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.
Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other ...conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C p.Glu373Ala) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T p.Cys268Phe) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.
A high-performance magneto-mechano-triboelectric nanogenerator (MMTEG) was demonstrated by introducing accelerated water-soluble nano-bullet modified nanostructures to convert a gentle magnetic field ...into electric energy for powering an indoor wireless positioning system. NaCl salt nanoparticles were accelerated by an aerosol deposition (AD) process to collide on a perfluoroalkoxy (PFA) film with a high kinetic energy for the formation of a complicated nanomorphology on the triboelectric active surface. Under an alternating current (AC) magnetic field of 7 Oe, the MMTEG generated an open-circuit peak-to-peak voltage ( V pp ) and a short-circuit current of 708 V and 277 μA, respectively. The harvesting device also presented a maximum peak power of 21.8 mW as well as a continuous AC output power of 4.8 mW (4.8 mJ per second). A self-powered indoor IoT positioning system was constructed by integrating the MMTEG, a power managing circuit, a storage element, and an IoT Bluetooth beacon. The electric energy from the MMTEG device enabled continuous operation of a beacon device, and we successfully confirmed the accurate location of the installed wireless positioning system, subsequently resulting in transmission of our indoor position to the main monitoring computer. Lastly, the MMTEG generated an open-circuit V pp and a short-circuit current of 330 V and 23 μA, respectively, near a 60 Hz power cable connected to home appliances, which were large enough to turn on 108 blue light emitting diodes (LEDs).
Human behavior (e.g., the response to any incoming information) has very complex forms and is based on the response to consecutive external stimuli entering varied sensory receptors. Sensory ...adaptation is an elementary form of the sensory nervous system known to filter out irrelevant information for efficient information transfer from consecutive stimuli. As bioinspired neuromorphic electronic system is developed, the functionality of organs shall be emulated at a higher level than the cell. Because it is important for electronic devices to possess sensory adaptation in spiking neural networks, the authors demonstrate a dynamic, real‐time, photoadaptation process to optical irradiation when repeated light stimuli are presented to the artificial photoreceptor. The filtered electrical signal generated by the light and the adapting signal produces a specific range of postsynaptic states through the neurotransistor, demonstrating changes in the response according to the environment, as normally perceived by the human brain. This successfully demonstrates plausible biological sensory adaptation. Further, the ability of this circuit design to accommodate changes in the intensity of bright or dark light by adjusting the sensitivity of the artificial photoreceptor is demonstrated. Thus, the proposed artificial photoreceptor circuits have the potential to advance neuromorphic device technology by providing sensory adaptation capabilities.
Sol–gel‐derived neurotransistors integrated with perovskite‐based photodetectors are designed to serve as an artificial optoelectronic device array, which experimentally demonstrates the emulation of the dynamic adaptation process of the biological visual nervous system. The fundamental properties of biological adaptation, such as accuracy and desensitization behaviors, are characterized. These results enable post‐synaptic responses to be manipulated to obtain external‐environment‐dependent encoded images.
Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA ...sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.
Gut dysbiosis is closely associated with the occurrence of inflammatory bowel disease (IBD) and psychiatric disorder. Here, to understand the difference of gut microbiota composition and ...physiological effect between IBD patients with (IBD/D
) or without depression (IBD/D
), we analyzed the fecal microbiota composition of patients with IBD with (/D
) or without depression (/D
) and healthy volunteers (HVs) and examined the effects of these fecal microbiota transplantations (FMTs) on the occurrence of systemic inflammation and anxiety/depression in mice. FMTs from patients with IBD/D
or IBD/D
caused IBD-like colitis in the transplanted mice: they increased the myeloperoxidase activity, IL-1β and IL-6 expression, and NF-κB
/CD11c
cell population in the colon. Transplantation of the IBD/D
patient feces (IBD/D
-F) caused IBD-like colitis more strongly than that of IBD/D
-F. FMTs from patients with IBD/D
also caused anxiety-/depression-like behaviors, increased the NF-κB
/Iba1
and lipopolysaccharide (LPS)
/Iba1
cell populations, and decreased the BDNF
/NeuN
cell population in the hippocampus. They increased LPS levels in the blood. FMTs from patients with IBD/D
caused anxiety-like, but not depression-like, behaviors. α-/β-diversities and composition of gut microbiota in IBD-F were different from those of HV feces (HV-F). The Enterobacteriaceae and Enterococcaceae populations and LPS levels were higher in the IBD-F than in the HV-F. The Enterococcaceae population was higher in IBD/D
-F vs. IBD/D
-F. However, the transplantation of HV-F into mice previously transplanted with IBD/D
-F significantly reduced depression-like behaviors, NF-κB
/Iba1
and LPS
/Iba1
cell populations in the hippocampus, LPS levels in the feces and blood, and IL-1β expression in the colon. These findings suggest that the outbreak of depression/anxiety may be dependent on the systemic inflammation with a leaky gut through the gut dysbiosis-attributable overproduction of bacterial LPS and suppression of tight junction protein expression in patients with IBD.
Inflammatory processes in the central nervous system are feature among biological reactions to harmful stimuli such as pathogens and damaged cells. In resting conditions, microglia are involved in ...immune surveillance and brain homeostasis. However, the activation of abnormal microglia can be detrimental to neurons, even resulting in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Therefore, normalization of microglial activation is considered a promising strategy for developing drugs that can treat or prevent inflammation-related brain diseases. In the present study, we investigated the effects of piperlongumine, an active component of Piper longum, on lipopolysaccharide (LPS)-induced neuroinflammation using BV2 microglial cells. We found that piperlongumine significantly inhibited the production of nitric oxide and prostaglandin E2 induced by LPS. Piperlongumine also reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 as well as proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Piperlongumine exerted its anti-neuroinflammatory effects by suppressing the nuclear factor kappa B signaling pathway. These findings suggest that piperlongumine could be a candidate agent for the treatment of inflammation-related neurodegenerative diseases.
The main exclusion criteria were: current or planned participation in another clinical trial or non-study vaccination during or in the 4weeks pre-study (except for Bacille Calmette Guerin vaccine) or ...any planned non-study vaccination in the 8days post-any trial vaccination; any prior vaccination against D, T, P, poliomyelitis, HB (except the birth dose of HB vaccine), Hib, or any history of these infections; receipt of blood products or of any immune-modifying treatment for more than two consecutive weeks; personal/maternal history of human immunodeficiency virus or hepatitis C seropositivity; known hypersensitivity to any study vaccine component; history of seizures; bleeding disorder contraindicating intramuscular (IM) injection; chronic or acute illness that could interfere with study conduct/completion; a child of anyone directly involved in the study. Vaccines The hexavalent, investigational vaccine, DTaP-IPV-HB-PRP~T (batch numbers K0229-F04 and L0050-F03), was manufactured by Sanofi Pasteur, France, and presented as a preservative-free, fully liquid suspension for single-dose injection (0.5mL pre-filled syringes). Each pre-filled syringe contained >=20IU (30 limit of flocculation Lf) D-toxoid, >=40IU (10 Lf) T-toxoid, 25µg pertussis toxin (PT) and 25µg filamentous hemagglutinin (FHA), 40, 8 and 32 D antigen units of IPV type 1, 2 and 3, respectively, 10µg HBsAg, 12µg Hib polysaccharide (PRP) conjugated to 22-36µg tetanus toxoid protein, and 0.6mg aluminum hydroxide. 13 C. Lanata, B. Zambrano, L. Ecker, I. Amemiya, A. Gil, E. Santos-Lima, Immunogenicity and safety of a fully liquid DTaP-IPV-Hep B-PRP-T vaccine at 2-4-6 months of age in Peru, Vacc Vacc, Vol. 3, 2012 14 M. Macias, C.F. Lanata, B. Zambrano,...
The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer. Many studies have ...reported genomic driver mutations in non-small-cell lung cancers (NSCLCs) over the past decade; however, the molecular pathogenesis of >40% of NSCLCs is still unknown. To identify new molecular targets in NSCLCs, we performed the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue of a 33-yr-old lung adenocarcinoma patient, who is a never-smoker and has no familial cancer history. The cancer showed no known driver mutation in EGFR or KRAS and no EML4-ALK fusion. Here we report a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21. This fusion gene overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation. We identified the KIF5B-RET fusion in two more cases out of 20 primary lung adenocarcinomas in the replication study. Our data demonstrate that a subset of NSCLCs could be caused by a fusion of KIF5B and RET, and suggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer.
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.
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