Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by ...massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF
and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found ...that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
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•Aβ induces metabolic reprogramming of microglia from OXPHOS to glycolysis•Metabolic reprogramming of microglia is dependent on the mTOR-HIF-1α pathway•Chronic exposure to Aβ induces metabolic defects of microglia•Metabolic boosting with IFN-γ restores immunological function of microglia
Baik et al. report that amyloid-β acutely triggers microglial activation and metabolic reprogramming from OXPHOS to glycolysis. However, chronic exposure to amyloid-β induces overall metabolic defects in microglia in a model of Alzheimer's disease. Treatment with IFN-γ restores glycolytic metabolism and immunological function of microglia, suggesting that modulation of microglial metabolism may be a potential therapeutic strategy.
Summary Background In 2015, a large outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred following a single patient exposure in an emergency room at the Samsung ...Medical Center, a tertiary-care hospital in Seoul, South Korea. We aimed to investigate the epidemiology of MERS-CoV outbreak in our hospital. Methods We identified all patients and health-care workers who had been in the emergency room with the index case between May 27 and May 29, 2015. Patients were categorised on the basis of their exposure in the emergency room: in the same zone as the index case (group A), in different zones except for overlap at the registration area or the radiology suite (group B), and in different zones (group C). We documented cases of MERS-CoV infection, confirmed by real-time PCR testing of sputum samples. We analysed attack rates, incubation periods of the virus, and risk factors for transmission. Findings 675 patients and 218 health-care workers were identified as contacts. MERS-CoV infection was confirmed in 82 individuals (33 patients, eight health-care workers, and 41 visitors). The attack rate was highest in group A (20% 23/117 vs 5% 3/58 in group B vs 1% 4/500 in group C; p<0·0001), and was 2% (5/218) in health-care workers. After excluding nine cases (because of inability to determine the date of symptom onset in six cases and lack of data from three visitors), the median incubation period was 7 days (range 2–17, IQR 5–10). The median incubation period was significantly shorter in group A than in group C (5 days IQR 4–8 vs 11 days 6–12; p<0·0001). There were no confirmed cases in patients and visitors who visited the emergency room on May 29 and who were exposed only to potentially contaminated environment without direct contact with the index case. The main risk factor for transmission of MERS-CoV was the location of exposure. Interpretation Our results showed increased transmission potential of MERS-CoV from a single patient in an overcrowded emergency room and provide compelling evidence that health-care facilities worldwide need to be prepared for emerging infectious diseases. Funding None.
Abstract
Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF-target interactions is a key step toward understanding the regulatory ...circuitry underlying complex traits such as human diseases. We previously published a reference TF-target interaction database for humans-TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)-which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF-target interactions in mice, including 6552 TF-target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF-target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.
Lithium‐mediated reduction of dinitrogen is a promising method to evade electron‐stealing hydrogen evolution, a critical challenge which limits faradaic efficiency (FE) and thus hinders the success ...of traditional protic‐solvent‐based ammonia electro‐synthesis. A viable implementation of the lithium‐mediated pathway using lithium‐ion conducting glass ceramics involves i) lithium deposition, ii) nitridation, and iii) ammonia formation. Ammonia was successfully synthesized from molecular nitrogen and water, yielding a maximum FE of 52.3 %. With an ammonia synthesis rate comparable to previously reported approaches, the fairly high FE demonstrates the possibility of using this nitrogen fixation strategy as a substitute for firmly established, yet exceedingly complicated and expensive technology, and in so doing represents a next‐generation energy storage system.
The fix is N: The strong reducing power of lithium allows facile dinitrogen dissociation to be used in an ammonia electro‐synthesis process with extraordinary faradaic efficiency. This straightforward three‐step process represents a promising nitrogen cycle for next‐generation energy storage systems.
Photomultiplication‐type organic photodetectors (PM‐OPDs) with high external quantum efficiency (EQE) of over 100% are attracting increasing attention due to their potential importance in detecting ...weak incident light. Considering that the gain of PM‐OPD is determined by the ratio of carrier lifetime over carrier transit time, a systematic study on the effect of the end‐functionalization of a new extended aromatic fused‐ring non‐fullerene acceptor (NFA) on the carrier trap/transit time of the PM‐OPD. Photophysical analyses by means of ultraviolet‐visible absorption, ultraviolet photoelectron spectroscopy, and photoluminescence combined with structural analyses through grazing‐incidence wide‐angle X‐ray scattering show that fluorination of the NFA with the deepest lowest unoccupied molecular orbital level and non‐isotropic molecular ordering can yield the longest carrier lifetime. Furthermore, surface energy study show that fluorination of the NFA can also yield the most hydrophobic nature, which can allow the most efficient injection barrier thinning/lowering of the active layer/cathode interface under illumination due to the localized acceptor distribution toward cathode, maximizing the hole injection efficiency from cathode. As a result, an unprecedentedly high EQE of 156 000% is obtained from the optimized PM‐OPD. This work shows the importance of the molecular design of acceptor molecules in fabricating high‐performance PM‐OPDs.
A series of new non‐fullerene acceptors (NFAs) with a large fused aromatic system are synthesized and used as electron‐trapping acceptors for realizing high‐performance photomultiplication‐type organic photodetectors (PM‐OPDs). The end‐functionalization of the extended fused‐ring NFA significantly affect the charge carrier lifetime of the resulting PM‐OPDs and preferentially focused acceptor distribution. Consequently, an unprecedentedly high external quantum efficiency over 150 000% is achieved.
An artificial ionic mechanotransducer skin with an unprecedented sensitivity over a wide spectrum of pressure by fabricating visco‐poroelastic nanochannels and microstructured features, directly ...mimicking the physiological tactile sensing mechanism of Piezo2 protein is demonstrated. This capability enables voice identification, health monitoring, daily pressure measurements, and even measurements of a heavy weight beyond capabilities of human skin.
This paper analytically and experimentally shows effectiveness and simplicity of mover teeth arrangement design, which dramatically reduces detent force and consequently speed ripple at low speed. ...For this purpose, this paper describes two design steps that include the conventional magnetic circuit optimization by response surface methodology (RSM) and a slight modification of the optimized model based on the proposed mover teeth arrangement. Two prototypes were fabricated, tested, and compared from various perspectives. It was experimentally confirmed that the proposed design is very effective in reduction of detent force and speed ripple with the least sacrifice of performance.
The reaction mechanism of α‐MnO2 having 2×2 tunnel structure with zinc ions in a zinc rechargeable battery, employing an aqueous zinc sulfate electrolyte, was investigated by in situ monitoring ...structural changes and water chemistry alterations during the reaction. Contrary to the conventional belief that zinc ions intercalate into the tunnels of α‐MnO2, we reveal that they actually precipitate in the form of layered zinc hydroxide sulfate (Zn4(OH)6(SO4)⋅5 H2O) on the α‐MnO2 surface. This precipitation occurs because unstable trivalent manganese disproportionates and is dissolved in the electrolyte during the discharge process, resulting in a gradual increase in the pH value of the electrolyte. This causes zinc hydroxide sulfate to crystallize from the electrolyte on the electrode surface. During the charge process, the pH value of the electrolyte decreases due to recombination of manganese on the cathode, leading to dissolution of zinc hydroxide sulfate back into the electrolyte. An analogous phenomenon is also observed in todorokite, a manganese dioxide polymorph with 3×3 tunnel structure that is an indication for the critical role of pH changes of the electrolyte in the reaction mechanism of this battery system.
The pH matters: Investigation of the reaction mechanism of tunneled manganese dioxide with zinc ions reveals that contrary to the conventional belief that zinc ions intercalate into the tunnels, a series of conversion reactions involving active manganese dissolution and concomitant electrolyte pH change lead to the reversible formation of layered zinc hydroxide sulfate.
Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast ...cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. SIGNIFICANCE: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.
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