Nanomodulator-Mediated Restructuring of Adipose Tissue Immune Microenvironments for Antiobesity Treatment.

In obesity, the interactions between proinflammatory macrophages and adipocytes in white adipose tissues are known to play a crucial role in disease progression by providing inflammatory microenvironments. Here, we report that the functional nanoparticle-mediated modulation of crosstalk between adipocytes and macrophages can remodel adipocyte immune microenvironments. As a functional nanomodulator, we designed antivascular cell adhesion molecule (VCAM)-1 antibody-conjugated and amlexanox-loaded polydopamine nanoparticles (VAPN). Amlexanox was used as a model drug to increase energy expenditure. Compared to nanoparticles lacking antibody modification or amlexanox, VAPN showed significantly greater binding to VCAM-1-expressing adipocytes and lowered the interaction of adipocytes with macrophages. In high fat diet-fed mice, repeated subcutaneous administration of VAPN increased the populations of beige adipocytes and ameliorated inflammation in white adipose tissues. Moreover, the localized application of VAPN in vivo exerted a systemic metabolic effect and reduced metabolic disorders, including insulin tolerance and liver steatosis. These findings suggested that VAPN had potential to modulate the immune microenvironments of adipose tissues for the immunologic treatment of obesity. Although we used amlexanox as a model drug and anti-VCAM-1 antibody in VAPN, the concept of immune nanomodulators can be widely applied to the immunological treatment of obesity.

RNA Nanomedicine: Delivery Strategies and Applications.

Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique challenges due to its susceptibility to degradation and the requirement for efficient intracellular delivery. The integration of nanotechnologies with RNA delivery has addressed many of these challenges. In this review, we discuss different strategies employed in the design and development of nanomaterials for RNA delivery. We also highlight recent advances in the pharmaceutical applications of RNA delivered via nanomaterials. Various nanomaterials, such as lipids, polymers, peptides, nucleic acids, and inorganic nanomaterials, have been utilized for delivering functional RNAs, including messenger RNA (mRNA), small interfering RNA, single guide RNA, and microRNA. Furthermore, the utilization of nanomaterials has expanded the applications of functional RNA as active pharmaceutical ingredients. For instance, the delivery of antigen-encoding mRNA using nanomaterials enables the transient expression of vaccine antigens, leading to immunogenicity and prevention against infectious diseases. Additionally, nanomaterial-mediated RNA delivery has been investigated for engineering cells to express exogenous functional proteins. Nanomaterials have also been employed for co-delivering single guide RNA and mRNA to facilitate gene editing of genetic diseases. Apart from the progress made in RNA medicine, we discuss the current challenges and future directions in this field.

Nanomaterials for antigen-specific immune tolerance therapy.

Impairment of immune tolerance might cause autologous tissue damage or overactive immune response against non-pathogenic molecules. Although autoimmune disease and allergy have complicated pathologies, the current strategies have mainly focused on symptom amelioration or systemic immunosuppression which can lead to fatal adverse events. The induction of antigen-specific immune tolerance may provide therapeutic benefits to autoimmune disease and allergic response, while reducing nonspecific immune adverse responses. Diverse nanomaterials have been studied to induce antigen-specific immune tolerance therapy. This review will cover the immunological background of antigen-specific tolerance, clinical importance of antigen-specific immune tolerance, and nanomaterials designed for autoimmune and allergic diseases. As nanomaterials for modulating immune tolerances, lipid-based nanoparticles, polymeric nanoparticles, and biological carriers have been covered. Strategies to provide antigen-specific immune tolerance have been addressed. Finally, current challenges and perspectives of nanomaterials for antigen-specific immune tolerance therapy will be discussed.

Development of a Soil Organic Matter Content Prediction Model Based on Supervised Learning Using Vis-NIR/SWIR Spectroscopy.

In the current scenario of anthropogenic climate change, carbon credit security is becoming increasingly important worldwide. Topsoil is the terrestrial ecosystem component with the largest carbon sequestration capacity. Since soil organic matter (SOM), which is mostly composed of organic carbon, and can be affected by rainfall, cultivation, and pollutant inflow, predicting SOM content through regular monitoring is necessary to secure a stable carbon sink. In addition, topsoil in the Republic of Korea is vulnerable to erosion due to climate, topography, and natural and anthropogenic causes, which is also a serious issue worldwide. To mitigate topsoil erosion, establish an efficient topsoil management system, and maximize topsoil utilization, it is necessary to construct a database or gather data for the construction of a database of topsoil environmental factors and topsoil composition. Spectroscopic techniques have been used in recent studies to rapidly measure topsoil composition. In this study, we investigated the spectral characteristics of the topsoil from four major rivers in the Republic of Korea and developed a machine learning-based SOM content prediction model using spectroscopic techniques. A total of 138 topsoil samples were collected from the waterfront area and drinking water protection zone of each river. The reflection spectrum was measured under the condition of an exposure time of 136 ms using a spectroradiometer (Fieldspec4, ASD Inc., Alpharetta, GA, USA). The reflection spectrum was measured three times in wavelengths ranging from 350 to 2500 nm. To predict the SOM content, partial least squares regression and support vector regression were used. The performance of each model was evaluated through the coefficient of determination (R2) and root mean square error. The result of the SOM content prediction model for the total topsoil was R2 = 0.706. Our findings identified the important wavelength of SOM in topsoil using spectroscopic technology and confirmed the predictability of the SOM content. These results could be used for the construction of a national topsoil database.

Selective Allowance of Precipitation from Oversaturated Solution Using Surface Structures.

Precipitation is a well-known phenomenon commonly observed in salt ponds. However, it causes pipe clogging in industrial sites, which can be resolved by controlling the direction of precipitation. Herein, we propose a method to control the precipitation direction by changing the structures and properties of the solid surface. Bare, nanostructured, microstructured, and micro/nanostructured surfaces were immersed in the same saturated aqueous NaCl solution, and the heights at which precipitation occurred in the different specimens were compared. On bare and nanostructured surfaces, NaCl deposits as a flat layer on the surface, while on micro and micro/nanostructured surfaces, it forms a thick deposit in a direction perpendicular to the surface. When the same experiment was conducted on surfaces made by patterning different structural surfaces, the precipitates did not spread on the surface with microscale structures. We believe that this novel approach may prove useful in solving the problems caused by precipitation.

Bioactive Lipids and Their Derivatives in Biomedical Applications.

Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.

Photosensitizer-Trapped Gold Nanocluster for Dual Light-Responsive Phototherapy.

Photoresponsive nanomaterials have recently received great attention in the field of cancer therapy. Here, we report a photosensitizer-trapped gold nanocluster that can facilitate dual light-responsive cancer therapy. We utilized methylene blue (MB) as a model photosensitizer, gold nanocluster as a model photothermal agent, and a polymerized DNA as the backbone of the nanocluster. We synthesized MB-intercalated gold DNA nanocluster (GMDN) via reduction and clustering of gold ions on a template consisting of MB-intercalated long DNA. Upon GMDN treatment, cancer cells revealed clear cellular uptake of MB and gold clusters; following dual light irradiation (660 nm/808 nm), the cells showed reactive oxygen species generation and increased temperature. Significantly higher cancer cell death was observed in cells treated with GMDN and dual irradiation compared with non-irradiated or single light-irradiated cells. Mice systemically injected with GMDN showed enhanced tumor accumulation compared to that of free MB and exhibited increased temperature upon near infrared irradiation of the tumor site. Tumor growth was almost completely inhibited in GMDN-treated tumor-bearing mice after dual light irradiation, and the survival rate of this group was 100% over more than 60 days. These findings suggest that GMDN could potentially function as an effective phototherapeutic for the treatment of cancer disease.

Miniature Millimeter-Wave 5G Antenna Fabricated Using Anodized Aluminum Oxide for Mobile Devices.

A miniature millimeter-wave 5G antenna fabricated using anodized aluminum oxide (AAO) is devised and demonstrated for mobile devices. The proposed structure creates a dielectric layer on an aluminum plate using AAO topology and allows the antenna pattern to be placed on the dielectric layer. The proposed AAO-based antenna reduces the size (1.87 (0.18λ0) mm × 2.34 (0.22λ0) mm) of the antenna in proportion to the dielectric constant (εr = 6.7), which is higher than those of the conventional materials such as polycarbonates (PC) or a flame retardant (FR4). In addition, it is possible to precisely control the dielectric layer dimensions and generate a dielectric layer on the metal substrate itself, which greatly increases the design freedom. As a result, the devised antenna resonates at 29 GHz, and the measured gain is 5.02 dBi.

Indoor levels of volatile organic compounds and formaldehyde from emission sources at elderly care centers in Korea.

The objective of this study is to characterize indoor and outdoor levels of volatile organic compounds (VOCs) and formaldehyde (HCHO) and identify indoor emission sources in thirty elderly care centers (ECCs) located in the Seoul metropolitan city and Gyeonggi province in Korea. Air monitoring samples from indoor and outdoor environments were collected from January to December in 2007. Statistical analyses of indoor and outdoor VOCs and HCHO levels in three rooms (a bedroom, living, and dining rooms) of each ECC were performed, and these were compared to identify environmental factors associated with an increase of indoor pollution levels. Total volatile organic compounds (TVOC) levels were significantly (p<0.05) different between indoor (230.7±1.7 µg/m3) and outdoor (137.8±1.9 µg/m3) environments, with an I/O ratio of 1.67. The indoor HCHO level (20.1±1.6 µg/m3) was significantly (p<0.05) higher than the outdoor level (8.1±1.9 µg/m3), with an I/O ratio of 2.48. Indoor VOCs and HCHO levels in the bedrooms were significantly (p<0.05) higher than those in the living and dining rooms. Furthermore, indoor levels of VOCs and HCHO at ECCs were significantly (p<0.05) different depending on environmental factors such as the use of carpet, paint, and wooden furniture. In multiple regression analysis, indoor VOCs and HCHO levels at ECCs were significantly (p<0.05) correlated with two micro-environmental factors: the use of carpet and paint. This study confirmed that indoor VOCs and HCHO levels were significantly higher than those in outdoor environments. These air pollutants were mainly emitted from indoor sources, such as carpet, paint, and construction materials at the ECCs in Korea.

Gastrointestinal malignancies harbor actionable MET exon 14 deletions.

Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.

Enhanced proliferation and altered calcium handling in RGS2-deficient vascular smooth muscle cells.

CONTEXT: Regulator of G-protein signaling-2 (RGS2) inhibits Gq-mediated regulation of Ca(2+) signalling in vascular smooth muscle cells (VSMC). OBJECTIVE: RGS2 knockout (RGS2KO) mice are hypertensive and show arteriolar remodeling. VSMC proliferation modulates intracellular Ca(2+) concentration [Ca(2+)]i. RGS2 involvement in VSMC proliferation had not been examined. METHODS: Thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) conversion assays measured cell proliferation. Fura-2 ratiometric imaging quantified [Ca(2+)]i before and after UTP and thapsigargin. [(3)H]-labeled inositol was used for phosphoinositide hydrolysis. Quantitative RT-PCR and confocal immunofluorescence of select Ca(2+) transporters was performed in primary aortic VSMC. RESULTS AND DISCUSSION: Platelet-derived growth factor (PDGF) increased S-phase entry and proliferation in VSMC from RGS2KO mice to a greater extent than in VSMC from wild-type (WT) controls. Consistent with differential PDGF-induced changes in Ca(2+) homeostasis, RGS2KO VSMC showed lower resting [Ca(2+)]i but higher thapsigargin-induced [Ca(2+)]i as compared with WT. RGS2KO VSMC expressed lower mRNA levels of plasma membrane Ca(2+) ATPase-4 (PMCA4) and Na(+) Ca(2+) Exchanger (NCX), but higher levels of sarco-endoplasmic reticulum Ca(2+) ATPase-2 (SERCA2). Western blot and immunofluorescence revealed similar differences in PMCA4 and SERCA2 protein, while levels of NCX protein were not reduced in RGS2KO VSMC. Consistent with decreased Ca(2+) efflux activity, (45)Ca-extrusion rates were lower in RGS2KO VSMC. These differences were reversed by the PMCA inhibitor La(3+), but not by replacing extracellular Na(+) with choline, implicating differences in the activity of PMCA and not NCX. CONCLUSION: RGS2-deficient VSMC exhibit higher rates of proliferation and coordinate plasticity of Ca(2+)-handling mechanisms in response to PDGF stimulation.

USP8 modulates ubiquitination of LRIG1 for Met degradation.

The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301.

Complete gate control of supercurrent in graphene p-n junctions.

In a conventional Josephson junction of graphene, the supercurrent is not turned off even at the charge neutrality point, impeding further development of superconducting quantum information devices based on graphene. Here we fabricate bipolar Josephson junctions of graphene, in which a p-n potential barrier is formed in graphene with two closely spaced superconducting contacts, and realize supercurrent ON/OFF states using electrostatic gating only. The bipolar Josephson junctions of graphene also show fully gate-driven macroscopic quantum tunnelling behaviour of Josephson phase particles in a potential well, where the confinement energy is gate tuneable. We suggest that the supercurrent OFF state is mainly caused by a supercurrent dephasing mechanism due to a random pseudomagnetic field generated by ripples in graphene, in sharp contrast to other nanohybrid Josephson junctions. Our study may pave the way for the development of new gate-tuneable superconducting quantum information devices.

Paranoid Adipsia-induced Severe Hypernatremia and Uremia treated with Hemodialysis.

We describe a patient with severe hypernatremia and uremia caused by paranoid adipsia who was treated successfully with hydration and hemodialysis. A previously healthy 40-year-old woman developed the paranoid idea that her water was poisoned, so she refused to drink any water. On admission, her blood urea nitrogen was 208mg/dL, creatinine 4.90mg/dL, serum osmolality 452mOsm/L, serum sodium 172mEq/L, urine specific gravity ≥1.030, urine osmolality 698mOsm/L, and urine sodium/potassium/chloride 34/85.6/8mEq/L. We diagnosed her with uremic encephalopathy and started intravenous dextrose, but the sodium correction was incomplete. She underwent two sessions of hemodialysis to treat the uremic encephalopathy and hypernatremia, and recovered fully without neurological sequelae. Although the standard treatment for severe hypernatremia is hydration, hemodialysis can be an additional treatment in cases of combined uremic encephalopathy.

A new anti-c-Met antibody selected by a mechanism-based dual-screening method: therapeutic potential in cancer.

c-Met, the high affinity receptor for hepatocyte growth factor (HGF), is one of the most frequently activated tyrosine kinases in many human cancers and a target for cancer therapy. However, inhibitory targeting of c-Met with antibodies has proven difficult, because most antibodies have intrinsic agonist activity. Therefore, the strategy for reducing the agonism is critical for successful development of cancer therapies based on anti-c-Met antibodies. Here we developed a mechanism-based assay method for rapid screening of anti-c-Met antibodies, involving the determination of Akt phosphorylation and c-Met degradation for agonism and efficacy, respectively. Using the method, we identified an antibody, F46, that binds to human c-Met with high affinity (Kd = 2.56 nM) and specificity, and induces the degradation of c-Met in multiple cancer cells (including MKN45, a gastric cancer cell line) with minimal activation of c-Met signaling. F46 induced c-Met internalization in both HGF-dependent and HGF-independent cells, suggesting that the degradation of c-Met results from antibody-mediated receptor internalization. Furthermore, F46 competed with HGF for binding to c-Met, resulting in the inhibition of both HGF-mediated invasion and angiogenesis. Consistently, F46 inhibited the proliferation of MKN45 cells, in which c-Met is constitutively activated in an HGF-independent manner. Xenograft analysis revealed that F46 markedly inhibits the growth of subcutaneously implanted gastric and lung tumors. These results indicate that F46, identified by a novel mechanism-based assay, induces c-Met degradation with minimal agonism, implicating a potential role of F46 in therapy of human cancers.

Electrically tunable macroscopic quantum tunneling in a graphene-based Josephson junction.

Stochastic switching-current distribution in a graphene-based Josephson junction exhibits a crossover from the classical to quantum regime, revealing the macroscopic quantum tunneling of a Josephson phase particle at low temperatures. Microwave spectroscopy measurements indicate a multiphoton absorption process occurring via discrete energy levels in washboard potential well. The crossover temperature for macroscopic quantum tunneling and the quantized level spacing are controlled with the gate voltage, implying its potential application to gate-tunable superconducting quantum bits.

Peptide-mediated disruption of calmodulin-cyclin E interactions inhibits proliferation of vascular smooth muscle cells and neointima formation.

RATIONALE: Cell cycle progression in vascular smooth muscle cells (VSMCs) is a therapeutic target for restenosis. OBJECTIVE: Having discovered that calmodulin (CaM)-dependent cyclin E/CDK2 activity underlies Ca(2+)-sensitive G(1)-to-S phase transitions in VSMCs, we sought to explore the physiological importance of the CaM-cyclin E interaction. METHODS AND RESULTS: A peptide based on the CaM binding sequence (CBS) of cyclin E was designed to interfere with CaM-cyclin E binding. Compared with control peptides, CBS blocked activating Thr160 phosphorylation of CDK2, decreased basal cyclin E/CDK2 activity, and eliminated Ca(2+)-sensitive cyclin E/CDK2 activity in nuclear extracts from mouse VSMCs. Nucleofection with CBS, or treatment with CBS conjugated to the HIV-1 TAT protein transduction domain to improve bioavailability, inhibited G(1)-to-S cell cycle progression in a dose-dependent manner. These effects were not observed with control peptides. TAT-CBS inhibited (3)H-thymidine incorporation in primary human aortic SMCs (HA-SMCs) in vitro, manifested greater transduction into HA-SMCs compared with endothelial cells in vitro, and limited decreased SM22α expression, neointima formation, and medial thickening without affecting collagen deposition or reendothelialization in a mouse model of carotid artery injury in vivo. The antiproliferative effects of CBS remained evident in mouse embryonic fibroblasts derived from wild-type mice but not cyclin E1/E2 double knockout mice. CONCLUSIONS: A synthetic peptide designed to disrupt CaM-cyclin E binding inhibits Ca(2+)/CaM-dependent CDK2 activity, cell cycle progression, and proliferation in VSMCs and limits arterial remodeling following injury. Importantly, this effect appears to be cyclin E-dependent and may form the basis of a potentially novel therapeutic approach for restenosis.

How good is cola for dissolution of gastric phytobezoars?

AIM: To evaluate the efficacy of cola treatment for gastric phytobezoars, including diospyrobezoars. METHODS: A total of 17 patients (range: 48 to 78 years) with symptomatic gastric phytobezoars treated with cola and adjuvant endoscopic therapy were reviewed. Three liters of cola lavage (10 cases) or drink (7 cases) were initially used, and then endoscopic fragmentation was done for the remnant bezoars by using a lithotripsy basket or a polypectomy snare. The overall success of dissolving a gastric phytobezoars with using three liters of cola and the clinical and endoscopic findings were compared retrospectively between four cases of complete dissolution by using only cola and 13 cases of partial dissolution with cola. RESULTS: After 3 L of cola lavage or drinking, a complete dissolution of bezoars was achieved in four patients (23.5%), while 13 cases (76.5%) were only partially dissolved. Phytobezoars (4 of 6 cases) were observed more frequently than diospyrobezoars (0 of 11) in the group that underwent complete dissolution (P = 0.006). Gender, symptom duration, size of bezoar and method of cola administration were not significantly different between the two groups. Twelve of 13 patients with residual bezoars were completely treated with a combination of cola and endoscopic fragmentation. CONCLUSION: The rate of complete dissolution with three liters of cola was 23.5%, but no case of diospyrobezoar was completely dissolved using this method. However, pretreatment with cola may be helpful and facilitate endoscopic fragmentation of gastric phytobezoars.

Josephson-vortex-flow terahertz emission in layered high-Tc superconducting single crystals.

We report on the successful terahertz emission (0.6-1 THz) that is continuous and tunable in its frequency and power, by driving Josephson vortices in resonance with the collective standing Josephson plasma modes excited in stacked Bi2Sr2CaCu2O8+x intrinsic Josephson junctions. Shapiro-step detection was employed to confirm the terahertz-wave emission. Our results provide a strong feasibility of developing long-sought solid-state terahertz-wave emission devices.

Calmodulin-mediated cell cycle regulation: new mechanisms for old observations.

The significance of divalent calcium ions (Ca(2+)) to cell cycle progression has been a subject of study for several decades, with a regulatory role for Ca(2+) suggested in distinct cell types and multiple organisms. Our interest in proliferative vascular diseases led us to focus on mammalian vascular smooth muscle cells (VSMC) in particular, in which we and others had shown that a coordinate elevation in the intracellular free Ca(2+) concentration is required for G(1) to S phase cell cycle progression. However, the molecular basis for this Ca(2+)-sensitive cell cycle transition was not known. Our recent discovery of a functional protein-protein interaction between the late G1-active cyclin E1 and the major calcium signal-transducing factor calmodulin (CaM) sheds new light on the mechanism(s) through which Ca2+ concentrations regulate cell cycle. Having identified a CaM-binding site on cyclin E1, our studies support a direct role for CaM in mediating Ca2+-sensitive cyclin E/CDK2 activity and G1 to S phase transitions in VSMC. The CaM binding site identified on cyclin E1 has a Kd for CaM consistent with that of known CaM-binding proteins, and is composed of a 22 amino acids N-terminal sequence that is highly conserved across several mammalian species. Deletion of this binding site abolished CaM binding and Ca2+-sensitive cyclin E/Cdk2 activity. Here we provide our perspectives on the literature supporting a role for Ca2+ in cell cycle regulation, focusing on the evidence implicating CaM in this functionality, and discuss the potential for therapeutic modulation of CaM-dependent cell cycle machinery.