Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, ...we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promoting the nuclear accumulation of poly(GR) granules. In fact, LSM12 posttranscriptionally up-regulated EPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects in LSM12-deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression of LSM12 and EPAC1. Lentiviral overexpression of LSM12 or EPAC1 indeed restored the RAN gradient, mitigated the pathogenic mislocalization of TDP-43, and suppressed caspase-3 activation for apoptosis in C9-ALS iPSNs. EPAC1 depletion biochemically dissociated RAN-importin β1 from the cytoplasmic nuclear pore complex, thereby dissipating the nucleocytoplasmic RAN gradient essential for NCT. These findings define the LSM12-EPAC1 pathway as an important suppressor of the NCT-related pathologies in C9-ALS/FTD.
Nonsense-mediated mRNA decay (NMD), which is arguably the best-characterized translation-dependent regulatory pathway in mammals, selectively degrades mRNAs as a means of post-transcriptional gene ...control. Control can be for the purpose of ensuring the quality of gene expression. Alternatively, control can facilitate the adaptation of cells to changes in their environment. The key to NMD, no matter what its purpose, is the ATP-dependent RNA helicase upstream frameshift 1 (UPF1), without which NMD fails to occur. However, UPF1 does much more than regulate NMD. As examples, UPF1 is engaged in functionally diverse mRNA decay pathways mediated by a variety of RNA-binding proteins that include staufen, stem-loop-binding protein, glucocorticoid receptor, and regnase 1. Moreover, UPF1 promotes tudor-staphylococcal/micrococcal-like nuclease-mediated microRNA decay. In this review, we first focus on how the NMD machinery recognizes an NMD target and triggers mRNA degradation. Next, we compare and contrast the mechanisms by which UPF1 functions in the decay of other mRNAs and also in microRNA decay. UPF1, as a protein polymath, engenders cells with the ability to shape their transcriptome in response to diverse biological and physiological needs.
Various sensors and electronic devices are recently developed to monitor human health in mechanically flexible or even stretchable forms for intimate contact with non‐flat curvilinear surfaces of the ...human body. For successful operation of these devices, finding a proper way to electrically power them is very important. In this work, glucose/oxygen fueled enzymatic biofuel cells (EBFCs) based on microfluidic structured elastomeric polydimethylsiloxane substrate with wrinkled gold (Au) electrodes are suggested for power supply. For doing that, firstly, bottom surface of microfluidic channel is covered with buckled Au electrodes for stretchability. By microfluidic design showing capillary imbibition through fluidic channels, loading of catalyts is promoted. Interestingly, buckled Au electrodes induce much better anodic and cathodic reaction rates than those of non‐buckled Au electrodes by 25% and 33%, respectively. This is because surface area and the amount of catalyst loading in electrodes increase by Au wrinkling. In evaluations of EBFCs using the buckled Au electrodes, maximum power density reaches 7.1 ± 0.64 µW cm−2, while they show decent performance of 5.4 ± 0.49 µW cm−2 even under external stretching. Taken together, it is corroborated that such proposed stretchable EBFCs are alternative for providing electrical power in wearable or implantable devices.
The suggested enzymatic biofuel cell (EBFC) is fabricated by the collaboration of an elastomeric PDMS substrate with a microfluidic structure and buckled Au electrode that has stretchability due to its wrinkled shape. Catalysts are easily and evenly dispersed by capillary imbibition, resulting in a stretchable EBFC with high performance.
A recent study by Hu et al. describes N
-methyladenosine (m
A)-selective allyl chemical labeling and sequencing (m
A-SAC-seq), which allows for quantitative, stoichiometric, and positional analyses ...of m
A at single-nucleotide resolution across the whole transcriptome level. Information on the m
A stoichiometry will provide additional layers of gene regulatory pathways mediated by m
A modification during diverse molecular, cellular, and physiological events.
Iterative reconstruction degrades image quality. Thus, further advances in image reconstruction are necessary to overcome some limitations of this technique in low-dose computed tomography (LDCT) ...scan of the chest. Deep-learning image reconstruction (DLIR) is a new method used to reduce dose while maintaining image quality. The purposes of this study was to evaluate image quality and noise of LDCT scan images reconstructed with DLIR and compare with those of images reconstructed with the adaptive statistical iterative reconstruction-Veo at a level of 30% (ASiR-V 30%).
This retrospective study included 58 patients who underwent LDCT scan for lung cancer screening. Datasets were reconstructed with ASiR-V 30% and DLIR at medium and high levels (DLIR-M and DLIR-H, respectively). The objective image signal and noise, which represented mean attenuation value and standard deviation in Hounsfield units for the lungs, mediastinum, liver, and background air, and subjective image contrast, image noise, and conspicuity of structures were evaluated. The differences between CT scan images subjected to ASiR-V 30%, DLIR-M, and DLIR-H were evaluated.
Based on the objective analysis, the image signals did not significantly differ among ASiR-V 30%, DLIR-M, and DLIR-H (
= 0.949, 0.737, 0.366, and 0.358 in the lungs, mediastinum, liver, and background air, respectively). However, the noise was significantly lower in DLIR-M and DLIR-H than in ASiR-V 30% (all
< 0.001). DLIR had higher signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) than ASiR-V 30% (
= 0.027, < 0.001, and < 0.001 in the SNR of the lungs, mediastinum, and liver, respectively; all
< 0.001 in the CNR). According to the subjective analysis, DLIR had higher image contrast and lower image noise than ASiR-V 30% (all
< 0.001). DLIR was superior to ASiR-V 30% in identifying the pulmonary arteries and veins, trachea and bronchi, lymph nodes, and pleura and pericardium (all
< 0.001).
DLIR significantly reduced the image noise in chest LDCT scan images compared with ASiR-V 30% while maintaining superior image quality.
Realization of a highly flexible, lightweight, and high performance flexible supercapacitor was achieved using three-dimensional graphene on flexible graphite-paper. A simple and fast self-assembly ...approach was utilized for the uniform deposition of chemical vapor deposition (CVD)-grown high quality 3D-graphene powders on a flexible graphite-paper substrate. The fabricated paper-based symmetric supercapacitor exhibited a maximum capacitance of 260 F g−1 (15.6 mF cm−2) in a three electrode system, 80 F g−1 (11.1 mF cm−2) in a full cell, high capacitance retention and a high energy density of 8.8 Wh kg−1 (1.24 μWh cm−2) at a power density of 178.5 W kg−1 (24.5 μW cm−2). The flexible supercapacitor maintained its supercapacitor performance well, even under bent, rolled, or twisted conditions, signifying the excellent flexibility of the fabricated device. Our straightforward approach to the fabrication of highly flexible and lightweight supercapacitors offers new design opportunities for flexible/wearable electronics and miniaturized device applications that require energy storage units that meet the demands of the multifarious applications.
•A fully flexible supercapacitor based on 3D-graphene/graphite-paper was fabricated.•The 3D-porous architecture provided space for easy migration of electrolyte ions.•Our device exhibited excellent electrochemical performance and flexibility.•The present approach is simple, fast, scalable, and highly efficient.
Nontuberculous mycobacterium (NTM) species are ubiquitous microorganisms. NTM pulmonary disease (NTM-PD) is thought to be caused not by human-to-human transmission but by independent environmental ...acquisition. However, recent studies using next-generation sequencing (NGS) have reported trans-continental spread of Mycobacterium abscessus among patients with cystic fibrosis.
We investigated NTM genomes through NGS to examine transmission patterns in three pairs of co-habiting patients with NTM-PD who were suspected of patient-to-patient transmission. Three pairs of patients with NTM-PD co-habiting for at least 15 years were enrolled: a mother and a daughter with M. avium-PD, a couple with M. intracellulare-PD, and a second couple, one of whom was infected with M. intracellulare and the other of whom was infected with M. abscessus. Whole genome sequencing was performed using patients' NTM isolates as well as environmental specimens. Genetic distances were estimated based on single nucleotide polymorphisms (SNPs). By comparison with the genetic distances among 78 publicly available NTM genomes, NTM isolates derived from the two pairs of patients infected with the same NTM species were not closely related to each other. In phylogenetic analysis, the NTM isolates from patients with M. avium-PD clustered with isolates from different environmental sources.
In conclusion, considering the genetic distances between NTM strains, the likelihood of patient-to-patient transmission in pairs of co-habiting NTM-PD patients without overt immune deficiency is minimal.
LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation ...of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway.
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► CLIP-seq and ribosome footprinting reveal numerous spliced mRNAs as LIN28A targets ► Let-7 is the only effective miRNA target of LIN28A in embryonic stem cells ► LIN28A binds to AAGNNG, AAGNG, and UGUG in the loop of a small hairpin ► LIN28A is localized in peri-ER area and suppresses ER-associated translation
An unexpected role of LIN28A in translational suppression is revealed by a genome-wide search for the functional targets of LIN28A by CLIP-seq and ribosome footprinting.
Abstract
Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified >1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance ...MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.
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