LAMTOR1 inhibition of TRPML1-dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function.

Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca2+ release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1-mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N-terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1-TRPML1 binding increases TRPML1-mediated Ca2+ release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object-recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1-mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning.

Deterministic Loading of Microwaves onto an Artificial Atom Using a Time-Reversed Waveform.

Loading quantum information deterministically onto a quantum node is an important step toward a quantum network. Here, we demonstrate that coherent-state microwave photons with an optimal temporal waveform can be efficiently loaded onto a single superconducting artificial atom in a semi-infinite one-dimensional (1D) transmission-line waveguide. Using a weak coherent state (the number of photons (N) contained in the pulse ≪1) with an exponentially rising waveform, whose time constant matches the decoherence time of the artificial atom, we demonstrate a loading efficiency of 94.2% ± 0.7% from 1D semifree space to the artificial atom. The high loading efficiency is due to time-reversal symmetry: the overlap between the incoming wave and the time-reversed emitted wave is up to 97.1% ± 0.4%. Our results open up promising applications in realizing quantum networks based on waveguide quantum electrodynamics.

Anti-tumor necrosis factor-α is potentially better than tumor necrosis factor-α as the biomarker for sarcopenia: Results from the I-Lan longitudinal aging study.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-α to be an ideal sarcopenia biomarker. Anti-TNF-α, a natural consequent autoantibody to TNF-α, is an indicator of relatively prolonged TNF-α exposure, has more stable concentrations than TNF-α and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-α were determined by a sandwich ELISA approach, and levels of TNF-α were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-α (0.73 ± 0.19 vs. 0.79 ± 0.25 OD, p = 0.045). Plasma levels of anti-TNF-α were positively correlated with TNF-α (r = 0.24, p < 0.001), and plasma levels of anti-TNF-α were positively correlated with adiposity (r = 0.16, p < 0.001) and negatively correlated with lean body mass (r = -0.14, p = 0.003). Individuals with increasing levels of anti-TNF-α had higher odds of being sarcopenic (OR 5.4, 95 % CI: 1.1-25.8, p = 0.035), and these associations were stronger among women and younger adults. An association between TNF-α and sarcopenia was noted only in middle-aged adults (OR 6.2, 95 % CI: 1.8-21.7, p = 0.004). Plasma anti-TNF-α levels were positively correlated with TNF-α and were significantly associated with sarcopenia. Anti-TNF-α may be a more appropriate biomarker than TNF-α for sarcopenia, but further investigations are needed to confirm its roles in sarcopenia diagnosis and treatment response evaluation.

Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth.

Regulation of fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid raft, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion. It also promotes fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diet exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen in transgenic animals fed with regular diet. Inhibitions of stomatin by gene knockdown or OB-1 inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involves ERK signaling; however, an alternate pathway may also exist.

Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D.

The antimicrobial peptide, tilapia hepcidin (TH) 2-3, belongs to the hepcidin family, and its antibacterial function has been reported. Here, we examined the TH2-3-mediated regulation of proinflammatory cytokines in bacterial endotoxin lipopolysaccharide (LPS)-stimulated mouse macrophages. The presence of TH2-3 in LPS-stimulated cells reduced the amount of tumor necrosis factor (TNF)-α secretion. From a microarray, real-time polymerase chain reaction (PCR), and cytokine array studies, we showed down-regulation of the proinflammatory cytokines TNF-α, interleukin (IL)-1α, IL-1ß, IL-6, and the prostaglandin synthesis gene, cyclooxygenase (COX)-2, by TH2-3. Studies with the COX-2-specific inhibitor, melaxicam, and with COX-2-overexpressing cells demonstrated the positive regulation of TNF-α and negative regulation of cAMP degradation-specific phosphodiesterase (PDE) 4D by COX-2. In LPS-stimulated cells, TH2-3 acts like melaxicam and down-regulates COX-2 and up-regulates PDE4D. The reduction in intracellular cAMP by TH2-3 or melaxicam in LPS-stimulated cells supports the negative regulation of PDE4D by COX-2 and TH2-3. This demonstrates that the inhibition of COX-2 is among the mechanisms through which TH2-3 controls TNF-α release. At 1 h after treatment, the presence of TH2-3 in LPS-stimulated cells had suppressed the induction of pERK1/2 and prevented the LPS-stimulated nuclear accumulation of NF-κB family proteins of p65, NF-κB2, and c-Rel. In conclusion, TH2-3 inhibits TNF-α and other proinflammatory cytokines through COX-2-, PDE4D-, and pERK1/2-dependent mechanisms.

3-N-butylphthalide protects against high-fat-diet-induced obesity in C57BL/6 mice and increases metabolism in lipid-accumulating cells.

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.

Coherent Förster resonance energy transfer: A new paradigm for electrically driven quantum dot random lasers.

The many distinct advantages of random lasers focused efforts on developing a breakthrough from optical pumping to electrical pumping. However, progress in these is limited due to high optical loss and low gain. In this work, we demonstrate an electrically pumped quantum dot (QD) random laser with visible emission based on a previously unexplored paradigm named coherent Förster resonance energy transfer (CFRET). In the CFRET process, when a coherent photonic mode is formed because of multiple scattering of the emitted light traveling in mixed donor and acceptor QDs, the donor QDs not only serve as scattering centers but are also enable coherent energy transfer to acceptor QDs. Therefore, the laser action can be easily achieved, and the lasing threshold is greatly reduced. Our approach of electrically pumped QD-based random lasers represents a substantial step toward a full-spectrum random laser for practical applications.

PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome.

The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca2+-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.

Epinecidin-1, an antimicrobial peptide from fish (Epinephelus coioides) which has an antitumor effect like lytic peptides in human fibrosarcoma cells.

Epinecidin-1, a synthetic 21-mer antimicrobial peptide originally identified from grouper (Epinephelus coioides), specifically exhibited high antimicrobial activities against both Gram-negative and Gram-positive bacteria. In the current study we report on the in vitro cytotoxicity of the peptide, an important factor before it can be considered for further applications in cancer therapy. The cytotoxicity of epinecidin-1 was investigated against several cancer cells (A549, HA59T/VGH, HeLa, HepG2, HT1080, RAW264.7, and U937) and normal cells (AML-12, NIH3T3, and WS-1) with the MTT assay, and the inhibition of cancer cell growth was confirmed by a soft agar assay and scanning electron microscopy. However, cell variations were detected with AO/EtBr staining, while apoptosis and necrosis gene expressions in HT1080 cells after treatment with the epinecidin-1 peptide and Nec-1 showed that epinecidin-1 had an anti-necrosis function in HT1080 cells. The data presented here indicate that epinecidin-1 has in vitro antitumor activity against the HT1080 cell line, and functions like lytic peptides. In addition, our results suggest that epinecidin-1 may prove to be an effective chemotherapeutic agent for human fibrosarcoma cells in the future.

Self-Healing Nanophotonics: Robust and Soft Random Lasers.

Self-healing technology promises a generation of innovation in cross-cutting subjects ranging from electronic skins, to wearable electronics, to point-of-care biomedical sensing modules. Recently, scientists have successfully pulled off significant advances in self-healing components including sensors, energy devices, transistors, and even integrated circuits. Lasers, one of the most important light sources, integrated with autonomous self-healability should be endowed with more functionalities and opportunities; however, the study of self-healing lasers is absent in all published reports. Here, the soft and self-healable random laser (SSRL) is presented. The SSRL can not only endure extreme external strain but also withstand several cutting/healing test cycles. Particularly, the damaged SSRL enables its functionality to be restored within just few minutes without the need of additional energy, chemical/electrical agents, or other healing stimuli, truly exhibiting a supple yet robust laser prototype. It is believed that SSRL can serve as a vital building block for next-generation laser technology as well as follow-on self-healing optoelectronics.

A Novel Target Pathogen Identification and Tracking System Using Capillary Electrophoresis-Random Amplified Polymorphic DNA.

Rapid and accurate identification of pathogen is a major quarantine strategy for outbreak prevention. We used capillary electrophoresis-random amplified polymorphic DNA (CE-RAPD) to generate highly discriminatory pathogen profiles, reduced batch effects between profiles by novel normalization procedure and pattern of technical repeats, followed by target similarity evaluation using target identification score (TIS). A full target signature contains several patterns. TIS system was optimized by training set isolates that included three species, and validated using two hundred clinical Klebsiella pneumoniae isolates. Hierarchical clustering analysis showed CE-RAPD profiles arrange clusters according to the species or the source. Moreover, samples with similar profile may display similar antibiotic susceptibility. By using a signature of four patterns, the TIS system could accurately identify target among different isolates. The variation between isolates may be caused by small change in genome. TIS system provides a standardized tool for building of outbreak firewall and facilitate data exchange.

Ultrahigh Sensitive and Flexible Magnetoelectronics with Magnetic Nanocomposites: Toward an Additional Perception of Artificial Intelligence.

In recent years, flexible magnetoelectronics has attracted a great attention for its intriguing functionalities and potential applications, such as healthcare, memory, soft robots, navigation, and touchless human-machine interaction systems. Here, we provide the first attempt to demonstrate a new type of magneto-piezoresistance device, which possesses an ultrahigh sensitivity with several orders of resistance change under an external magnetic field (100 mT). In our device, Fe-Ni alloy powders are embedded in the silver nanowire-coated micropyramid polydimethylsiloxane films. Our devices can not only serve as an on/off switch but also act as a sensor that can detect different magnetic fields because of its ultrahigh sensitivity, which is very useful for the application in analog signal communication. Moreover, our devices contain several key features, including large-area and easy fabrication processes, fast response time, low working voltage, low power consumption, excellent flexibility, and admirable compatibility onto a freeform surface, which are the critical criteria for the future development of touchless human-machine interaction systems. On the basis of all of these unique characteristics, we have demonstrated a nontouch piano keyboard, instantaneous magnetic field visualization, and autonomous power system, making our new devices be integrable with magnetic field and enable to be implemented into our daily life applications with unfamiliar human senses. Our approach therefore paves a useful route for the development of wearable electronics and intelligent systems.

A White Random Laser.

Random laser with intrinsically uncomplicated fabrication processes, high spectral radiance, angle-free emission, and conformal onto freeform surfaces is in principle ideal for a variety of applications, ranging from lighting to identification systems. In this work, a white random laser (White-RL) with high-purity and high-stability is designed, fabricated, and demonstrated via the cost-effective materials (e.g., organic laser dyes) and simple methods (e.g., all-solution process and self-assembled structures). Notably, the wavelength, linewidth, and intensity of White-RL are nearly isotropic, nevertheless hard to be achieved in any conventional laser systems. Dynamically fine-tuning colour over a broad visible range is also feasible by on-chip integration of three free-standing monochromatic laser films with selective pumping scheme and appropriate colour balance. With these schematics, White-RL shows great potential and high application values in high-brightness illumination, full-field imaging, full-colour displays, visible-colour communications, and medical biosensing.

A fish antimicrobial peptide, tilapia hepcidin TH2-3, shows potent antitumor activity against human fibrosarcoma cells.

As part of a continuing search for potential anticancer drug candidates from antimicrobial peptides of marine organisms, tilapia (Oreochromis mossambicus) hepcidin TH2-3 was evaluated in several tumor cell lines. The results indicated that TH2-3, a synthetic 20-mer antimicrobial peptide, specifically inhibited human fibrosarcoma cell (HT1080 cell line) proliferation and migration. The way in which TH2-3 inhibited HT1080 cell growth was then studied. TH2-3 inhibited HT1080 cell growth in a concentration-dependent manner according to an MTT analysis, which was confirmed by a soft-agar assay and AO/EtBr staining. Scanning electron microscopy revealed that TH2-3 caused lethal membrane disruption in HT1080 cancer cells, and a wound healing assay supported that TH2-3 decreased the migration of HT1080 cells. In addition, c-Jun mRNA expression was downregulated after treatment with TH2-3 for 48-96 h compared to the untreated group. These findings suggest a mechanism of cytotoxic action of TH2-3 and indicate that TH2-3 may be a promising chemotherapeutic agent against human fibrosarcoma cells.

Epinecidin-1 peptide induces apoptosis which enhances antitumor effects in human leukemia U937 cells.

Epinecidin-1 is an antimicrobial peptide present in the grouper (Epinephelus coioides). In this study, the antitumor activity of a synthetic epinecidin-1 peptide was tested. The in vitro results showed that epinecidin-1 inhibited the proliferation of human leukemia U937 cells and increased the ADP/ATP ratio after 24h of treatment. The DNA fragmentation assay, flow cytometric assay, and caspases-3, -8, and -9 assays indicated that epinecidin-1 could induce apoptosis in U937 cells. Real-time RT-PCR results showed regular increases in tumor necrosis factor (TNF)-alpha after treatment with 4 microg/ml epinecidin-1 from 4 to 24h; interleukin (IL)-10, interferon (INF)-r, p53, IL-15, and IL-6 increased after treatment with 2 microg/ml epinecidin-1 for 4-12h. These results suggest that the epinecidn-1 inhibited U937 cells, induced apoptosis in response to cytokine production, and may have pleiotropic effects on different cells.