examining multiple aspects of the DNA damage response in a single population of cells that can be applied for a diverse array of carcinogenic and chemotherapeutic agents.

Highly specific and sensitive method for measuring nucleotide excision repair kinetics of ultraviolet photoproducts in human cells.

The nucleotide excision repair pathway removes ultraviolet (UV) photoproducts from the human genome in the form of short oligonucleotides ∼ 30 nt in length. Because there are limitations to many of the currently available methods for investigating UV photoproduct repair in vivo, we developed a convenient non-radioisotopic method to directly detect DNA excision repair events in human cells. The approach involves extraction of oligonucleotides from UV-irradiated cells, DNA end-labeling with biotin and streptavidin-mediated chemiluminescent detection of the excised UV photoproduct-containing oligonucleotides that are released from the genome during excision repair. Our novel approach is robust, with essentially no signal in the absence of UV or a functional excision repair system. Furthermore, our non-radioisotopic methodology allows for the sensitive detection of excision products within minutes following UV irradiation and does not require additional enrichment steps such as immunoprecipitation. Finally, this technique allows for quantitative measurements of excision repair in human cells. We suggest that the new techniques presented here will be a useful and powerful approach for studying the mechanism of human nucleotide excision repair in vivo.

DNA repair synthesis and ligation affect the processing of excised oligonucleotides generated by human nucleotide excision repair.

Ultraviolet (UV) photoproducts are removed from genomic DNA by dual incisions in humans in the form of 24- to 32-nucleotide-long oligomers (canonical 30-mers) by the nucleotide excision repair system. How the small, excised, damage-containing DNA oligonucleotides (sedDNAs) are processed in cells following the dual incision event is not known. Here, we demonstrate that sedDNAs are localized to the nucleus in two biochemically distinct forms, which include chromatin-associated, transcription factor II H-bound complexes and more readily solubilized, RPA-bound complexes. Because the nuclear mobility and repair functions of transcription factor II H and RPA are influenced by post-incision gap-filling events, we examined how DNA repair synthesis and DNA ligation affect sedDNA processing. We found that although these gap filling activities are not essential for the dual incision/sedDNA generation event per se, the inhibition of DNA repair synthesis and ligation is associated with a decrease in UV photoproduct removal rate and an accumulation of RPA-sedDNA complexes in the cell. These findings indicate that sedDNA processing and association with repair proteins following the dual incisions may be tightly coordinated with gap filling during nucleotide excision repair in vivo.

Rapid Low-Temperature 3D Integration of Silicon Nanowires on Flexible Substrates.

The vertical integration of 1D nanostructures onto the 2D substrates has the potential to offer significant performance gains to flexible electronic devices due to high integration density, large surface area, and improved light absorption and trapping. A simple, rapid, and low temperature transfer bonding method has been developed for this purpose. Ultrasonic vibration is used to achieve a low temperature bonding within a few seconds, resulting in a polymer-matrix-free, electrically conducting vertical assembly of silicon nanowires (SiNWs) with a graphene/PET substrate. The microscopic structure, and mechanical and electrical characteristics of the interface between the transferred SiNW array and graphene layer are subsequently investigated, revealing that this creates a mechanically robust and electrically Ohmic contact. This newly developed ultrasonic transfer bonding technique is also found to be readily adaptable for diverse substrates of both metal and polymer. It is therefore considered as a valuable technique for integrating 1D vertical nanostructures onto the 2D flexible substrates for flexible photovoltaics, energy storage, and water splitting systems.

A facile patterning of silver nanowires using a magnetic printing method.

Patterning of metal nanowires (NWs) is vital for the fabrication of NW-based, high-performance devices such as sensors, transparent conducting electrodes, and optoelectronics. However, the majority of existing patterning methods require complex and expensive technologies. For this reason, we report for the first time a facile and quick patterning method of silver (Ag) NWs using a magnetic printing method. We successfully demonstrated a patterned AgNW grid structure ona flexible substrate as transparent electrodes. The flexible AgNW grid electrode exhibited optical and electrical properties comparable to those of commercial transparent conducting electrodes.We believe our work will be broadly applicable to other NW-based devices such as sensors,energy storage devices, meta devices, nanoscale electronics, and optoelectronics.

Nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying DNA damage in vivo.

Nucleotide excision repair is the sole mechanism for removing the major UV photoproducts from genomic DNA in human cells. In vitro with human cell-free extract or purified excision repair factors, the damage is removed from naked DNA or nucleosomes in the form of 24- to 32-nucleotide-long oligomers (nominal 30-mer) by dual incisions. Whether the DNA damage is removed from chromatin in vivo in a similar manner and what the fate of the excised oligomer was has not been known previously. Here, we demonstrate that dual incisions occur in vivo identical to the in vitro reaction. Further, we show that transcription-coupled repair, which operates in the absence of the XPC protein, also generates the nominal 30-mer in UV-irradiated XP-C mutant cells. Finally, we report that the excised 30-mer is released from the chromatin in complex with the repair factors TFIIH and XPG. Taken together, our results show the congruence of in vivo and in vitro data on nucleotide excision repair in humans.