Low temperatures delay aging and promote longevity in many organisms. However, the metabolic and homeostatic aspects of low-temperature-induced longevity remain poorly understood. Here, we show that ...lipid homeostasis regulated by Caenorhabditis elegans Mediator 15 (MDT-15 or MED15), a transcriptional coregulator, is essential for low-temperature-induced longevity and proteostasis. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase that converts saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), at low temperatures. We then demonstrate that maintaining a high UFA/SFA ratio is essential for proteostasis at low temperatures. We show that dietary supplementation with a monounsaturated fatty acid, oleic acid (OA), substantially mitigates the short life span and proteotoxicity in mdt-15(-) animals at low temperatures. Thus, lipidostasis regulated by MDT-15 appears to be a limiting factor for proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of lipid regulation in maintaining normal organismal physiology under different environmental conditions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dendritic network implementable organic neurofiber transistors with enhanced memory cyclic endurance for spatiotemporal iterative learning are proposed. The architecture of the fibrous organic ...electrochemical transistors consisting of a double‐stranded assembly of electrode microfibers and an iongel gate insulator enables the highly sensitive multiple implementation of synaptic junctions via simple physical contact of gate‐electrode microfibers, similar to the dendritic connections of a biological neuron fiber. In particular, carboxylic‐acid‐functionalized polythiophene as a semiconductor channel material provides stable gate‐field‐dependent multilevel memory characteristics with long‐term stability and cyclic endurance, unlike the conventional poly(alkylthiophene)‐based neuromorphic electrochemical transistors, which exhibit short retention and unstable endurance. The dissociation of the carboxylic acid of the polythiophene enables reversible doping and dedoping of the polythiophene channel by effectively stabilizing the ions that penetrate the channel during potentiation and depression cycles, leading to the reliable cyclic endurance of the device. The synaptic weight of the neurofiber transistors with a dendritic network maintains the state levels stably and is independently updated with each synapse connected with the presynaptic neuron to a specific state level. Finally, the neurofiber transistor demonstrates successful speech recognition based on iterative spiking neural network learning in the time domain, showing a substantial recognition accuracy of 88.9%.
Dendritic network implementable organic neurofiber transistors with enhanced memory cyclic endurance for spatiotemporal iterative learning are proposed. The architecture of the fibrous organic electrochemical transistors consisting of a double‐stranded assembly of electrode microfibers and an iongel gate insulator enables multiple implementation of synaptic junctions via simple physical contact of gate‐electrode microfibers, as the dendritic connections of a biological neuron fiber.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
We utilized human midbrain‐like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α‐synuclein (α‐syn; SNCA) perturbations to ...investigate genotype‐to‐phenotype relationships in Parkinson disease, with the particular aim of recapitulating α‐syn– and Lewy body–related pathologies and the process of neurodegeneration in the hMLO model.
Methods
We generated and characterized hMLOs from GBA1−/− and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body–like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol‐b‐epoxide–treated SNCA triplication hMLOs.
Results
We identified for the first time that the loss of glucocerebrosidase, coupled with wild‐type α‐syn overexpression, results in a substantial accumulation of detergent‐resistant, β‐sheet–rich α‐syn aggregates and Lewy body–like inclusions in hMLOs. These Lewy body–like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α‐syn with ubiquitin, and can also be formed in Parkinson disease patient–derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body–like inclusions in hMLOs derived from patients carrying the SNCA triplication.
Interpretation
Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild‐type α‐syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490–505
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Gastric and colonic alpha-synuclein immunoreactivity has been reported in patients with Parkinson's disease (PD). However, enteric alpha-synuclein also has been reported in healthy individuals.
We ...aimed to investigate the utility of alpha-synuclein immunoreactivity from gastric and colonic mucosal tissues obtained by routine endoscopy to detect PD, and to correlate the pathological burden of alpha-synuclein with motor and nonmotor features of PD.
We recruited 104 study subjects, consisting of 38 patients with PD, 13 patients with probable multiple system atrophy (MSA), and 53 healthy controls. Gastric and colonic mucosal tissues obtained by endoscopic gastroduodenoscopy and colonoscopy were assessed using alpha-synuclein immunohistochemistry. Detailed motor and nonmotor features of PD were correlated with enteric alpha-synuclein immunoreactivity.
No difference was seen in the enteric α-SYN immunoreactivity among patients with PD (31.6% for stomach and 10.4% for colon), patients with MSA (40.0% for stomach and 8.0% for colon), and healthy controls (33.3% for stomach and 18.5% for colon). The frequency of positive alpha-synuclein immunoreactivity was higher in gastric biopsy tissues than in colonic biopsy tissues in all of the study groups (P < 0.05). No significant correlation was found between the presence of alpha-synuclein immunoreactivity and the motor and nonmotor features of PD.
The presence of alpha-synuclein immunoreactivity in gastric and colonic mucosa was detected in a similar manner in patients with PD, patients with MSA, and controls, thus suggesting a limited role of enteric mucosal alpha-synuclein as a diagnostic biomarker for PD. Future studies are warranted to detect pathological alpha-synuclein strains.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Parkinson's disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how ...differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.
AIM To investigate the temporal trends in the misdiagnosis rate between Crohn’s disease(CD) and intestinal tuberculosis(ITB) in South Korea. METHODS We retrospectively reviewed the medical records of ...patients managed for CD or ITB at Asan Medical Center, a tertiary referral hospital, Seoul, Korea between 1996 and 2014. The temporal trends in the misdiagnosis rates between the two diseases were analyzed. The demographic and clinical characteristics were compared between CD patients who were initially misdiagnosed as ITB(final CD group) and vice versa(final ITB group). Final diagnostic criteria for ITB and medication for CD before definite diagnosis of TB were also analyzed in final ITB group.RESULTS In total, 2760 patients were managed for CD and 772 patients for ITB between 1996 and 2014. As well, 494 of the 2760 CD patients(17.9%) were initially misdiagnosed as ITB and 83 of the 772 ITB patients(10.8%) as CD. The temporal trend in misdiagnosing CD as ITB showed a decrease(OR = 0.89, 95%CI: 0.87-0.91, P < 0.001), whereas the temporal trend in misdiagnosing ITB as CD showed an increase(OR = 1.06, 95%CI: 1.01-1.11, P = 0.013). Age at diagnosis, presenting symptoms, and proportion of patients with active/past perianal fistula and active/inactive pulmonary tuberculosis(TB) were significantly different between final CD group and final ITB group. Forty patients(48.2%) in final ITB group were diagnosed by favorable response to empirical anti-TB treatment. Seventeen patients(20.5%) in final ITB group had inappropriately received corticosteroids and/or thiopurines due to misdiagnosis as CD. However, there were no mortalities in both groups. CONCLUSION Cases of CD misdiagnosed as ITB have been decreasing, whereas cases of ITB misdiagnosed as CD have been increasing over the past two decades.
Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production ...and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
NAD(H) pool size increased during colorectal cancer (CRC) progression due to activation of the enzymes in the salvage pathway of NAD+ synthesis, especially NAMPT. The increases in the NAD(H) pool promoted colon cancer progression by decreasing excessive ROS levels. Detection of NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly ...couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.
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► Leucyl-tRNA synthetase (LRS) senses leucine for mTORC1 signaling ► mTORC1 activity, lysosomal localization, cell size, and autophagy are regulated by LRS ► LRS acts as GTPase-activating protein (GAP) for RagD GTPase, an mTORC1 regulator ► The interaction between LRS and RagD GTPase is amino acid dependent
In response to leucine, leucyl-tRNA synthetase activates the mTORC1 pathway by acting as a GTPase-activating protein for a component of mTORC1. The findings reveal a mechanism for transducing amino acid availability to TOR signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Designing highly conductive and (electro)chemical stable inorganic solid electrolytes using cost-effective materials is crucial for developing all-solid-state batteries. Here, we report halide ...nanocomposite solid electrolytes (HNSEs) ZrO
(-ACl)-A
ZrCl
(A = Li or Na) that demonstrate improved ionic conductivities at 30 °C, from 0.40 to 1.3 mS cm
and from 0.011 to 0.11 mS cm
for Li
and Na
, respectively, compared to A
ZrCl
, and improved compatibility with sulfide solid electrolytes. The mechanochemical method employing Li
O for the HNSEs synthesis enables the formation of nanostructured networks that promote interfacial superionic conduction. Via density functional theory calculations combined with synchrotron X-ray and
Li nuclear magnetic resonance measurements and analyses, we demonstrate that interfacial oxygen-substituted compounds are responsible for the boosted interfacial conduction mechanism. Compared to state-of-the-art Li
ZrCl
, the fluorinated ZrO
-2Li
ZrCl
F HNSE shows improved high-voltage stability and interfacial compatibility with Li
PS
Cl and layered lithium transition metal oxide-based positive electrodes without detrimentally affecting Li
conductivity. We also report the assembly and testing of a Li-In||LiNi
Co
Mn
O
all-solid-state lab-scale cell operating at 30 °C and 70 MPa and capable of delivering a specific discharge of 115 mAh g
after almost 2000 cycles at 400 mA g
.
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