Feedforward cysteine regulation maintains melanoma differentiation state and limits metastatic spread.

The inherent ability of melanoma cells to alter the differentiation-associated transcriptional repertoire to evade treatment and facilitate metastatic spread is well accepted and has been termed phenotypic switching. However, how these facets of cellular behavior are controlled remains largely elusive. Here, we show that cysteine availability, whether from lysosomes (CTNS-dependent) or exogenously derived (SLC7A11-dependent or as N-acetylcysteine), controls melanoma differentiation-associated pathways by acting on the melanocyte master regulator MITF. Functional data indicate that low cysteine availability reduces MITF levels and impairs lysosome functions, which affects tumor ferroptosis sensitivity but improves metastatic spread in vivo. Mechanistically, cysteine-restrictive conditions reduce acetyl-CoA levels to decrease p300-mediated H3K27 acetylation at the melanocyte-restricted MITF promoter, thus forming a cysteine feedforward regulation that controls MITF levels and downstream lysosome functions. These findings collectively suggest that cysteine homeostasis governs melanoma differentiation by maintaining MITF levels and lysosome functions, which protect against ferroptosis and limit metastatic spread.

Lithium-Ion Transport and Exchange between Phases in a Concentrated Liquid Electrolyte Containing Lithium-Ion-Conducting Inorganic Particles.

Understanding Li+ transport in organic-inorganic hybrid electrolytes, where Li+ has to lose its organic solvation shell to enter and transport through the inorganic phase, is crucial to the design of high-performance batteries. As a model system, we investigate a range of Li+-conducting particles suspended in a concentrated electrolyte. We show that large Li1.3Al0.3Ti1.7P3O12 and Li6PS5Cl particles can enhance the overall conductivity of the electrolyte. When studying impedance using a cell with a large cell constant, the Nyquist plot shows two semicircles: a high-frequency semicircle related to ion transport in the bulk of both phases and a medium-frequency semicircle attributed to Li+ transporting through the particle/liquid interfaces. Contrary to the high-frequency resistance, the medium-frequency resistance increases with particle content and shows a higher activation energy. Furthermore, we show that small particles, requiring Li+ to overcome particle/liquid interfaces more frequently, are less effective in facilitating Li+ transport. Overall, this study provides a straightforward approach to study the Li+ transport behavior in hybrid electrolytes.

Lipid-Lowering and Antioxidant Effects of Self-Assembled Astaxanthin-Anthocyanin Nanoparticles on High-Fat Caenorhabditis elegans.

Obesity has become a serious global public health risk threatening millions of people. In this study, the astaxanthin-anthocyanin nanoparticles (AXT-ACN NPs) were used to investigate their effects on the lipid accumulation and antioxidative capacity of the high-sugar-diet-induced high-fat Caenorhabditis elegans (C. elegans). It can be found that the lifespan, motility, and reproductive capacity of the high-fat C. elegans were significantly decreased compared to the normal nematodes in the control group. However, treatment of high-fat C. elegans with AXT-ACN NPs resulted in a prolonged lifespan of 35 days, improved motility, and a 22.06% increase in total spawn production of the nematodes. Furthermore, AXT-ACN NPs were found to effectively extend the lifespan of high-fat C. elegans under heat and oxidative stress conditions. Oil-red O staining results also demonstrated that AXT-ACN NPs have a remarkable effect on reducing the fat accumulation in nematodes, compared with pure astaxanthin and anthocyanin nanoparticles. Additionally, AXT-ACN NPs can significantly decrease the accumulation of lipofuscin and the level of reactive oxygen species (ROS). The activities of antioxidant-related enzymes in nematodes were further measured, which revealed that the AXT-ACN NPs could increase the activities of catalase (CAT), superoxidase dismutase (SOD), and glutathione peroxidase (GSH-Px), and decrease the malondialdehyde (MDA) content. The astaxanthin and anthocyanin in AXT-ACN NPs showed sound synergistic antioxidation and lipid-lowering effects, making them potential components in functional foods.

Mechanically and Thermally Robust Gel Electrolytes Built from A Charged Double Helical Polymer.

Polymer electrolytes have received tremendous interest in the development of solid-state batteries, but often fall short in one or more key properties required for practical applications. Herein, a rigid gel polymer electrolyte prepared by immobilizing a liquid mixture of a lithium salt and poly(ethylene glycol) dimethyl ether with only 8 wt% poly(2,2'-disulfonyl-4,4'-benzidine terephthalamide) (PBDT) is reported. The high charge density and rigid double helical structure of PBDT lead to formation of a nanofibrillar structure that endows this electrolyte with stronger mechanical properties, wider temperature window, and higher battery rate capability compared to all other poly(ethylene oxide) (PEO)-based electrolytes. The ion transport mechanism in this rigid polymer electrolyte is systematically studied using multiple complementary techniques. Li/LiFePO4 cells show excellent capacity retention over long-term cycling, with thermal cycling reversibility between ambient temperature and elevated temperatures, demonstrating compelling potential for solid-state batteries targeting fast charging at high temperatures and slower discharging at ambient temperature.

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.

Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunits Ndufs4 and Ndufs6 , but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting of Ndufs4 , or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

Recent advances on natural colorants-based intelligent colorimetric food freshness indicators: fabrication, multifunctional applications and optimization strategies.

With the increasing concerns of food safety and public health, tremendous efforts have been concentrated on the development of effective, reliable, nondestructive methods to evaluate the freshness level of different kinds of food. Natural colorants-based intelligent colorimetric indicators which are typically constructed with natural colorants and polymer matrices has been regarded as an innovative approach to notify the customers and retailers of the food quality during the storage and transportation procedure in real-time. This review briefly elucidates the mechanism of natural colorants used for intelligent colorimetric indicators and fabrication methodologies of natural colorants-based food freshness indicators. Subsequently, their multifunctional applications in intelligent food packaging systems like antioxidant packaging, antimicrobial packaging, biodegradable packaging, UV-blocking packaging and inkless packaging are well introduced. This paper also summarizes several optimizing strategies for the practical application of this advanced technology from different perspectives. Strategies like adopting a hydrophobic matrix, constructing double-layer film and encapsulation have been developed to improve the stability of the indicators. Co-pigmentation, metal ion complexation, pigment-mixing and using substrates with high surface area are proved to be effective to enhance the sensitivity of the indicators. Approaches include multi-index evaluation, machine learning and smartphone-assisted evaluation have been proven to improve the accuracy of the intelligent food freshness indicators. Finally, future research opportunities and challenges are proposed. Based on the fundamental understanding of natural colorants-based intelligent colorimetric food freshness indicators, and the latest research and findings from literature, this review article will help to develop better, lower cost and more reliable food freshness evaluation technique for modern food industry.

Pulse high energy Fe: ZnSe laser pumped by Q-switched Er: YAG laser.

We report a pulse Fe: ZnSe laser pumped by an optical chopper Q-switched Er: YAG laser. By analyzed the spatial and temporal match of the gain and chopper, the maximum energy of the optical chopper Q-switched Er: YAG laser is 31mJ with the pulse width of 165 ns. By employing this Er: YAG laser as pump laser of Fe: ZnSe crystal, the maximum output energy of Fe: ZnSe laser is 10mJ with the pulse width of 80 ns at room temperature, that is the maximum energy of Fe: ZnSe laser at this Q-switched system to the best of our knowledge. We also study the directly Q-switched Fe: ZnSe laser, and the 2.7mJ mid-infrared laser with the pulse width of 200 ns is obtained at 80 K.

Reversible Switch in Charge Storage Enabled by Selective Ion Transport in Solid Electrolyte Interphase.

Solid-electrolyte interphases (SEIs) in advanced rechargeable batteries ensure reversible electrode reactions at extreme potentials beyond the thermodynamic stability limits of electrolytes by insulating electrons while allowing the transport of working ions. Such selective ion transport occurs naturally in biological cell membranes as a ubiquitous prerequisite of many life processes and a foundation of biodiversity. In addition, cell membranes can selectively open and close the ion channels in response to external stimuli (e.g., electrical, chemical, mechanical, and thermal), giving rise to "gating" mechanisms that help manage intracellular reactions. We wondered whether the chemistry and structure of SEIs can mimic those of cell membranes, such that ion gating can be replicated. That is, can SEIs realize a reversible switching between two electrochemical behaviors, i.e., the ion intercalation chemistry of batteries and the ion adsorption of capacitors? Herein, we report such SEIs that result in thermally activated selective ion transport. The function of open/close gate switches is governed by the chemical and structural dynamics of SEIs under different thermal conditions, with precise behaviors as conducting and insulating interphases that enable battery and capacitive processes within a finite temperature window. Such an ion gating function is synergistically contributed by Arrhenius-activated ion transport and SEI dissolution/regrowth. Following the understanding of this new mechanism, we then develop an electrochemical method to heal the SEI layer in situ. The knowledge acquired in this work reveals the possibility of hitherto unknown biomimetic properties of SEIs, which will guide us to leverage such complexities to design better SEIs for future battery chemistries.

Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas.

While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression.

Uncorrelated Lithium-Ion Hopping in a Dynamic Solvent-Anion Network.

Lithium batteries rely crucially on fast charge and mass transport of Li+ in the electrolyte. For liquid and polymer electrolytes with added lithium salts, Li+ couples to the counter-anion to form ionic clusters that produce inefficient Li+ transport and lead to Li dendrite formation. Quantification of Li+ transport in glycerol-salt electrolytes via NMR experiments and MD simulations reveals a surprising Li+-hopping mechanism. The Li+ transference number, measured by ion-specific electrophoretic NMR, can reach 0.7, and Li+ diffusion does not correlate with nearby ion motions, even at high salt concentration. Glycerol's high density of hydroxyl groups increases ion dissociation and slows anion diffusion, while the close proximity of hydroxyls and anions lowers local energy barriers, facilitating Li+ hopping. This system represents a bridge between liquid and inorganic solid electrolytes, thus motivating new molecular designs for liquid and polymer electrolytes to enable the uncorrelated Li+-hopping transport needed for fast-charging and all-solid-state batteries.

Pickering emulsions stabilized by Chlorella pyrenoidosa protein-chitosan complex for lutein encapsulation.

Lutein has many physiological functions like antioxidation, anti-cancer, and anti-inflammation, which presents good potential in the development of functional food for eye protection. However, the hydrophobicity and harsh environment factors during digestive absorption process will greatly reduce lutein bioavailability. In this study, Chlorella pyrenoidosa protein-chitosan complex stabilized Pickering emulsions were prepared, and lutein was encapsulated into corn oil droplets to increase its stability and bioavailability in gastrointestinal digestion. The interaction between Chlorella pyrenoidosa protein (CP) and chitosan (CS), and the effect of chitosan concentration on the emulsifying ability of the complex and emulsion stability were studied. With the increase of CS concentration from 0% to 0.8%, the emulsion droplet size obviously decreased, and the emulsion stability and viscosity increased significantly. In particular, when the concentration was 0.8%, the emulsion system was stable at 80 °C and 400 mM sodium chloride. After ultraviolet irradiation for 48 h, the retention rate of lutein encapsulated in Pickering emulsions was 54.33%, which was significantly higher than that (30.67%) of lutein dissolved in corn oil. The retention rate of lutein in Pickering emulsions stabilized by CP-CS complex was significantly higher than that in Pickering emulsions stabilized by CP only and corn oil after heating at 90 °C for 8 h. The results of simulated gastrointestinal digestion showed that the bioavailability of lutein encapsulated in Pickering emulsions stabilized by CP-CS complex reached 44.83%. These results explored the high-value utilization of Chlorella pyrenoidosa and provided new insights into the preparation of Pickering emulsions and the protection for lutein.

Regulation of metabolic health by dietary histidine in mice.

Low-protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycaemic control in both rodents and humans. While the effects of an LP diet on glycaemic control are mediated by reduced levels of the branched-chain amino acids, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to an LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction that was started in midlife promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity. KEY POINTS: Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. Restriction of specific individual essential amino acids can recapitulate the benefits of PR. Reduced histidine promotes leanness and increased energy expenditure in male mice. Reduced histidine does not extend the lifespan of mice when begun in midlife. Dietary levels of histidine are positively associated with body mass index in humans.

Prediction of the electronic structure of single-walled GeS nanotubes.

The structure and electronic properties of puckered GeS nanotubes have been investigated using first-principles density functional theory calculation. Our results show that both the armchair and zigzag GeS nanotubes are semiconductor materials with an adjustable band gap. The band gap increases gradually with increasing the tube diameter, and slowly converges to the monolayer limit. On the application of strain, the GeS nanotubes provide interesting strain-induced band gap variation. When the compressive strain reached 20%, zigzag GeS nanotubes are completely transformed into armchair GeS nanotubes. In addition, the elastic properties of the relatively stable armchair GeS nanotubes have been studied, the Young's modulus of the armchair (11, 11), (13, 13) and (15, 15) nanotubes were calculated to be 227.488 GPa, 211.888 GPa and 213.920 GPa, respectively. Our work confirms that compared with carbon nanotubes, two-dimensional materials with a puckered structure are easier to realize phase transition by stress.

Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11.

Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels of glutathione, making them sensitive to inhibitors of cystine uptake and cyst(e)inase. Gamma-glutamyl transferase 1 (GGT1), a key enzyme in glutathione homeostasis, is markedly suppressed in ChRCC relative to normal kidney. Importantly, GGT1 overexpression inhibits the proliferation of ChRCC cells in vitro and in vivo, suppresses cystine uptake, and decreases levels of GSH and GSSG. Collectively, these data identify ferroptosis as a metabolic vulnerability in ChRCC, providing a potential avenue for targeted therapy for these distinctive tumors.

Preparation and Evaluation of Undaria pinnatifida Nanocellulose in Fabricating Pickering Emulsions for Protection of Astaxanthin.

Pickering emulsions stabilized from natural sources are often used to load unstable bio-active ingredients, such as astaxanthin (AXT), to improve their functionality. In this study, AXT-loaded Pickering emulsions were successfully prepared by 2,2,6,6-tetramethy-1-piperidine oxide (TEMPO)-oxidized cellulose nanofibers (TOCNFs) from Undaria pinnatifida. The morphology analysis showed that TOCNFs had a high aspect ratio and dispersibility, which could effectively prevent the aggregation of oil droplets. The stable emulsion was obtained after exploring the influence of different factors (ultrasonic intensity, TOCNFs concentration, pH, and ionic strength). As expected, AXT-loaded Pickering emulsions showed good stability at 50 °C and 14 days of storage. The results of simulated in vitro digestion showed that the emulsions exhibited higher release of free fatty acids (FFAs) and bioaccessibility of AXT than those in sunflower oil. Hence, our work brought new insights into the preparation of Pickering emulsions and their applications in protection and sustained, controlled release of AXT.

Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction.

Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions.

Food-Borne Nanocarriers for Calcium Delivery: A New Choice for Nutrient Supplements.

Calcium is considered as an important nutrient element for the maintenance of human health, and food-borne nanoparticles (FNs) produced during food processing may have potential as nanocarriers for calcium ion delivery. Beef is an important source of animal protein that has high protein and low fat content and is rich in a variety of amino acids; thus, beef may be a suitable material for the development of calcium nanocarriers. In this paper, FNs were synthesized from beef by one-step hydrothermal synthesis. The FNs had a spherical shape with a size of about 3.0 nm and emitted a bright blue fluorescence under 365 nm ultraviolet irradiation. The amino nitrogen atom and carboxyl oxygen atom of the functional groups on the surface of the FNs were the main binding sites for the chelation of Ca(II). The size of the FNs-Ca(II) complex was about 4.75 nm, and the specific signal peak of calcium at 3.7 keV was observed in its energy dispersive X-ray spectroscopy spectrum. The viability of cells treated with FNs-Ca(II) was more than 65%, while viability was only 60% after treatment with CaCl2. The results showed that the FNs from beef have great potential in calcium delivery for the development of a calcium supplement.

Theoretical studies on the two-photon absorption of II-VI semiconductor nano clusters.

Semiconductor clusters, ZnnOn, ZnnSn, and CdnSn (n = 2-8), were optimized and the corresponding stable structures were acquired. The symmetry, bond length, bond angle, and energy gap between HOMO and LUMO were analyzed. According to reasonable calculation and comparative analysis for small clusters Zn2O2, Zn2S2, and Cd2S2, an effective method based on density function theory (DFT) and basis set which lay the foundation for the calculation of the large clusters have been obtained. The two-photon absorption (TPA) results show that for the nano clusters with planar configuration, sizes play important role on the TPA cross section, while symmetries determine the TPA cross section under circumstance of 3D stable structures. All our conclusions provide theoretical support for the development of related experiments.

Dosimetric Comparison of Helical Tomotherapy, Volume-Modulated Arc Therapy, and Fixed-Field Intensity-Modulated Radiation Therapy in Locally Advanced Nasopharyngeal Carcinoma.

OBJECTIVE: To compare the dosimetric parameters of different radiotherapy plans [helical tomotherapy (HT), volume-modulated arc therapy (VMAT), and fixed-field intensity-modulated radiation therapy (FF-IMRT)] for locally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 15 patients with locally advanced NPC were chosen for this retrospective analysis and replanned for HT, VMAT, and FF-IMRT. The prescribed planning target volume (PTV) dose for the primary tumor and metastatic lymph nodes was 70 Gy (2.12 Gy/fraction, delivered over 33 fractions). The prescribed PTV dose for the high-risk subclinical region was 59.4 Gy (1.8 Gy/fraction, delivered over 33 fractions). The dosimetric parameters of the PTV and organs at risk (OARs) and the efficiency of radiation delivery were assessed and compared using the paired-samples t-test. RESULTS: Compared with VMAT and FF-IMRT plans, HT plans significantly improved the mean conformity index (CI) and homogeneity index (HI). The HT plans reduced the maximum doses delivered to OARs, such as the brainstem, spinal cord, and optic nerves, and significantly reduced the volume delivered to the high-dose region, especially when examining the V 30 value of the parotid glands. However, VMAT reduced the treatment time and improved the efficiency of radiation delivery compared with HT. CONCLUSIONS: For locally advanced NPC, the results showed that HT and VMAT possessed better target homogeneity and conformity, reducing the dose delivered to OARs compared with conventional FF-IMRT, with HT achieving the best effect. Among the techniques studied, VMAT had the shortest radiation delivery time. The results of this study can provide guidance for the selection of appropriate radiation technologies used to treat patients with locally advanced NPC who are undergoing concurrent chemoradiotherapy.

Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.