T cells play a key role in cell-mediated immunity, and strategies to genetically modify T cells, including chimeric antigen receptor (CAR) T cell therapy and T cell receptor (TCR) T cell therapy, ...have achieved substantial advances in the treatment of malignant tumors. In clinical trials, CAR-T cell and TCR-T cell therapies have produced encouraging clinical outcomes, thereby demonstrating their therapeutic potential in mitigating tumor development. This article summarizes the current applications of CAR-T cell and TCR-T cell therapies in clinical trials worldwide. It is predicted that genetically engineered T cell immunotherapies will become safe, well-tolerated, and effective therapeutics and bring hope to cancer patients.
The plating/stripping of Li dendrites can fracture the static solid electrolyte interphase (SEI) and cause significant dynamic volume variations in the Li anode, which give rise to poor cyclability ...and severe safety hazards. Herein, a tough polymer with a slide‐ring structure was designed as a self‐adaptive interfacial layer for Li anodes. The slide‐ring polymer with a dynamically crosslinked network moves freely while maintaining its toughness and fracture resistance, which allows it can to dissipate the tension induced by Li dendrites on the interphase layer. Moreover, the slide‐ring polymer is highly stretchable, elastic, and displays an ultrafast self‐healing ability, which allows even pulverized Li to remain coalesced without disintegrating upon consecutive cycling. The Li anodes demonstrate greatly improved suppression of Li dendrite formation, as evidenced by the high critical current density (6 mA cm−2) and stable cycling for the full cells with high‐areal capacity LiFePO4, high‐voltage NCM, and S cathodes.
A slide‐ring polymer with a high stiffness, high toughness and excellent fracture resistance is designed to adapt its shape to dynamic electrode volume variations and stabilize the lithium anode upon cycling.
The development of bifunctional electrocatalysts with high performance for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) with earth-abundant elements is still a challenge ...in electrochemical water splitting technology. Herein, we fabricated a free-standing electrocatalyst in the form of vertically oriented Fe-doped Ni3S2 nanosheet array grown on three-dimensional (3D) Ni foam (Fe-Ni3S2/NF), which presented a high activity and durability for both HER and OER in alkaline media. On the basis of systematic experiments and calculation, the Fe-doping was evidenced to increase the electrochemical surface area, improve the water adsorption ability, and optimize the hydrogen adsorption energy of Ni3S2, which resulted in the enhancement of HER activity on Fe-Ni3S2/NF. Moreover, metal sites of Fe-Ni3S2/NF were proved to play a significant role in the HER process. During the catalysis of OER, the formation of Ni–Fe (oxy)hydroxide was observed on the near-surface section of Fe-Ni3S2/NF, and the introduction of the Fe element dramatically enhanced the OER activity of Ni3S2. The overall water splitting electrolyzer assembled by Fe-Ni3S2/NF exhibited a low cell voltage (1.54 V @ 10 mA cm–2) and a high durability in 1 M KOH. This work demonstrated a promising bifunctional electrocatalyst for water electrolysis in alkaline media with potential application in the future.
A predictive MOSFET model is critical for early circuit design research. To accurately predict the characteristics of nanoscale CMOS, emerging physical effects, such as process variations and ...correlations among model parameters, must be included. In this paper, a new generation of predictive technology model (PTM) is developed to accomplish this goal. Based on physical models and early-stage silicon data, the PTM of bulk CMOS is successfully generated for 130- to 32-nm technology nodes, with an L eff of as low as 13 nm. The accuracy of PTM predictions is comprehensively verified: The error of I on is below 10% for both n-channel MOS and p-channel MOS. By tuning only ten primary parameters, the PTM can be easily customized to cover a wide range of process uncertainties. Furthermore, the new PTM correctly captures process sensitivities in the nanometer regime, particularly the interactions among L eff , V th , mobility, and saturation velocity. A website has been established for the release of PTM: http://www.eas.asu.edu/~ptm
TWIK-related spinal cord K(+) (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K(+) channels in primary afferent ...neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA. Functional studies indicate that reduction of endogenous TRESK channel activity results in hyper-excitation of primary afferent neurons, suggesting that TRESK is a potential target for the development of new analgesics. However, whether and how enhancing TRESK channel activity would decrease the excitability of primary afferent neurons has not been directly tested. Here, we over-expressed TRESK subunits in cultured mouse TG neurons by lipofectamine-mediated transfection and investigated how this altered the membrane properties and the excitability of the small-diameter TG population. To account for the heterogeneity of neurons, we further divided small TG neurons into two groups, based on their ability to bind to fluorescently-labeled isolectin B (IB4). The transfected TG neurons showed a 2-fold increase in the level of TRESK proteins. This was accompanied by a significant increase in the fraction of lamotrigine-sensitive persistent K(+) currents as well as the size of total background K(+) currents. Consequently, both IB4-positive and IB4-negative TG neurons over-expressing TRESK subunits exhibited a lower input resistance and a 2-fold increase in the current threshold for action potential initiation. IB4-negative TG neurons over-expressing TRESK subunits also showed a significant reduction of the spike frequency in response to supra-threshold stimuli. Importantly, an increase in TRESK channel activity effectively inhibited capsaicin-evoked spikes in TG neurons. Taken together, our results suggest that potent and specific TRESK channel openers likely would reduce the excitability of primary afferent neurons and therefore are potential therapeutics for the treatment of migraine and other chronic pain symptoms.
TRPM8 and Migraine Dussor, Greg; Cao, Yu-Qing
Headache,
October 2016, Letnik:
56, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the ...identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptor-potential M8 (TRPM8) channel in migraine. This channel is predominantly expressed on peripheral sensory neurons and is known as the sensor for cold temperature in cutaneous tissue but is also expressed on deep visceral afferents where cold is not likely a stimulus. Consequently, a number of alternative endogenous agonists have been proposed. Apart from its role in cold sensation, TRPM8 also contributes to cold allodynia after nerve injury or inflammation, and it is necessary for cooling/menthol-based analgesia. How it might contribute to migraine is less clear. The purpose of this review is to discuss the anatomical and physiological mechanisms by which meningeal TRPM8 may play a role in migraine as well as the potential of TRPM8 as a therapeutic target. TRPM8 is expressed on sensory afferents innervating the meninges, and these neurons are subject to developmental changes that may influence their contribution to migraine. As in viscera, meningeal TRPM8 channels are unlikely to be activated by temperature fluctuations and their endogenous ligands remain unknown. Preclinical migraine studies show that activation of meningeal TRPM8 by exogenous agonists can both cause and alleviate headache behaviors, depending on whether other meningeal afferents concurrently receive noxious stimuli. This is reminiscent of the fact that cold can trigger migraine in humans but menthol can also alleviate headache. We propose that both TRPM8 agonists and antagonists may be potential therapeutics, depending on how migraine is triggered in individual patients. In this regard, TRPM8 may be a novel target for personalized medicine in migraine treatment.
Silicon has attracted much attention as a promising anode material for lithium-ion batteries (LIBs) due to its high theoretical capacity and rich resource abundance. However, the practical battery ...use of Si is challenged by its low conductivity and drastic volume variation during the Li uptake/release process. Tremendous efforts have been made on shrinking the particle size of Si into nanoscale so that the volume variation could be accommodated. However, the bare nano-Si material would still pulverize upon (de)lithiation. Moreover, it shows an excessive surface area to invite unlimited growth of solid electrolyte interface that hinders the transportation of charge carriers, and an increased interparticle resistance. As a result, the Si nanoparticles gradually lose their electrical contact during the cycling process, which accounts for poor thermodynamic stability and sluggish kinetics of the anode reaction versus Li. To address these problems and improve the Li storage performance of nano-Si anode, proper structural design should be applied on the Si anode. In this perspective, we will briefly review some strategies for improving the electrochemistry versus Li of nano-Si materials and their derivatives, and show opinions on the optimal design of nanostructured Si anode for advanced LIBs.
Exosomes are a novel class of intercellular signal modulators that contain a wide range of molecules and deliver information between cells and tissues. MicroRNAs (miRNAs), a type of regulatory ...non‐coding RNA, are often incorporated into exosomes as signaling molecules. In this review, we discuss the expression of exosomal miRNAs from diverse origins such as tumor cells, solid tumor tissue, and biological fluids in various cancers (lung, breast, colorectal, liver, stomach, and pancreatic). We address the biological functions of exosome‐derived miRNAs in processes such as tumor‐cell proliferation, angiogenesis, metastasis, and chemoresistance in the tumor microenvironment. In particular, we discuss three oncogenic miRNAs, miR‐21, miR‐141, and miR‐451, which occur within exosomes, in terms of gene regulation and intercellular communication. We consider therapeutic miRNA‐based nanoparticles, which are widely expressed in tumors and show promise in drug therapy. The review assesses the wide‐ranging evidence for using exosomal miRNAs as tumor markers in molecular diagnosis. Further, we consider the use of nanoparticle platforms to transport miRNAs, in the targeted treatment of disease and tumors.
Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth ...type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.
The objective of this study was to investigate the effects of applying different amounts of water and nitrogen on yield, fruit quality, water use efficiency （WUE）, irrigation water use efficiency ...（IWUE） and nitrogen use efficiency （NUE） of drip-irrigated greenhouse tomatoes in northwestern China. The plants were irrigated every seven days at various proportions of 20-cm pan evaporation （Ep）. The experiment consisted of three irrigation levels （11, 50% Ep; 12, 75% Ep; and 13, 100% Ep） and three N application levels （N1, 150 kg N ha^-1; N2, 250 kg N ha^-1;and N3, 350 kg N ha^-1）. Tomato yield increased with the amount of applied irrigation water in 12 and then decreased in 13. WUE and IWUE were the highest in Ii. WUE was 16.5% lower in 12 than that in I1, but yield was 26.6% higher in 12 than that in I1. Tomato yield, WUE, and IWUE were significantly higher in N2 than that in N1 and N3. NUIE decreased with increasing N levels but NUE increased with increase the amount of water applied. Increasing both water and N levels increased the foliar net photosynthetic rate. I1 and 12 treatments significantly increased the contents of total soluble solids （TSS）, vitamin C （VC）, lycopene, soluble sugars （SS）, and organic acids （OA） and the sugar：acid ratio in the fruit and decreased the nitrate content. TSS, VC, lycopene, and SS contents were the highest in N2. The harvest index （HI） was the highest in 12N2. 12N2 provided the optimal combination of tomato yield, fruit quality, and WUE. The irrigation and fertilisation regime of 75% Ep and 250 kg N ha^-1 was the best strategy of water and N management for the production of drip-irrigated greenhouse tomato.
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