Multifunctional Modulator Research Articles

A MXene Modulator Enabled High‐Loading Iodine Composite Cathode for Stable and High‐Energy‐Density Zn‐I2 Battery

AbstractAchieving both high iodine loading cathode and high Zn anode depth of discharge (DOD) is pivotal to unlocking the full potential of energy‐dense Zn‐I2 batteries. However, this combination exacerbates the detrimental shuttle effect of polyiodide intermediates, significantly impairing the battery's reversibility and stability. Herein, this study reports an advanced high‐loading iodine cathode (denoted as MX‐AB@I) enabled by a multifunctional Ti3C2Tx MXene modulator, which presents high stability and energy density in Zn‐I2 batteries. Through comprehensive experimental and theoretical analyses, the intrinsic regulating mechanisms are elucidated by which the MXene modulator effectively suppresses polyiodide shuttling, enhances iodine conversion kinetics, and dramatically improves Zn anode reversibility. With the aid of the MXene modulator, the MX‐AB@I composite cathode achieves a high iodine mass loading of 23 mg cm−2 and realizes a practically high areal capacity of 4.0 mAh cm−2. When paired with a thin Zn anode (10 µm), this configuration realizes a high Zn DOD of 78.7% and a high energy density of 171.3 Wh kg−1, surpassing the majority of Zn‐I2 battery systems reported in the literature. This study presents an effective approach to designing high‐loading iodine cathodes for Zn‐I2 batteries by leveraging MXene modulators to regulate critical electrochemical reaction processes.

Drain self-blocking ambipolar transistors for complementary circuit applications

The development of complementary metal-oxide-semiconductor field-effect transistor (CMOSFET) based on two-dimensional (2D) materials offers an important opportunity to reduce static power and increase the integration density of integrated circuits. One promising approach to realize these CMOSFETs is to employ ambipolar 2D materials as channel materials with designed device structure to control the carrier transport properties for CMOSFET characteristics. However, these devices always suffer from complex multi-gate electrode structure, and hence face challenges in complicated inter-connection design and excessive voltage source requirement for circuit implementation. Here, we develop a three-terminal CMOSFET using ambipolar 2D material based on the drain electric field-induced carrier injection self-blocking mechanism. The designed drain electrode can effectively suppress carrier injection from the drain to the channel material, while the gate voltage can only regulate carrier injection in the source region. As a result, we can configure the device as either N-field-effect transistors (FET) or P-FET with a high current on/off ratio of over 105 by adjusting the three voltages (gate, source, and drain). Furthermore, we utilize these devices to demonstrate multifunctional wave modulator, low-static-power logic inverter (<5 pW), and combinational logic computing in the form of a compact complementary circuit. Our work would explore an efficient approach for implementing complementary circuits using 2D materials.

Photo-charging sodium-ion battery by gallium arsenide solar cell generating an overall efficiency exceeding 30 %

Photo-charging energy storage system integrating photovoltaic harvest and energy storage functions creates a sustainable power source. The system not only alleviates the inherent limitations of intermittent, fluctuating, and unstable sunlight irradiation, but also facilitates the effective and sustainable utilization of green energy. However, the photo-charging efficiency of the system is relatively low nowadays. Herein, we report a photo-chargeable sodium-ion battery (PC-SIB) that leverages a self-designed multi-functional modulator to directly charge sodium-ion battery using GaAs solar cells. By harmonizing function portfolio management, PC-SIB achieves a photo-charging efficiency milestone of 30.24 %, along with excellent charge-discharge stability. Even in −20 °C, PC-SIB still maintains outstanding performance. The great leap in efficiency will strongly promote the high-efficient development of solar charging and storage integrated devices.

Promoting adsorption-diffusion-deposition of Zn2+ via a highly reactive modulator for dendrite-free and kinetics-enhanced Zn metal anode

The uncontrol growth of Zn dendrite and sluggish transport kinetics considerably hampered the practical application of aqueous zinc-ion batteries (AZIBs). Herein, we originally develop a simple and low-cost spinel oxide Zn2TiO4 (ZTO) nanoparticle as a multifunctional artificial protective modulator to optimize the Zn anode. As verified by comprehensive experimental and theoretical analyses, the highly reactive ZTO modulator possesses prominent zincophilicity to preferentially adsorb Zn2+, accelerates the de-solvation and diffusion kinetics of Zn2+, and achieves uniform Zn2+ deposition by regulation the surface electric field distribution of Zn anode. Through this “adsorption-diffusion-deposition” process of Zn2+, a dendrite-free and kinetics-enhanced Zn metal anode was achieved. Consequently, the ZTO@Zn symmetric cell manifests the excellent reversibility, achieving 10,000 cycles plating/stripping processes at 20 mA cm−2 and stable cycling for more than 85 h even at 85 % depth of discharge. Notably, the ZTO@Zn||MnO2 pouch cell exhibits an exceptional capacity of 215.9 mAh g−1 at 0.5 A g−1 and nearly 100 % coulombic efficiency after 300 cycles. This study provides a promising insight into the design of low-cost and highly reactive spinel oxide as an artificial protective modulator for Zn anode.

Multifunctional redox modulator prevents blast-induced loss of cochlear and vestibular hair cells and auditory spiral ganglion neurons

Blast wave exposure, a leading cause of hearing loss and balance dysfunction among military personnel, arises primarily from direct mechanical damage to the mechanosensory hair cells and supporting structures or indirectly through excessive oxidative stress. We previously reported that HK-2, an orally active, multifunctional redox modulator (MFRM), was highly effective in reducing both hearing loss and hair cells loss in rats exposed to a moderate intensity workday noise that likely damages the cochlea primarily from oxidative stress versus direct mechanical trauma. To determine if HK-2 could also protect cochlear and vestibular cells from damage caused primarily from direct blast-induced mechanical trauma versus oxidative stress, we exposed rats to six blasts of 186 dB peak SPL. The rats were divided into four groups: (B) blast alone, (BEP) blast plus earplugs, (BHK-2) blast plus HK-2 and (BEPHK-2) blast plus earplugs plus HK-2. HK-2 was orally administered at 50 mg/kg/d from 7-days before to 30-day after the blast exposure. Cochlear and vestibular tissues were harvested 60-d post-exposure and evaluated for loss of outer hair cells (OHC), inner hair cells (IHC), auditory nerve fibers (ANF), spiral ganglion neurons (SGN) and vestibular hair cells in the saccule, utricle and semicircular canals. In the untreated blast-exposed group (B), massive losses occurred to OHC, IHC, ANF, SGN and only the vestibular hair cells in the striola region of the saccule. In contrast, rats treated with HK-2 (BHK-2) sustained significantly less OHC (67%) and IHC (57%) loss compared to the B group. OHC and IHC losses were smallest in the BEPHK-2 group, but not significantly different from the BEP group indicating lack of protective synergy between EP and HK-2. There was no loss of ANF, SGN or saccular hair cells in the BHK-2, BEP and BEPHK-2 groups. Thus, HK-2 not only significantly reduced OHC and IHC damage, but completely prevented loss of ANF, SGN and saccule hair cells. The powerful protective effects of this oral MFRM make HK-2 an extremely promising candidate for human clinical trials.

Switchable dual ultra-broadband perfect absorber based on graphene and vanadium dioxide hybrid metamaterials

The phase transition property of vanadium dioxide (VO2) makes it an attractive field in temperature-controlled chips. In this paper, a microstructure based on a graphene disk and a ring-shaped VO2 hybrid metamaterial is proposed to achieve switchable dual ultra-broadband perfect absorption in the terahertz region, which is analyzed by the phase transition property of VO2 and the dynamic electrical regulation of graphene. When the graphene disk is not present, the absorption intensity can reach up to 97.07%. When the graphene disk is present and respectively interacts with the VO2 metallic and insulated phases, the results exhibit an ultra-broadband perfect absorption (>90%) from 1.620 THz to 4.533 THz and from 1.506 THz to 3.576 THz, respectively, where the bandwidths are as high as 2.913 THz and 2.070 THz, respectively. Adjusting the Fermi level of graphene and the VO2 conductivity allows the absorption intensity and bandwidth to be effectively controlled, where the fractional bandwidth from 81.46% to 94.69% and a high modulation depth of 95.09% can be achieved. These results suggest that dual ultra-broad perfect absorption can be dynamically switched within a single absorber and has various modulation means, which are expected to be developed in applying multifunctional modulators.

WSSV early protein WSSV004 enhances viral replication by suppressing LDH activity

White spot syndrome virus (WSSV) is known to upregulate glycolysis to supply biomolecules and energy for the virus's replication. At the viral genome replication stage, lactate dehydrogenase (LDH), a glycolytic enzyme, shows increased activity without any increase in expression. In the present study, yeast 2-hybrid screening was used to identify WSSV proteins that interacted with LvLDH isoform 1 and 2, and these included the WSSV early protein WSSV004. The interaction between WSSV004 and LvLDH1/2 was confirmed by co-immunoprecipitation. Immunofluorescence showed that WSSV004 co-localized with LvLDH1/2 in the cytoplasm. dsRNA silencing experiments showed that WSSV004 was crucial for WSSV replication. However, although WSSV004 silencing led to the suppression of total LvLDH gene expression during the viral late stage, there was nevertheless a significant increase in LvLDH activity at this time. We also used affinity purification-mass spectrometry to identify cellular proteins that interact with WSSV004, and found a total of 108 host proteins and 3 WSSV proteins with which it potentially interacts. Bioinformatics analysis revealed that WSSV004 and its interacting proteins might be responsible for various biological pathways during infection, including vesicular transport machinery and RNA-related functions. Collectively, our study suggests that WSSV004 serves as a multifunctional modulator to facilitate WSSV replication.

Reprogramming the Microenvironment of Cobalt Phthalocyanine by a Targeted Multifunctional π-Conjugated Modulator Enables Concerted CO2 Electroreduction

Reprogramming the Microenvironment of Cobalt Phthalocyanine by a Targeted Multifunctional π-Conjugated Modulator Enables Concerted CO₂ Electroreduction

Research on the phase error of a Sagnac interferometer induced by modulation of a multifunctional integrated optical modulator.

High-precision IFOG requires an optical sensitivity of up to 10-8 rads-1 for interferometers; noise and error are two of the main reasons limiting its accuracy improvement. Any potential source of the signal error is worth being studied. This article introduces work on the modulation signal error caused by the mechanical vibration energy loss of MIOC crystals. This article theoretically derives and simulates the frequency spectrum of an energy loss from the perspective of electromechanical coupling and verifies it through experiments. This article also verifies the influence of MIOC mechanical loss on the output of a Sagnac interferometer through experiments. This study is an indispensable part of the bottleneck for improving the accuracy of ultrahigh-precision closed-loop IFOG and has potential engineering application value.

Multifunctional metasurface for ultrafast all-optical efficient modulation of terahertz wave

Metasurfaces have been widely used to terahertz (THz) modulators due to their unique electromagnetic (EM) modulation properties. However, to realize ultrafast and efficient control of the active metasurfaces remains a critical challenge. Herein, we first demonstrate a multifunctional metasurface modulator based on metal square rings, which have central rotational symmetry with local asymmetry. The former captures more EM energy to achieve strong enhancement of the local EM responses, and the latter generates high quality factor (Q-factor) Fano resonance. By scaling the unit structure, the resonant frequency shifts in an ultra-wideband range of ∼0.29-10 THz, which shows a linear relation between the Q-factor and the scaling factor, and an exponential variation between the full width at half maximum (FWHM) and the scaling factor. The results provide an effective approach to predict the frequency selection characteristics of the modulators in the THz regime. More importantly, by embedding the silicon into the specific position of the metasurface, external optical control results in the unit structure is constructed from meta-atom to molecularization model, the shifting of resonant frequency and the multi-level modulation of amplitude are realized, and the maximum modulation depth (MD) reaches ∼100 %. By systematically studying the dynamics of frequency and amplitude regulation, benefiting from the ultra-short relaxation time of the photo-carriers in silicon bridge, an ultrafast full recovery time of 2000 ps is achieved. Combined with the local field characteristics, the scaled unit structure achieves efficient modulation of the resonant frequency and amplitude under optical pumping, which provides a promising approach for the development of active metasurface modulator suitable for the whole THz band. This work demonstrates the viability of optical control molecularization of specific meta-atoms is applicable to the entire THz band, which has great potential use for future state-of-the-art THz modulators.

Dimethylamine oxalate manipulating CsPbI3 perovskite film crystallization process for high efficiency carbon electrode based perovskite solar cells

Crystallization process determines the quality of perovskite films and the performances of resultant perovskite solar cells (PSCs). Dimethylamine oxalate has been proven as a multifunctional modulator, and is explored as an efficient additive in manipulating the crystallization process of CsPbI3 perovskite films. On one hand, oxalate serves as the precipitator that facilitates the nucleation process of intermediate. The larger size of intermediate is conductive to the larger size and smaller grain boundaries of resultant perovskite. On the other hand, in subsequent annealing process, the phase conversion and growth process of transient perovskite can be decelerated due to the strong interactions of oxalate with both dimethylamine cation (DMA+) and Pb2+. Due to the optimized crystallization kinetics, the morphology and quality of CsPbI3 perovskite films are comprehensively improved with lower defect concentrations, and charge recombination loss is effectively suppressed. Benefiting from the optimized crystal quality of perovskite films, the carbon electrode-based CsPbI3 PSCs exhibit a champion efficiency of 18.48%. This represents one of the highest levels among all hole transport layer-free inorganic perovskite solar cells.

An optimized metastructure switchable between ultra-wideband angle-insensitive absorption and transmissive polarization conversion: a theoretical study.

An optimized metastructure (MS) switchable between ultra-wideband (UWB) angle-insensitive absorption, and transmissive linear-to-circular (LTC) polarization conversion (PC), is proposed, which is a theoretical study. The structural parameters of this MS are optimized by the thermal exchange optimization algorithm. By modulating the chemical potential (μc) of the graphene-based hyperbolic metamaterial embedded in the MS, the MS can achieve UWB absorption in the absorption state and LTC PC in the transmission state. At normal incidence, in the absorption state, the MS exhibits absorptivity exceeding 0.9 within 7-15.45 THz, with a relative bandwidth (RBW) of 75.28%. By elevating μc, an UWB LTC PC is realized, with a RBW of 118.8%, achieving transmittance above 0.9 and the axial ratio below 3 dB. When prioritizing the angular stability, in the absorption state, the MS secures the angular stability of 75° for TE waves and 65° for TM ones. In the transmission state, the angular stability of PC reaches 60°, with RBW = 100.7%. Moreover, by manipulating μc, the tunability of UWB absorption is realized. The optimized MS provides a reference for designing multifunctional intelligent terahertz modulators, with promising application potential in domains like electromagnetic shielding, communication systems, and THz modulation.

Formula supplementation with human and bovine milk oligosaccharides modulates blood IgG and T-helper cell populations, and ex vivo LPS-stimulated cytokine production in a neonatal preclinical model.

Human milk contains structurally diverse oligosaccharides (HMO), which are multifunctional modulators of neonatal immune development. Our objective was to investigate formula supplemented with fucosylated (2'FL) + neutral (lacto-N-neotetraose, LNnt) oligosaccharides and/or sialylated bovine milk oligosaccharides (BMOS) on immunological outcomes. Pigs (n=46) were randomized at 48h of age to four diets: sow milk replacer formula (CON), BMOS (CON + 6.5 g/L BMOS), HMO (CON + 1.0 g/L 2'FL + 0.5 g/L LNnT), or BMOS+HMO (CON + 6.5 g/L BMOS + 1.0 g/L 2'FL + 0.5 g/L LNnT). Blood and tissues were collected on postnatal day 33 for measurement of cytokines and IgG, phenotypic identification of immune cells, and ex vivo lipopolysaccharide (LPS)-stimulation of immune cells. Serum IgG was significantly lower in the HMO group than BMOS+HMO but did not differ from CON or BMOS. The percentage of PBMC T-helper cells was lower in BMOS+HMO than the other groups. Splenocytes from the BMOS group secreted more IL-1β when stimulated ex vivo with LPS compared to CON or HMO groups. For PBMCs, a statistical interaction of BMOS*HMO was observed for IL-10 secretion (p=0.037), with BMOS+HMO and HMO groups differing at p=0.1. The addition of a mix of fucosylated and sialylated oligosaccharides to infant formula provides specific activities in the immune system that differ from formulations supplemented with one oligosaccharide structure.

Low terahertz frequency on-chip multi-functional modulator with amplitude and phase modulation

Terahertz amplitude and phase modulation technologies are crucial for terahertz communication, radar, and imaging. However, most current approaches can only achieve either amplitude or phase modulation. In this paper, we present a low terahertz frequency on-chip multi-functional modulator that consists of a hybrid coupler and reflection meta-structure. High-performance amplitude modulation is achieved by combining series resonant absorption of series coupling branch with resonance enhancement of parallel coupling branch in the reflection meta-structure. Meanwhile, the enhanced resonance provides a larger range of phase shifts, enabling effective amplitude and phase modulation in two different frequency regions. Therefore, we realize an amplitude modulation in the range of 115–135 GHz with a minimum transmission loss of 4 dB and a modulation depth of over 10 dB. At the same time, we achieved a continuous phase shift in the 103–113 GHz region, as well as a 180° two-bit phase shift in the 107–109 GHz range with only 5.7 dB transmission loss. Our simple method for terahertz amplitude and phase multi-functional modulation offers the potential to construe terahertz multifunctional integrated systems.

Formamidine formate as the multifunctional modulator at buried interface for efficient FAPbI3 perovskite solar cells

Interface modification is recognized as an effective strategy to promote the performance of perovskite solar cells (PSCs) especially after the thorough optimization on film fabrication process. Device performance is augmented considerably by passivating the perovskite surface utilizing variety of materials. On the other hand, buried interface revealed a higher defect density than top surface, hence, rational optimization of buried interface is getting paramount for the further amelioration on efficiency and stability of PSCs. Herein, formamidine formate (FAFa) with both carboxyl and amino groups is employed to modify the buried interface between SnO2 and perovskite. It is demonstrated that FAFa treatment can enhance the electrical properties of SnO2 and optimize the band alignment. Meanwhile, it improves the contact performance by constructing a chemical bridge at the buried interface. Moreover, it endows high quality perovskite by modulating the growth process. Consequently, the power conversion efficiency of FAPbI3 PSCs is elevated substantially from 20.89% to 23.11% mainly benefitted from the suppressed carrier recombination and facilitated electron extraction at the buried interface. Meanwhile, corresponding device illustrated reinforced durability both in inert and atmospheric environment. Our work presented a convenient way to modify the buried interface for the further enhancement of PSC performance.

In silico design and identification of new peptides for mitigating hIAPP aggregation in type 2 diabetes

The aberrant misfolding and self-aggregation of human islet amyloid polypeptide (hIAPP or amylin) into cytotoxic aggregates are implicated in the pathogenesis of type 2 diabetes (T2D). Among various inhibitors, short peptides derived from the amyloidogenic regions of hIAPP have been employed as hIAPP aggregation inhibitors due to their low immunogenicity, biocompatibility, and high chemical diversity. Recently, hIAPP fragment HSSNN18-22 was identified as an amyloidogenic sequence and displayed higher antiproliferative activity to RIN-5F cells. Various hIAPP aggregation inhibitors have been designed by chemical modifications of the highly amyloidogenic sequence (NFGAIL) of hIAPP. In this work, a library of pentapeptides based on fragment HSSNN18-22 was designed and assessed for their efficacy in blocking hIAPP aggregation using an integrated computational screening approach. The binding free energy calculations by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method identified HSSQN and HSSNQ that bind to hIAPP monomer with a binding affinity of −21.25 ± 4.90 and −19.73 ± 3.10 kcal/mol, respectively, which is notably higher as compared to HSSNN (–11.90 ± 4.12 kcal/mol). The sampling of the non aggregation-prone helical conformation was notably increased from 23.5 ± 3.0 in the hIAPP monomer to 38.1 ± 3.6, and 33.8 ± 3.0% on the incorporation of HSSQN, and HSSNQ, respectively, which indicate reduced aggregation propensity of hIAPP monomer. The pentapeptides, HSSQN and HSSNQ, identified as hIAPP aggregation inhibitors in this work can be further conjugated with various metal chelating peptides to yield more efficacious and clinically relevant multifunctional modulators for targeting various pathological hallmarks of T2D.

Graphene oxide/gallium nanoderivative as a multifunctional modulator of osteoblastogenesis and osteoclastogenesis for the synergistic therapy of implant-related bone infection.

Currently, implant-associated bacterial infections account for most hospital-acquired infections in patients suffering from bone fractures or defects. Poor osseointegration and aggravated osteolysis remain great challenges for the success of implants in infectious scenarios. Consequently, developing an effective surface modification strategy for implants is urgently needed. Here, a novel nanoplatform (GO/Ga) consisting of graphene oxide (GO) and gallium nanoparticles (GaNPs) was reported, followed by investigations of its in vitro antibacterial activity and potential bacterium inactivation mechanisms, cytocompatibility and regulatory actions on osteoblastogenesis and osteoclastogenesis. In addition, the possible molecular mechanisms underlying the regulatory effects of GO/Ga nanocomposites on osteoblast differentiation and osteoclast formation were clarified. Moreover, an in vivo infectious microenvironment was established in a rat model of implant-related femoral osteomyelitis to determine the therapeutic efficacy and biosafety of GO/Ga nanocomposites. Our results indicate that GO/Ga nanocomposites with excellent antibacterial potency have evident osteogenic potential and inhibitory effects on osteoclast differentiation by modulating the BMP/Smad, MAPK and NF-κB signaling pathways. The in vivo experiments revealed that the administration of GO/Ga nanocomposites significantly inhibited bone infections, reduced osteolysis, promoted osseointegration located in implant-bone interfaces, and resulted in satisfactory biocompatibility. In summary, this synergistic therapeutic system could accelerate the bone healing process in implant-associated infections and can significantly guide the future surface modification of implants used in bacteria-infected environments.

Yeast mannoproteins: Organoleptic modulating functions, mechanisms, and product development trends in winemaking

AbstractMannoproteins (MPs) originate from yeast cells and can play important roles in maintaining wine stability and modulating wine organoleptic properties. Due to their natural presence in wines, MP products are allowed to be used as enological additives in wine industry. To guarantee an appropriate application of these products during winemaking, it is necessary for both researchers and winemakers to understand the mechanisms of MPs as multifunctional organoleptic modulators. This review has introduced the current state of knowledge of the researches focus on the application of different MP products in red wines and also the interactions between MPs and wine sensory active components (polyphenols, aroma compounds) in model wine solutions. We have summarized the possible mechanisms of MPs that affect the color, astringency, and aroma of red wines and the relationship between the physicochemical characteristics and functionalities of MPs. Besides, development trends of MP products are also discussed. It seems that yeast biomass, especially those from non‐Saccharomyces yeasts show good potential in producing large quantities of MPs, an appropriate combination of yeast cultivation and preservation methods with extraction and purification techniques may obtain MPs of ideal production, purity, and functionality in an industrial scale, which should be put more efforts by both scientists and manufacturers in the future.

Multifunctional IL-Based Hydrogel Modulator for the Synergistic Acceleration of Wound Healing: Optimizing Drug Solubility, Antioxidant, and Anti-Inflammatory Effects

Inflammatory infection can cause the chronic nonhealing of wounds, posing considerable challenges to skin tissue reconstruction. Thus, an injectable wound dressing hydrogel with multiple functions such as remodelability, self-healing, and enhanced bioavailability has been developed to promote defect tissue regeneration, thereby offering great biomedical value for clinical application. In this study, the etodolac (ETC)-based ionic liquid (IL), LCE, was utilized for the first time as a drug template to enhance the bioavailability of the reference drug (ETC). Silk sericin (SS)/poly(vinyl alcohol) (PVA) hydrogel substrates were used to prepare a novel LCE-loaded hydrogel modulator, Gel-LCE. Additionally, LCE as a main functional group, which exhibited excellent antioxidant activity and high water solubility, was immobilized on the SS/PVA hydrogel via the formation of stable hydrogen bonds, and the fabricated Gel-LCE exhibited excellent biocompatibility and drug utilization, as well as synergistic anti-inflammatory behaviors. Furthermore, this versatile hydrogel (Gel-LCE) could completely fit the irregular wound shape geometry during drug injection, thereby preventing secondary infections. More strikingly, the hydrogel facilitated excellent wound recovery in an experiment involving an animal wound model, reflecting its ability to significantly accelerate wound healing, as further demonstrated by its robust reactive oxygen species (ROS) scavenging capacity, as well as comparable levels of control over inflammatory cytokines (TNF-α and PGE-2). Therefore, this IL-based hydrogel, Gel-LCE, can become a very attractive and popular multifunctional wound dressing material, which can optimize the solubility of the drug to further exert stronger biomedical value.

RKIP localizes to the nucleus through a bipartite nuclear localization signal and interaction with importin α to regulate mitotic progression

Raf kinase inhibitor protein (RKIP) is a multifunctional modulator of intracellular signal transduction. Although most of its functions have been considered cytosolic, we show here that the localization of RKIP is primarily nuclear in both growing and quiescent Madin-Darby canine kidney epithelial cells and in Cal-51 and BT-20 human breast cancer cells. We have identified a putative bipartite nuclear localization signal (NLS) in RKIP that maps to the surface of the protein surrounding a known regulatory region. Like classical NLS sequences, the putative NLS of RKIP is rich in arginine and lysine residues. Deletion of and point mutations in the putative NLS lead to decreased nuclear localization. Point mutation of all the basic residues in the putative NLS of RKIP particularly strongly reduces nuclear localization. We found consistent results in reexpression experiments with wildtype or mutant RKIP in RKIP-silenced cells. A fusion construct of the putative NLS of RKIP alone to a heterologous reporter protein leads to nuclear localization of the fusion protein, demonstrating that this sequence alone is sufficient for import into the nucleus. We found that RKIP interacts with the nuclear transport factor importin α in BT-20 and MDA-MB-231 human breast cancer cells, suggesting importin-mediated active nuclear translocation. Evaluating the biological function of nuclear localization of RKIP, we found that the presence of the putative NLS is important for the role of RKIP in mitotic checkpoint regulation in MCF-7 human breast cancer cells. Taken together, these findings suggest that a bipartite NLS in RKIP interacts with importin α for active transport of RKIP into the nucleus and that this process may be involved in the regulation of mitotic progression.