The tissue inhibitors of metalloproteinases (TIMPs) constitute a family of proteins, of which three members have so far been described. Using the expressed sequence tag sequencing approach, we have identified a novel TIMP-related cDNA fragment and subsequently cloned a fourth human TIMP (TIMP-4) from a human heart cDNA library. The open reading frame encodes a 224-amino acid precursor including a 29-residue secretion signal. The predicted structure of the new protein shares 37% sequence identity with TIMP-1 and 51% identity with TIMP-2 and -3. The protein has a predicted isoelectric point of 7.34. The open reading frame-directed expression of TIMP-4 protein in MDA-MB-435 human breast cancer cells showed metalloproteinase inhibitory activity on reverse zymography. By Northern analysis, only the adult heart showed abundant TIMP-4 transcripts with a 1.4-kilobase predominant transcript band; very low levels of the transcripts were detected in the kidney, placenta, colon, and testes, and no transcripts were detected in the liver, brain, lung, thymus, and spleen. This unique expression pattern suggests that TIMP-4 may function in a tissue-specific fashion in extracellular matrix homeostasis. Matrix metalloproteinases (MMPs)1 play a critical role in ECM homeostasis. Controlled remodeling of the ECM is an essential aspect in the process of normal development, and deregulated remodeling has been indicated to have a role in the etiology of diseases such as arthritis, periodontal disease, and cancer metastasis (1-5). The overproduction and unrestrained activity of MMPs has been linked to malignant conversion of tumor cells (4 -12). The down-regulation of MMPs may occur at the levels of transcriptional regulation of the genes and activation of secreted proenzymes and through interaction with specific inhibitor proteins such as TIMPs. TIMPs are secreted multifunctional proteins that play pivotal roles in the regulation of ECM metabolism. Their most widely recognized action is as inhibitors of matrix MMPs. Thus, the net MMP activity in the ECM is the result of the balance between activated enzyme levels and TIMPs levels. Augmented MMP activity is associated with the metastatic phenotype of carcinomas, especially breast cancer (7-9, 13-16); the decreased production of TIMP could also result in greater effective enzyme activity and invasive potentials (17-19). These results suggest that an increase in the amount of TIMPs relative to MMPs could function to block tumor cell invasion and metastasis. In fact, tumor cell invasion and metastasis can be inhibited by up-regulation of TIMP expression or by an exogenous supply of TIMPs (17, 40 -44).Three mammalian TIMPs have been characterized at the sequence level: TIMP-1 (20), TIMP-2 (21), and 36). The proteins are classified based on structural similarity to each other as well as their ability to inhibit matrix metalloproteinases. There have been other reports of inhibitors of metalloproteases (IMPs) with characteristics different from these known TIMPs. In some cases these activitie...

Responsive photonic structures can respond to external stimuli by transmitting optical signals. Because of their important technological applications such as color signage and displays, biological and chemical sensors, security devices, ink and paints, military camouflage, and various optoelectronic devices, researchers have focused on developing these functional materials. Conventionally, self-assembled colloidal crystals containing periodically arranged dielectric materials have served as the predominant starting frameworks. Stimulus-responsive materials are incorporated into the periodic structures either as the initial building blocks or as the surrounding matrix so that the photonic properties can be tuned. Although researchers have proposed various versions of responsive photonic structures, the low efficiency of fabrication through self-assembly, narrow tunability, slow responses to the external stimuli, incomplete reversibility, and the challenge of integrating them into existing photonic devices have limited their practical application. In this Account, we describe how magnetic fields can guide the assembly of superparamagnetic colloidal building blocks into periodically arranged particle arrays and how the photonic properties of the resulting structures can be reversibly tuned by manipulating the external magnetic fields. The application of the external magnetic field instantly induces a strong magnetic dipole-dipole interparticle attraction within the dispersion of superparamagnetic particles, which creates one-dimensional chains that each contains a string of particles. The balance between the magnetic attraction and the interparticle repulsions, such as the electrostatic force, defines the interparticle separation. By employing uniform superparamagnetic particles of appropriate sizes and surface charges, we can create one-dimensional periodicity, which leads to strong optical diffraction. Acting remotely over a large distance, magnetic forces drove the rapid formation of colloidal photonic arrays with a wide range of interparticle spacing. They also allowed instant tuning of the photonic properties because they manipulated the interparticle force balance, which changed the orientation of the colloidal assemblies or their periodicity. This magnetically responsive photonic system provides a new platform for chromatic applications: these colloidal particles assemble instantly into ordered arrays with widely, rapidly, and reversibly tunable structural colors, which can be easily and rapidly fixed in a curable polymer matrix. Based on these unique features, we demonstrated many applications of this system, such as structural color printing, the fabrication of anticounterfeiting devices, switchable signage, and field-responsive color displays. We also extended this idea to rapidly organize uniform nonmagnetic building blocks into photonic structures. Using a stable ferrofluid of highly charged magnetic nanoparticles, we created virtual magnetic moments inside the nonmagnetic particles. This "magnetic hol...

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A tensegrity strategy has been explored to construct a rigid geometrical structure (triangles) from flexible DNA four-arm junctions. The resulting DNA triangles could self-assemble into 1D and 2D arrays. This tensegrity strategy is expected to play an important role in the design of biomimetic nanomaterials.

The distinct synergetic characteristics between each component in inorganic-organic hybrids offer various possibilities to obtain new "smart", high performing materials. Growing interest in this field has largely expanded the content of photochromic materials for the purpose of improving existing photochromic materials, fabricating photoresponsive devices, and exploring new families of photochromic materials. In this feature article, we give a brief review of photochromic hybrids of metal halides, metal cyanides, polyoxometalates, and metal chalcogenides as well as photochromic metal-organic complexes.

Substitutional carbon doping of the honeycomb-like boron nitride (BN) lattices in two-dimensional (nanosheets) and one-dimensional (nanoribbons and nanotubes) nanostructures was achieved via in situ electron beam irradiation in an energy-filtering 300 kV high-resolution transmission electron microscope using a C atoms feedstock intentionally introduced into the microscope. The C substitutions for B and N atoms in the honeycomb lattices were demonstrated through electron energy loss spectroscopy, spatially resolved energy-filtered elemental mapping, and in situ electrical measurements. The preferential doping was found to occur at the sites more vulnerable to electron beam irradiation. This transformed BN nanostructures from electrical insulators to conductors. It was shown that B and N atoms in a BN nanotube could be nearly completely replaced with C atoms via electron-beam-induced doping. The doping mechanism was proposed to rely on the knockout ejections of B and N atoms and subsequent healing of vacancies with supplying C atoms.

A direct white-light metal-organic framework (MOF), [AgL](n) x nH(2)O (1, L = 4-cyanobenzoate), obtained by the reaction of deprotonated 4-cyanobenzoic acid and AgNO(3) in water, was found to exhibit tunable yellow-to-white photoluminescence by variation of excitation light. Interestingly, the close pure white emission of 1 has CIE-1931 chromaticity coordinates of (0.33, 0.34) when excited by 349-nm UV light, which is compatible to the light output of the deep UV LED.

Renal cell carcinoma (RCC) occurs in 2-4% of patients with tuberous sclerosis complex (TSC). Previous reports have noted a variety of histologic appearances in these cancers, but the full spectrum of morphologic and molecular features has not been fully elucidated. We encountered 46 renal epithelial neoplasms from 19 TSC patients and analyzed their clinical, pathological and molecular features, enabling separation of these 46 tumors into three groups. The largest subset of tumors (n=24) had a distinct morphological, immunological and molecular profile, including prominent papillary architecture and uniformly deficient SDHB expression prompting the novel term “TSC-associated papillary RCC.” The second group (n=15) was morphologically similar to a hybrid oncocytic/chromophobe tumor (HOCT) while the last 7 renal epithelial neoplasms of group 3 remained unclassifiable. The TSC-associated papillary RCCs (PRCC) had prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules. All 24 (100%) of these tumors were the International Society of Urological Pathology (ISUP) nucleolar grade 2 or 3 with mostly basally located nuclei. Tumor cells from 17 of 24 TSC-associated PRCC showed strong, diffuse labeling for CA-IX (100%), CK7 (94%), vimentin (88%), CD10 (83%), and were uniformly negative for succinate dehydrogenase subunit B (SDHB), TFE3 and AMACR. Gains of chromosomes 7 and 17 were found in 2 tumors, whereas chromosome 3p deletion and TFE3 translocations were not detected. In this study, we reported a sizable cohort of renal tumors seen in TSC and were able to identify them as different morphotypes which may help to expand the morphologic spectrum of TSC-associated RCC.