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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases. Previous studies revealed actions of inositol phosphates and their metabolic enzymes in the modulation of inflammation such as Toll-like receptor-triggered innate immunity. However, the physiological roles of inositol polyphosphate (IP) metabolism in the regulation of RA remain largely uncharacterized. Therefore, our study sought to determine the role of inositol polyphosphate multikinase (IPMK), a key enzyme for IP metabolism and various cellular signaling control mechanisms, in mediating RA. Using myeloid cell-specific IPMK knockout (KO) mice, arthritis was induced via intraperitoneal K/BxN serum injection, after which disease severity was evaluated. Both wild-type and IPMK KO mice developed similar RA phenotypes; however, conditional deletion of IPMK in myeloid cells led to elevated arthritis scores during the resolution phase, suggesting that IPMK deficiency in myeloid cells impairs the resolution of inflammation. Bone marrow-derived IPMK KO macrophages exhibited no apparent defects in immunoglobulin Fc receptor (FcR) activation, osteoclast differentiation, or resolvin signaling. Taken together, our findings suggest that myeloid IPMK is a key determinant of RA resolution.

Cryogenic ion spectroscopy was used to characterize adenine complexes containing alkali metal cations (M+A, M = Cs, Rb, K, Na, and Li) produced by electrospray ionization. The ultraviolet (UV) photodissociation spectra of the complexes stored in a cryogenic ion trap exhibited well-resolved vibronic bands near their origin bands of the S0–S1 transition. The UV-UV hole-burning and infrared ion-dip spectra showed that all the M+A ions in the ion trap were single isomers of M+A7a, where the M+ ion was not bound to canonical 9H-adenine (A9) but bound to a rare tautomer, 7H-adenine (A7). Density functional theory calculations showed lower tautomerization barriers for M+A9 than for bare A9 in aqueous solution. We suggest that M+ ions not only play a catalytic role in the tautomerization of A9 to A7 but also increase the tautomerization yield by forming stable M+A7a isomers.

The development of new battery technologies requires to be well established in the same era of lithium ion batteries (LIBs), a well commercialized technology, and the merits should surpass over oth...

This study was preformed to establish a simple and reliable HPLC/UV analytical method to determine p-coumaric acid contents for the standardization of water extracts of Allium hookeri and Curcuma longa complex as functional health food ingredients. The quantitative HPLC method was optimized using a reversed-phase C18 column at 35°C with methanol and H2O (30:70, v/v) as the gradient mobile phase at a flow rate of 1.0 mL/min and along with detection wavelength of UV 300 nm. This HPLC/UV analytical method exhibited good specificity and high linearity in the tested range of 1.0–10.0 mg/mL with excellent coefficient of determination (R2) of 1.0. The limit of detection and limit of quantification were 0.08 and 0.24 μg/mL, respectively. In addition, the relative standard deviation values from the intra and inter-day precision measurements were 0.4 and 0.1%, respectively. These results indicate that the established HPLC/UV analytical method is simple, specific, precise, accurate, and reproducible and so could be employed in the quantitative analysis of p-coumaric acid as a functional compound in Allium hookeri Thwaites and Curcuma longa complex.

Transition-metal sulfides are of significant interest as rechargeable battery anodes owing to their low cost, wide availability, eco-friendliness, and high theoretical capacities. However, extraordinary structural changes in these materials cause pulverization of the electrode, thereby limiting their practical electrochemical abilities. Herein, a simple one-pot polyol refluxing method is used for fabricating a manganese sulfide (MnS) electrode composited with nitrogen and sulfur co-doped carbon (MnS@NS-C) for high-power lithium-ion batteries. This electrode exhibits unique spherical particle morphology with optimized average particle size (300 < x < 500 nm) and porous features. Owing to its nanostructure, porous nature, and an electrically conducting carbon network co-doped with heteroatoms, the composite electrode overcomes the strong structural variations to afford high practical storage capacities, long-term cycle stability, and outstanding rate capability. The MnS@NS-C electrode demonstrated high reversible storage capacities of 999 mA h g−1 at 0.1 A g−1, the highest reversible capacity of 761 mA h g−1 at 2 A g−1 for over 300 cycles, and average rate capacities of 453 mA h g−1 at 10 A g−1. In situ synchrotron X-ray diffraction investigations indicated a uniquely combined intercalation-cum-conversion reaction mechanism leading to β-Li2(1−x)MnS, Li2S, and Mn discharge products. The results of this study can provide deep insights into understanding intriguing reactions and motivate further study of transition-metal sulfides for prospective high-energy battery applications.

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC-38 or B16-F10 pre-clinical syngeneic tumor models. These results elucidates the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

In this study, major phytochemical compounds of Vaccinium bracteatum Thunb. (VB) aqueous leaf extract were isolated and analyzed using a HPLC-based method, followed by method validation in accordance with the International Conference on Harmonisation (ICH) guidelines for drug development. Five major compounds were isolated in VB extract. Apart from vaccinoside, which had been the only compound isolated in VB extract to date, vanillic acid and protocatechuic acid were isolated for the first time. Isolation of orientin and isoorientin in the VB extract helped validate the reverse-phase analytical method. A new simple and rapid high-performance liquid chromatography (HPLC)-based method was developed for the validation of orientin and isoorientin in VB extract and was determinated according to the ICH guidelines. The analytical method was validated through a Waters Alliance HPLC System containing an e2695 separation module and a 2998 photodiode array (PDA) detector. The VB extract and solutions of orientin and isoorientin were analyzed using a reverse-phase Eclipse XDB-C18 column (4.6 × 250 mm ID, 5 µm, Waters), which was maintained at 30 °C. A mobile phase of methanol and 0.01% formic acid in water was used at a flow rate of 1.0 mL/min to achieve gradient elution. The linearity of the orientin and isoorientin was excellent results (R2 ≥ 0.9999) in the concentration range of 1.0–50.0 μg/mL. Precision values ranged 98.55–101.70% and 98.70–101.18%, respectively. The intra-day and inter-day relative standard deviation (RSD) values of the orientin and isoorientin were all &lt, 2.0%. The average recoveries of orientin ranged 98.30–101.57%, whereas isoorientin ranged 97.81–102.14% with RSD values &lt, 2.0%. Quantitative analysis found that VB extract contained 2.90 mg/g of orientin and 3.45 mg/g of isoorientin.

Catechols are prone to oxidative polymerization as well as complex formation with metal ions. These two features of catechols have played an important role in the construction of functional films on various surfaces. For example, marine antifouling films and antibacterial films were successfully prepared by oxidative polymerization and metal complexation of catechol-containing molecules, respectively. However, the effect of simultaneous metal complexation and oxidative polymerization on functional film formation has not yet been fully investigated. Herein, as a derivative of 3-(3,4-dihydroxyphenyl)-l-alanine (DOPA), we synthesized an ethylene glycol-derivatized DOPA (OEG-DOPA) and formed OEG-DOPA thin films based on (1) oxidative polymerization and (2) the complexation between catechol groups of OEG-DOPA and iron(III) (FeIII) ions. Either or both approaches were used for the film formation. OEG-DOPA film formation was characterized by ellipsometry, contact angle goniometry, field emission scanning electron microscopy, and X-ray photoelectron spectroscopy. Among the conditions used, the formation of a uniform film was only achieved with the dual cross-linking system of FeIII complexation and oxidation-induced covalent bond formation. Compared to the uncoated substrate and other OEG-DOPA films prepared under different conditions, the uniform OEG-DOPA film strongly inhibited bacterial adhesion, showing excellent antibacterial capability. We think that our surface-coating strategy can be applied to medical devices, tools, and implants where bacterial adhesion and biofilm formation should be prevented. This work can also serve as a basis for the construction of functional thin films for other catechol-functionalized materials.

Polyamidoamine (PAMAM) dendrimer is one of the cationic polymers widely used in nonviral vector-based gene therapy. As PAMAM comprises biodegradable peptide bonds, it shows biocompatibility and relatively low cytotoxicity. In comparison with polyethylenimine (PEI, 25 kDa) that shows high transfection efficiency, the native PAMAM dendrimer has limitations as a gene carrier. To improve the gene expression efficiency, we introduced KRTR peptides derived from the influenza B virus nucleoprotein, known as a nuclear localization signal (NLS), to PAMAM generation 3. We synthesized PAMAM-RTRK and PAMAM-HRTRK and evaluated the effects of the histidine residue on cytotoxicity. The transfection efficiency of PAMAM-RTRK and PAMAM-HRTRK was similar to that of PEI in HepG2 cells, while their gene expression capacities were much higher than capacity of PEI in A549 cells. PAMAM-HRTRK showed relatively lower cytotoxicity than PAMAM-RTRK in the two cell lines, but the transfection capacity was similar for the two polymers. These results imply that the combination of histidine and KRTR peptide may potentially result in a novel PAMAM-based vector that could be used for prolonged gene therapy through the reduction in cytotoxicity and enhancement of gene expression.

Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by selective activation of the mechanistic target of rapamycin (mTOR) regulatory enzyme p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. The IPMK mutants also manifested facilitated hippocampal long-term potentiation. These findings establish a signaling action of IPMK that mediates fear extinction.

In this work, a pre-designed NiMnO3/Mn2O3 nanocomposite is synthesized via a facile urea-assisted auto-combustion synthesis method followed by annealing at 600 °C for 5 h in air as an anode material for lithium-ion batteries. Powder X-ray diffraction analysis confirmed the formation of the NiMnO3/Mn2O3 nanocomposite. Using Rietveld refinement analysis, the phase fraction of NiMnO3 and Mn2O3 phases was found to be ∼89% and ∼11%, respectively. It is believed that the interaction between NiMnO3 and Mn2O3 nanoparticles enhanced the charge transfer efficiency, which is favorable for an excellent electrochemical performance of the nanocomposite electrode. Electrochemical properties are evaluated via cyclic voltammetry and galvanostatic cycling studies. Benefiting from the high structural integrity and synergistic effect between NiMnO3 and Mn2O3, this nanocomposite exhibits a high reversible capacity (854.4 mA h g−1 at 1.0C for 200 cycles and 444.1 mA h g−1 at 2.0C for 500 cycles), excellent cycling stability (98% capacity retention after 200 cycles) and good rate capability (811.2 mA h g−1 at 2.0C). The values are much higher than the theoretical capacity of graphite (372 mA h g−1).

Manganese (Mn)‐based cathode materials have garnered huge research interest for rechargeable aqueous zinc‐ion batteries (AZIBs) due to the abundance and low cost of manganese and the plentiful advantages of manganese oxides including their different structures, wide range of phases, and various stoichiometries. A novel in situ generated Mn‐deficient ZnMn2O4@C (Mn‐d‐ZMO@C) nanoarchitecture cathode material from self‐assembly of ZnO‐MnO@C for rechargeable AZIBs is reported. Analytical techniques confirm the porous and crystalline structure of ZnO‐MnO@C and the in situ growth of Mn deficient ZnMn2O4@C. The Zn/Mn‐d‐ZMO@C cell displays a promising capacity of 194 mAh g−1 at a current density of 100 mA g−1 with 84% of capacity retained after 2000 cycles (at 3000 mA g−1 rate). The improved performance of this cathode originates from in situ orientation, porosity, and carbon coating. Additionally, first‐principles calculations confirm the high electronic conductivity of Mn‐d‐ZMO@C cathode. Importantly, a good capacity retention (86%) is obtained with a year‐old cell (after 150 cycles) at 100 mA g−1 current density. This study, therefore, indicates that the in situ grown Mn‐d‐ZMO@C nanoarchitecture cathode is a promising material to prepare a durable AZIB., A novel battery consisting of zinc anode and Mn deficient ZnMn2O4@C cathode has been developed by immersing ZnO‐MnO@C electrode in 2 m ZnSO4 + 0.2 m MnSO4. The in situ formation of a reversible ZnMn2‐ xO4@C with Zn4(OH)6(SO4).xH2O surface layer exhibits extraordinary cycle performance.

We demonstrate the broadband visible luminescence from bulk crystalline silicon and silicon nanoparticles sized 100- 30 nm under near-infrared excitation. We show that the luminescence spectrum has two distinct peaks. The first being centered at 550 nm while the second appears close to the wavelength of the second harmonic of the excitation light. The appearance of the second peak is a signature of the highly athermal electron distribution never observed previously. The luminescence intensity and spectral shape strongly depend on the doping type and concentration. Despite being nonresonant, silicon nanoparticles enhance luminescence intensity when placed atop the silicon wafer. The observed phenomenon can be used for wafer inspection and defect detection, as well as for the creation of novel nanosources of light.

Adipose tissue plays a central role in regulating whole body energy and glucose homeostasis at both organ and systemic levels. Inositol polyphosphates, such as 5-diphosphoinositol pentakisphosphate, reportedly control adipocyte functions and energy expenditure. However, the physiological roles of the inositol polyphosphate (IP) pathway in the adipose tissue are not yet fully defined. The aim of the present study was to test the hypothesis that inositol polyphosphate multikinase (IPMK), a key enzyme in the IP metabolism, plays a critical role in adipose tissue biology and obesity. We generated adipocyte-specific IPMK knockout ( Ipmk AKO) mice and evaluated metabolic phenotypes by measuring fat accumulation, glucose homeostasis, and insulin sensitivity in adult mice fed either a regular-chow diet or high-fat diet (HFD). Despite substantial reduction of IPMK, Ipmk AKO mice exhibited normal glucose tolerance and insulin sensitivity and did not show changes in fat accumulation in response to HFD-feeding. In addition, loss of IPMK had no major impact on thermogenic processes in response to cold exposure. Collectively, these findings suggest that adipocyte IPMK is dispensable for normal adipose tissue and its physiological functions in whole body metabolism, suggesting the complex roles that inositol polyphosphate metabolism has in the regulation of adipose tissue.

Detection of a single nanoparticle on a bare silicon wafer has been a challenge in the semiconductor industry for decades. Currently, the most successful and widely used technique is dark-field microscopy. However, it is not capable of detecting single sub-10 nm particles owing to a low signal-to-noise ratio (SNR). As a new approach, we suggest using the second harmonic generation (SHG) to detect a single nanoparticle. The second harmonic generation in centrosymmetric materials, like silicon, is forbidden except for a thin and additionally increase local field factors, allowing for their persistent detection. Choosing the proper surface and increasing SNR. We demonstrate the feasibility of the nonlinear dark-field microscopy concept by detecting an isolated 80-nm silicon nanoparticle on the silicon wafer.

The present study evaluates the anti-oxidative stress activity of Vaccinium bracteatum Thunb. fruit extract (VBFW) to identify the mechanisms responsible for its antidepressant-like effects. To evaluate the antidepressant and anti-oxidant effects of VBFW, malondialdehyde (MDA), serotonin transporter (SERT), and monoamine oxidase A (MAO-A) levels were measured in a mouse model of chronic restraint stress (CRS). The underlying mechanisms preventing oxidative stress and neuronal apoptosis were investigated using in vitro models of hydrogen peroxide (H2O[Formula: see text]-induced neuronal damage. The results showed that VBFW treatment (200[Formula: see text]mg/kg) significantly reduced MDA, SERT, and MAO-A levels in the prefrontal cortex of CRS mice. Furthermore, VBFW (30[Formula: see text][Formula: see text]g/mL) exhibited protective effects against H2O2-induced cell death via inhibition of the H2O2-induced increase in Bax and decrease in Bcl-2 levels within the mitochondria of SH-SY5Y cells. Furthermore, VBFW (10 and 30[Formula: see text][Formula: see text]g/mL) exerted protective effects against H2O2-induced cell death through inhibition of key mitochondria-associated apoptotic proteins such as cytochrome c, caspase-3 and PARP. Additionally, VBFW (10 and 30[Formula: see text][Formula: see text]g/mL) could improve the activity of anti-oxidant enzymes (such as SOD and catalase) in H2O2-treated SH-SY5Y cells. These results suggest that the antidepressant and anti-oxidant effects of VBFW might be mediated by the regulation of SERT and MAO-A, and possibly associated with regulation of oxidative stress-induced apoptosis.

The aim of this work was to study the comparison of anti-oxidative activity in a single serving size of commercial coffees and teas. Commercial regular coffees and teas, including, brand regular coffees (BCA, BCB, BCC, BCD, and BCE), green tea (GTA, GTB, GTC, and GTD), black tea (BTA, BTB, and BTC), pu-erh tea (PTA, PTB, and PTC), chamomile tea (CTA, CTB, and CTC), peppermint tea (PA, PB, and PC), polygonatum odoratum tea (POTA, POTB, and POTC), and jujube tea (JTA, JTB, and JTC) were assayed for the levels of ascorbic acid, caffeine, total content of polyphenols and flavonoids, and ability to scavenge free radicals, using two in vitro antioxidant assays. The scavenging abilities of BCA and BCC were 664.91 ± 48.87 mg ascorbic acid equivalent/serving size and 624.36 ± 16.18 mg ascorbic acid equivalent/serving size, respectively. The four beverage samples (BCA, BCC, GTD, and BTA) significantly reduced the production of reactive oxygen species (ROS) and intracellular oxidative stress induced by H2O2. These results suggest that the beverages possess significant radical scavenging ability, which may be due to the presence of antioxidants. Furthermore, the significant reducing level of ROS evidences the potential antioxidant effects of these beverages in human cells.

Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP7) are inositol metabolites with high-energy phosphoanhydride bonds. The formation of PP-IPs is catalyzed by two groups of enzymes, the IP6 kinases and the PPIP5 kinases, which both phosphorylate inositol hexakisphosphate (IP6). In mammals, PP-IPs are implicated in diverse biological phenomena including cellular growth, vesicular trafficking, apoptosis, and metabolic homeostasis. Mechanistically, all the diverse actions of PP-IPs proceed in one of two ways: the PP-IPs modulate the activity of their target proteins either through allosteric binding or protein pyrophosphorylation. In this review, we highlight recent advances in our understanding of the pleiotropic functions of the mammalian PP-IPs and the metabolic enzymes that produce them. We also discuss some future challenges in the exploration of areas where PP-IPs play important but unknown roles in physiology and disease.

Peptide nanostructure has been widely explored for drug-delivery systems in recent studies. Peptides possess comparatively lower cytotoxicity and are more efficient than polymeric carriers. Here, we propose a peptide nanorod system, composed of an amphiphilic oligo-peptide RH3F8 (Arg–His3–Phe8), as a drug-delivery carrier. Arginine is an essential amino acid in typical cell-penetration peptides, and histidine induces endo- and lysosomal escape because of its proton sponge effect. Phenylalanine is introduced to provide rich hydrophobicity for stable self-assembly and drug encapsulation. The self-assembled structure of RH3F8 showed nanorod-shaped morphology, positive surface charge, and retained formation in water for 35 days. RH3F8, labeled with Nile Red, showed high cellar uptake and accumulation in both cytoplasm and nucleus. The RH3F8 nanorods demonstrated negligible cytotoxicity, as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and hemolys...

Fe2O3 nano-particles and nano-rods were synthesized by hydrothermal synthesis method under different reaction conditions and then applied as anode materials for Lithium ion batteries. Microstructural analysis confirmed these two shapes and structures for Fe2O3 samples. It was noticed that the electrochemical performance of Fe2O3 is highly influenced by its particle morphology. Unexpectedly, Fe2O3 nano-particles exhibit excellent electrochemical performances as compared to nano-rods morphology, which may be due to the least micro strain, high stability of nano-particles structure, small agglomerations, etc. It is believed that the nano-particles structure provides extra reaction sites to accommodate large Li-ions, shorten the Li-ion diffusion paths to improve the electronic conductivity and offers large electrolyte/electrode contact area for fast electrochemical reactions. In contrast, the nano-rods morphology could not hold its structural integrity during the lithiation/de-lithiation reactions and collapsed only after certain number of cycles giving rise to poor electrochemical performances, as confirmed by post cycling ex-situ studies. More precisely, Fe2O3 nano-particles electrode delivered the excellent reversible capacity of 1125 mAh g−1 and 1007 mAh g−1 at 1C and 4C after 100 and 80 cycles, respectively, while Fe2O3 nano-rods exhibit only 113.5 mAh g−1 at 1C and 326.7 mAh g−1 at 4C.

In the present work, one–dimensional porous NiO nano-rods as an anode material were synthesized using facile hydrothermal synthesis method to improve the electrochemical performance for LIBs application. The NiO nano-rods were typically several hundred nanometers in length, which are composed by loosely stacked nanoparticles. It is believed that the obtained architecture with mesoporous structure can ensure rapid electrons/ions transfer, penetration of the electrolyte to the electrode surfaces and buffer the volume expansion of NiO during charge/discharge processes. When evaluated as anode material, the NiO nano-rods exhibit excellent rate performance and long-life cycling performance with high reversibility. The porous NiO nano-rods exhibit a capacity of 1029.3 mA h g−1 at 1C up to 100 cycles and even retains a reversible capacity of 548.4 mA h g−1 at 4C after 80 cycles. Thus, it is believed that the current strategy can be applicable to improve the electrochemical performances of various metal oxide electrodes in rechargeable secondary battery.

Stabilized plasmid-lipid particles (SPLPs) have been developed to overcome the low stability issue of cationic liposomes, however, SPLPs that are too stable result in unsatisfactory transfection efficiency. In this article, we prepared enzyme-responsive SPLPs (eSPLPs) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and mPEG-GLFG-K-(C16)2, a PEG lipid with an enzymatically-cleavable linker (glycine-phenylalanine-leucine-glycine, GFLG). eSPLPs were successfully prepared with plasmid DNA (pDNA) encapsulation efficiency of over 80%, using the detergent dialysis method. The PEG shell stabilized eSPLPs and maintained a hydrodynamic diameter of around 200nm. Although typical SPLPs were relatively intact in endosomal condition, the PEG shell of eSPLPs was cleaved following the degradation of the GFLG linker by cathepsin B in the endosome. Then, eSPLPs collapsed and induced endosomal disruption triggering the controlled release of the encapsulated pDNA into cytoplasm. Owing to the enzyme-responsive destabilization, eSPLPs showed a 10 to 100-fold higher transfection efficiency than control SPLPs, which was confirmed using luciferase assay. These results suggest that eSPLPs might be promising candidates for practical use as gene delivery systems, with both stability and high transfection efficiency for future in vivo applications.

Inositol-derived metabolites (e.g., phosphoinositides and inositol polyphosphates) are key second messengers that are essential for controlling a wide range of cellular events. Inositol polyphosphate multikinase (IPMK) exhibits complex catalytic activities that eventually yield water-soluble inositol polyphosphates (e.g., IP4 and IP5) and lipid-bound phosphatidylinositol 3,4,5-trisphosphate. A series of recent studies have suggested that IPMK may be a multifunctional regulator in the nucleus of mammalian cells. In this review, we highlight the novel modes of action of IPMK in transcriptional and epigenetic regulation, and discuss its roles in physiology and disease.

We have successfully synthesized Reduced graphene oxide (rGO) sheets by modified Hummer’s method without additional reducing procedures, such as chemical and thermal treatment, by using appropriate drying temperatures under ambient atmosphere. The rGO sample dried at the optimum temperature of 250 has the most increased specific surface area and porosity as evidenced by SEM and BET analysis, leading to improved lithium-ion, sodium-ion and potassium-ion storage properties. We confirmed the use of a moderate drying temperature led to electrodes’ enhanced cyclability and good electrochemical performance at high current densities. The dimensions of the sheets ranged from nanometers to micrometres and these were entangled with each other to form aggregates. These morphological features of rGO facilitates the movement of guest ions larger than Li-ions, however there were slight instability during repeated cycling. To improve the electrochemical properties, we adopted simple chemical strategies using surfactant/solvent-assisted ultrasonication or mechanical or thermal methods. Our results will be useful for improving the full cell characteristics, and especially for preventing potential drop in sodium-ion batteries and potassium-ion batteries, which are expected to replace the lithium-ion battery system.

Research attention in aqueous rechargeable zinc-ion batteries (ARZIBs) is growing immensely because of their low-cost and eco-friendly cell components. However, its challenging to find new cathode materials towards practical application of ARZIBs. In this contribution, ground-breaking work on the potassium-pillared V2O5.nH2O (K0.5V2O5.nH2O) nanorod with exposed layer structure as high-performance cathode for ARZIB is presented. The storage mechanism of the K0.5V2O5.nH2O cathode in ARZIB is systematically elucidated using a combined of in situ synchrotron X-ray diffraction, ex situ synchrotron X-ray absorption spectroscopy, ex situ TEM analyses, and first-principle calculations. The K0.5V2O5. nH2O cathode displays a notable discharge capacity of 439 mAh g−1 at a current density of 50 mA g−1. Furthermore, it recovers 96% of the capacity after 1500 cycles at 8000 mA g−1. Impressively, the Zn/K0.5V2O5.nH2O battery offers a specific energy of 121 Wh kg−1 at a high specific power of 6480 W kg−1. The superior performance of the cathode is attributed to its unique exposed layer structure with high surface energy, high conductivity, and low migration barrier. The zinc (Zn) insertion pathway into K0.5V2O5.nH2O was studied using density function theory (DFT). This study provides an insight for designing high-performance cathode materials for ARZIBs and other electrochemical systems.

In this work, the nanorod structured Na2Ti6O13/Na2Ti3O7 nanocomposite anode is synthesized via facile solvothermal method for sodium ion battery application. The Lebail refinement analysis was performed to obtain the phase fractions ratio of Na2Ti6O13 and Na2Ti3O7 in the nanocomposite sample. It was found to be ~82% and ~ 18% for Na2Ti6O13 and Na2Ti3O7 phases, respectively. The microstructure analysis confirmed the nanorods morphology of the nanocomposite sample, which are self-assembled in hierarchal manner and exhibits the flower-like morphology at high magnifications. The obtained morphology demonstrates remarkable electrochemical performances such as superior cycling stability of 182 mAh g−1 at 100 mA g−1 after 165 cycles and high rate capability of 161 mAh g−1 at 500 mA g−1 over 100 cycles, which can be ascribed to the excellent synergetic effect between Na2Ti6O13 and Na2Ti3O7 phases that could effectively nullify the drawbacks of individual phases and thereby act as complementary to each other advantages.

Energy storage devices remain critical to meet the increasing demands of the modern society. Rechargeable lithium ion batteries (LIBs) are a crucial finding in this century to compensate the energy demand in the present day. As device performance is intimately correlated with the material properties, production of functional energy storage nanomaterials endowed with exceptional physico-chemical properties in view of their particle-size confinement has become critically significant. Low- or moderate-temperature synthetic strategies that are versatile, easily scalable, and efficiently produce size-tuned and efficient materials are essential. In the recent past, combustion-based synthetic process has emerged as one of the promising strategies for developing customized energy storage nanomaterials due to rapid synthesis and ease of preparations in a large scale, etc. In the present review, the advancements in the design and chemistry of these strategies in developing a wide range of high voltage cathode materials for LIBs have been discussed. Among the various combustion techniques, this study will focus mainly on solution combustion, sol-gel based combustion and polyol-based pyro-synthesis. The versatility of these processes to provide tailored particle morphologies and particle sizes at the nanoscale and their effects on the material performance in various applications, particularly in energy storage, is also discussed.

In recent decades, several types of anticancer drugs that inhibit cancer cell growth and cause cell death have been developed for chemotherapeutic application. However, these agents are usually associated with side effects resulting from nonspecific delivery, which may induce cytotoxicity in healthy cells. To reduce the nonspecific delivery issue, nanoparticles have been successfully used for the delivery of anticancer drugs to specific target sites. In this study, a functional polymeric lipid, PEG-GLFG-K(C16)2 (PEG-GLFG, polyethylene glycol-Gly-Leu-Phe-Gly-Lys(C16)2), was synthesized to enable controlled anticancer drug delivery using cathepsin B enzyme-responsive liposomes. The liposomes composed of PEG-GLFG/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane (chloride salt))/DPPC (dipalmitoylphosphatidylcholine)/cholesterol were prepared and characterized at various ratios. The GLFG liposomes formed were stable liposomes and were degraded when acted upon by cathepsin B enzyme. Doxorubicin (Dox) loaded GLFG liposomes (GLFG/Dox) were observed to exert an effective anticancer effect on Hep G2 cells in vitro and inhibit cancer cell proliferation in a zebrafish model.

Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP7) are inositol metabolites containing high-energy phosphoanhydride bonds. Biosynthesis of PP-IPs is mediated by IP6 kinases (IP6Ks) and PPIP5 kinases (PPIP5Ks), which transfer phosphate to inositol hexakisphosphate (IP6). Pleiotropic actions of PP-IPs are involved in many key biological processes, including growth, vesicular remodeling, and energy homeostasis. PP-IPs function to regulate their target proteins through allosteric interactions or protein pyrophosphorylation. This review summarizes the current understanding of how PP-IPs control mammalian cellular signaling networks in physiology and disease.

Background Matrix metalloproteinases (MMPs) are linked with several complications such as metastasis of cancer progression, oxidative stress, and hepatic fibrosis. Brown seaweeds are being extensively studied for their bioactive molecule content against cancer progression. In this context, Sargassum horneri was reported to possess various bioactivities including antiviral, antimicrobial, and anti-inflammatory partly due to its phenolic compound content. Methods In this study, potential of S. horneri was evaluated through anti-MMP effect in HT1080 fibrosarcoma cells. S. horneri crude extract was fractionated with organic solvents, namely, water (H2O), n-buthanol (n-BuOH), 85% aqueous methanol (85% aq. MeOH), and n-hexane. The non-toxicity of fraction samples (Sargassum horneri solvent-partitioned extracts (SHEs)) was confirmed by cell-viability assay. SHEs were tested for their ability to inhibit MMP enzymatic activity through gelatin digestion evaluation and cell migration assay. Expressions of MMP-2 and MMP-9 and tissue inhibitors of MMP (TIMPs) were evaluated by reverse transcription and Western blotting. Results All fractions inhibited the enzymatic activities of MMP-2 and MMP-9 according to gelatin zymography. Except H2O fraction, fractions hindered the cell migration significantly. All tested fractions suppressed both mRNA and protein levels of MMP-2, MMP-9, TIMP-1, and TIMP-2. Conclusion Overall, current results suggested that S. horneri has potential to be a good source for anti-MMP agents, and further investigations are underway for better understanding of the action mechanism and isolation and elucidation of the bioactive molecules.

Anthocyanins are flavonoid compounds that protect plant tissues from many environmental stresses including high light irradiance, freezing temperatures, and pathogen infection. Regulation of anthocyanin biosynthesis is intimately associated with environmental changes to enhance plant survival under stressful environmental conditions. Various factors, such as UV, visible light, cold, osmotic stress, and pathogen infection, can induce anthocyanin biosynthesis. In contrast, high temperatures are known to reduce anthocyanin accumulation in many plant species, even drastically in the skin of fruits such as grape berries and apples. However, the mechanisms by which high temperatures regulate anthocyanin biosynthesis in Arabidopsis thaliana remain largely unknown. Here, we show that high ambient temperatures repress anthocyanin biosynthesis through the E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) and the positive regulator of anthocyanin biosynthesis ELONGATED HYPOCOTYL5 (HY5). We show that an increase in ambient temperature decreases expression of genes required in both the early and late steps of the anthocyanin biosynthesis pathway in Arabidopsis seedlings. As a result, seedlings grown at a high temperature (28°C) accumulate less anthocyanin pigment than those grown at a low temperature (17°C). We further show that high temperature induces the degradation of the HY5 protein in a COP1 activity-dependent manner. In agreement with this finding, anthocyanin biosynthesis and accumulation do not respond to ambient temperature changes in cop1 and hy5 mutant plants. The degradation of HY5 derepresses the expression of MYBL2, which partially mediates the high temperature repression of anthocyanin biosynthesis. Overall, our study demonstrates that high ambient temperatures repress anthocyanin biosynthesis through a COP1-HY5 signaling module.

Overproduction and stimulation of tyrosinase result in increased melanogenesis of which several skin disorders such as freckles, spots, and hyperpigmentation appear as complications. Limonium tetragonum is a halophyte well-known for its antioxidative properties. This study investigated the anti-melanogenic effects of solvent-partitioned L. tetragonum extracts (LTEs) and its bioactive constituents, two isolated flavonoid glycosides. Current study followed a set of experiments on B16-F10 mouse melanoma cell model with a focus on tyrosinase activity and production. The anti-melanogenic capacity of LTEs was confirmed by their tyrosinase inhibitory effects, prevention of DOPA oxidation, and suppression of melanin production. The inhibition of tyrosinase and DOPA oxidation by LTEs was suggested to be related with the downregulation of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2, verified with mRNA and protein expression levels. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be the most active fractions which later yielded the two known compounds, myricetin 3-galactoside and quercetin 3-O-β-galactopyronaside. The anti-melanogenic potential of the compounds were confirmed by their tyrosinase inhibitory effects. These results suggested that L. tetragonum may serve as a potential source of bioactive substances with effective anti-melanogenesis properties.

• Mitochondria are exclusively employed to produce energy required for the vital metabolic functions of the cell. However, mitochondria also play a key role in mammalian cell death. Dissipation in the mitochondria membrane potential causes cell death. Therefore, in cancer therapy, mitochondria are a novel target. Herein, we developed a nano-formulation of Antimycin A specifically targeted towards mitochondria and lung cancer; A549 cell. The liposomes were prepared using cholesterol and a mitochondria-penetrating peptide (MPP) having a phenylalanine-arginine-phenylalanine-lysine (FRFK) peptide sequence. The FRFK peptide was synthesized using solid phase peptide synthesis (SPPS) and contained cholesterol in the N-terminal end of the phenylalanine (Chol-FRFK). The synthesized material was confirmed using 1H NMR, Fourier transform infrared spectroscopy (FT-IR) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF/MS). 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and Chol-FRFK, at a molar ratio of 1:1, were used for liposomal (Chol-FRFK/D) formulations; the sizes of the liposomes were confirmed using dynamic light scattering (DLS). Cytotoxicity was evaluated in A549 cells. Cellular uptake and mitochondria targeting were confirmed by flow cytometry and confocal microscopy, respectively. Antimycin A, a hydrophobic and mitochondrial electron transporter inhibitor was encapsulated into the Chol-FRFK/D liposomes. Our results indicate that Chol-FRFK/D liposomes may potentially be used for the nano-formulation of cytotoxic drugs and enhancing their bioavailability in cancer therapy.

Inositol polyphosphate multikinase acts as a key determinant of inflammation by stabilizing the signaling adaptor TRAF6., Toll-like receptor (TLR) signaling is tightly controlled to protect hosts from microorganisms while simultaneously preventing uncontrolled immune responses. Tumor necrosis factor receptor–associated factor 6 (TRAF6) is a critical mediator of TLR signaling, but the precise mechanism of how TRAF6 protein stability is strictly controlled still remains obscure. We show that myeloid-specific deletion of inositol polyphosphate multikinase (IPMK), which has both inositol polyphosphate kinase activities and noncatalytic signaling functions, protects mice against polymicrobial sepsis and lipopolysaccharide-induced systemic inflammation. IPMK depletion in macrophages results in decreased levels of TRAF6 protein, thereby dampening TLR-induced signaling and proinflammatory cytokine production. Mechanistically, the regulatory role of IPMK is independent of its catalytic function, instead reflecting its direct binding to TRAF6. This interaction stabilizes TRAF6 by blocking its K48-linked ubiquitination and subsequent degradation by the proteasome. Thus, these findings identify IPMK as a key determinant of TRAF6 stability and elucidate the physiological function of IPMK in TLR-induced innate immunity.

Mitochondria are targets with great potential for therapeutics for many human disorders. However, drug delivery systems for such therapeutics remain in need of more efficient mitochondrial-targeting carriers. In this study, we report that nanosomes composed of Dequalinium/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), called DQA80s, can act in the dual role of mitochondrial-targeting carrier and anticancer agent for therapeutic interventions against mitochondrial diseases. In cytotoxicity assays, DQA80s were shown to be more toxic than DQAsomes. The DQA80s showed significantly increased cellular uptake as compared to that of DQAsomes, and DQA80s also showed more efficient escape from the endolysosome to the cytosol. We observed the efficient targeting of DQA80s to mitochondria in living cells using flow cytometry, confocal microscopy, and TEM imaging. We also found evidence of anticancer potential that mitochondrial-targeted DQA80s induced apoptosis by production of reactive oxygen species (ROS) via MAPK signaling pathways, loss of mitochondrial membrane potential, and the caspase-3 activation. The present study demonstrates that DQA80s have excellent dual potential both as a carrier and as an anticancer therapeutic for mitochondria-related disease therapy in vivo.

The conformational relaxation of a polymer chain often slows down in various biological and engineering processes. The polymer, then, may stay in nonequilibrium states throughout the process such that one may not invoke the local thermal equilibrium (LTE) approximation, which has been usually employed to describe the kinetics of various processes. In this work, motivated by recent single-molecule experiments on DNA packaging into a viral capsid, we investigate how the nonequilibrium conformations and the LTE approximation would affect the packaging of a polymer chain into small confinement. We employ a simple but generic coarse-grained model and Langevin dynamics simulations to investigate the packaging kinetics. The polymer segments (both inside and outside the confinement) stay away from equilibrium under strong external force. We devise a simulation scheme to invoke the LTE approximation during packaging and find that the relaxation of nonequilibrium conformations plays a critical role in regulating the packaging rate.

Reduced graphene oxide (rGO) sheets were synthesized by a modified Hummer's method without additional reducing procedures, such as chemical and thermal treatment, by appropriate drying of graphite oxide under ambient atmosphere. The use of a moderate drying temperature (250°C) led to mesoporous characteristics with enhanced electrochemical activity, as confirmed by electron microscopy and N 2 adsorption studies. The dimensions of the sheets ranged from nanometres to micrometres and these sheets were entangled with each other. These morphological features of rGO tend to facilitate the movement of guest ions larger than Li + . Impressive electrochemical properties were achieved with the rGO electrodes using various charge-transfer ions, such as Li + , Na + and K + , along with high porosity. Notably, the feasibility of this system as the carbonaceous anode material for sodium battery systems is demonstrated. Furthermore, the results also suggest that the high-rate capability of the present rGO electrode can pave the way for improving the full cell characteristics, especially for preventing the potential drop in sodium-ion batteries and potassium-ion batteries, which are expected to replace the lithium-ion battery system

Zinc sulfide (ZnS(O)) thin films doped with Mn, Ni, and Co ions are synthesized by chemical bath deposition technique onto glass substrates. X-ray diffraction study reveals that the undoped and metal-doped ZnS(O) films possess a hexagonal wurtzite crystal structure. The morphological change, upon metal-ions doping, from nanorod structures to cluster (Mn doping), compact (Ni doping), and granular shapes (Co doping) is observed. X-ray photoelectron spectroscopy reveals the presence and incorporation of metal ions into ZnS(O) lattice sites and the formation of a metal–ZnS combined structure. The band gap energy of the undoped ZnS(O) film is found to be larger than 4.0 eV, while it is 3.8, 3.7, and 3.6 eV for the Mn–ZnS(O), Ni–ZnS(O), and Co–ZnS(O) films, respectively. All the undoped and metal-doped ZnS(O) samples exhibit blue luminescence, which originates from the surface defects and trap centers. Thus, the photoluminescence (PL) (blue light emission) is due to the radiative recombination from various trap levels (shallow donor levels) to the valence band. The decrease in the PL peak intensity for the doped samples indicates the reduction of surface defects suggesting the incorporation of metal ions into the host lattice of ZnS(O). Based on the PL results, the PL energy-level diagram for the undoped and metal-doped ZnS(O) samples is proposed.

An effective synthesis strategy is employed to fabricate Cu2ZnSnS4 (CZTS) thin films using radio frequency (rf) magnetron sputtering technique on soda lime glass substrates. The as-grown films are annealed at different temperatures ranging between 350 and 550 °C, and their chemical compositions and structural properties are investigated. The as-grown films have poor Cu/(Zn + Sn) ratios ranging between 0.39 and 0.44 and S/(Cu + Zn + Sn) ratios ranging between 0.97 and 1.21. The Cu/(Zn + Sn) ratio is improved by growing a thin additional Cu-capping layer on the as-grown film followed by annealing. An improved Cu/(Zn + Sn) ratio of ∼0.71 is obtained and the S/(Cu + Zn + Sn) ratio is slightly reduced to ∼0.85. The formation of a kesterite type CZTS is confirmed using X-ray diffraction and Raman spectroscopy measurements. Absorption measurements and band-gap energy determination of the CZTS films are carried out in order to confirm applicability to solar cells.

Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6 Synaptotagmin 1 (Syt1), a Ca(2+) sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7 Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6 In addition, 5-IP7-dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca(2+) levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca(2+) These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

The leaves of Perilla frutescens var. acuta (PFA) are commonly used as a traditional medicine in Korea, Japan, and China. We previously showed that PFA attenuates eye fatigue by improving visual accommodation through a clinical study. However, detailed mechanisms and chemical compounds have not been studied. In this study, we analyzed the active compounds in an aqueous extract of PFA involved in ciliary muscle relaxation in vitro and in vivo. NMR and MS analyses showed that the PFA extract contained mainly luteolin-7-O-diglucuronide and apigenin-7-O-diglucuronide. The composition after freeze-drying and spray-drying was similar. Freeze-dried PFA (50 &micro, g/mL, 100 &micro, g/mL, and 200 &micro, g/mL) increased nitric oxide and cGMP levels in ciliary muscle cells isolated from the eyes of rats. [Ca2+]i decreased in a dose-dependent manner. Furthermore, Sprague-Dawley rats treated with freeze-dried PFA (200 mg/kg, orally) showed significantly increased cGMP levels compared with the control group and irradiated with white light. Our results suggest that PFA extract has the potential to reduce eye fatigue by relaxing ciliary muscles.

Metal-organic framework (MOF) based synthesis of battery electrodes has presently become a hot topic of significant research interest. Considering the complications to prepare Co3V2O8 due to the criticality of its stoichiometric composition, we report here by a simple MOF formation by solvothermal technique followed by air annealing to synthesize Co3V2O8 for use as potential anodes for lithium battery applications. Structrual investigations by X-ray diffraction, X-ray photoelectron spectroscopy, high resolution electron microscopy, and surface area studies revealed that the phase pure Co3V2O8 nanoparticles are inter connected to form a sponge-like morphology with porous properties. Electrochemical measurements exposed the excellent lithium storage (~ 1000 mAhg-1 at 200 mAg-1) and retention properties (500 mAhg-1 at 1000 mAg-1 after 700 cycles) of the prepared Co3V2O8 electrode. A notable rate performance of 430 mAhg-1 at 3200 mAg-1 was also observed and ex-situ analysis confirmed the morphological and structural stability of this material after long cycles performance. These results validate that the unique nanostructured morphology arising from the use of the ordered array of MOF networks is favorable for improving the cyclability and rate capability in battery electrodes. The synthetic strategy presented herein may provide solutions to develop phase pure mixed metal oxides for high performance electrodes for useful energy storage applications. Figure 1

Inositol pyrophosphates such as IP7 (5-diphosphoinositol pentakisphosphate) are highly energetic inositol metabolites containing pyrophosphate bonds. While IP7 are known to regulate various biological events like metabolism, the molecular site of IP7 action in vesicle trafficking remains elusive. Here, we showed that IP7 potently inhibits synaptic vesicle exocytosis in both invitro reconstitution and cell culture settings. IP7 was identified as a high-affinity ligand for synaptotagmin 1 (Syt1), a calcium sensor essential for membrane fusion. Interactions of IP7 with Syt1 reduced the binding between Syt1 and Ca2+ as well as endowed Syt1 with its own negative effect, thereby suppressing Syt1 activation. These findings reveal a role of IP7 as an inhibitor of the exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

In mixtures of cetyltrimethylammonium bromide (CTAB) and sodium perfluorooctanoate (FC 7 ) in aqueous solution, novel bilayer cylinders with hemispherical end caps and open, flat discs coexist with spherical unilamellar vesicles, apparently at equilibrium. Such equilibrium among bilayer cylinders, spheres, and discs is only possible for systems with a spontaneous curvature, R o , and a positive Gaussian curvature modulus, κ̄. We have measured the size distributions of the spherical vesicles, cylinders, and discs by using cryo-electron microscopy; a simple analysis of this length distribution allows us to independently determine that the mean curvature modulus, κ ≈ 5 ± 1 k B T and κ̄ ≈ 2 ± 1 k B T. This is one of the few situations in which R o , κ, and κ̄ can be determined from the same experiment. From a similar analysis of the disk size distribution, we find that the edges of the discs are likely stabilized by excess CTAB. The fraction of discs, spherical vesicles, and cylinders depends on the CTAB/FC 7 mole ratio: increasing CTAB favors discs, while decreasing CTAB favors cylinders. This control over aggregate shape with surfactant concentration may be useful for the design of templates for polymerization, mesoporous silicates, etc.