To explore the photophysics of platinum acetylide chromophores with strong two-photon absorption cross-sections, we have investigated the synthesis and spectroscopic characterization of a series of platinum acetylide complexes that feature highly pi-conjugated ligands substituted with pi-donor or -acceptor moieties. The molecules (numbered 1-4) considered in the present work are analogs of bis(phenylethynyl)bis(tributylphosphine)platinum(II) complexes. Molecule 1 carries two alkynyl-benzothiazolylfluorene ligands, and molecule 2 has two alkynyl-diphenylaminofluorene ligands bound to the central platinum atom. Compounds 3 and 4 possess two dihexylaminophenyl substituents at their ends and differ by the number of platinum atoms in the oligomer "core" (one vs two in 3 and 4, respectively). The ligands have strong effective two-photon absorption cross-sections, while the heavy metal platinum centers give rise to efficient intersystem crossing to long-lived triplet states. Ultrafast transient absorption and emission spectra demonstrate that one-photon excitation of the chromophores produces an S1 state delocalized across the two conjugated ligands, with weak (excitonic) coupling through the platinum centers. Intersystem crossing occurs rapidly (Kisc approximately 1011 s-1) to produce the T1 state, which is possibly localized on a single conjugated fluorenyl ligand. The triplet state is strongly absorbing (epsilonTT > 5 x 104 M-1 cm-1), and it is very long-lived (tau > 100 micro s). Femtosecond pulses were used to characterize the two-photon absorption properties of the complexes, and all of the chromophores are relatively efficient two-photon absorbers in the visible and near-infrared region of the spectrum (600-800 nm). The complexes exhibit maximum two-photon absorption at a shorter wavelength than 2lambda for the one-photon band, consistent with the dominant two-photon transition arising from a two-photon-allowed gerade-gerade transition. Nanosecond transient absorption experiments carried out on several of the complexes with excitation at 803 nm confirm that the long-lived triplet state can be produced efficiently via a sequence involving two-photon excitation to produce S1, followed by intersystem crossing to produce T1.

It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin +/+ and Parkin -/-mice to a high-fat and -cholesterol diet (HFD). Parkin -/-mice resisted weight gain, steatohepatitis, and insulin resistance. Introduction PARK2 mutations associate with an autosomal recessive juvenileform of Parkinson disease (PD) (1). However, the role of Parkin in the development of PD in mice is surprisingly modest, as the genetic deletion of Parkin (2, 3) and the combined KO of Parkin with additional "candidate Parkinson susceptibility genes" PINK1 and DJ-1 do not substantially replicate the human condition (4). These unexpected findings suggest that the biological function of Parkin may not primarily modulate neurodegeneration but rather that PARK2 mutations increase biological susceptibility to stressors that manifest with substantia nigra neurodegeneration. Thus, the characterization of the functional actions of Parkin could be instrumental in delineating its role in the pathophysiology underpinning the development of PD.Parkin encodes an E3 ubiquitin protein ligase and contains 465 amino acids with multiple distinct domains, including a ubiquitinlike domain, a unique Parkin-specific domain, 2 RING domains, and an in-between-RING domain (5). The structure of this protein with its multiple binding domains is most likely central to the myriad of functions prescribed to Parkin (6). Additionally, the subcellular location of Parkin appears to be dynamic, with a predominant cytosolic localization with redistribution to the nucleus (7) and to the outer mitochondrial membrane (8, 9). Parkin exhibits mono- and multiubiquitination functions (10), and studies show that classical as well as nonclassical ubiquitin linkages facilitate proteosome-dependent and independent Parkin effects (11)(12)(13)(14).

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Chromophores and materials that exhibit nonlinear absorption over a broad spectrum and with high temporal dynamic range are of interest for application in materials engineering and biology. Recent work by a number of research groups has led to the development of a new family of organometallic chromophores and materials featuring interesting and useful nonlinear absorption properties. These systems contain the platinum acetylide moiety as a fundamental molecular unit, combined with delocalized, π-conjugated electron systems. These organometallic chromophores provide a unique combination of properties, such as negligible ground state absorption in the visible region, large spin-orbit coupling giving rise to high triplet excited state yield, triplet lifetime in the microsecond domain, high two-photon cross-section in the visible and near-infrared regions, and high triplet-triplet absorption cross-section in the visible and near-infrared region. This Spotlight on Application highlights recent developments in this area, combining background and review on nonlinear absorption in platinum acetylide chromophores and describing significant recent results from our own laboratory.

The photophysical properties of the complex (L)Ir(ppy)(2)(+), where ppy = 2-phenylpyridine and L = 4,4'-(2,2'-bipyridine-5,5'-diylbis(ethyne-2,1-diyl))bis(N,N-dihexylaniline), have been investigated under one- and two-photon excitation conditions. In THF solution, the complex exhibits broad ground-state absorption with lambda(max) approximately 500 nm and weak photoluminescence with lambda(max) approximately 730 nm. Excitation of (L)Ir(ppy)(2)(+) at 355 nm produces a long-lived excited state (tau approximately 1 mus) that features a strong excited-state absorption in the near-infrared (lambda(max) approximately 875 nm, Deltaepsilon approximately 6.1 x 10(4) M(-1) cm(-1)). Photoluminescence and transient absorption studies of (L)Ir(ppy)(2)(+) carried out using 5 ns, 1064 nm pulsed excitation demonstrate that the same long-lived and strongly absorbing excited state can be efficiently produced by two-photon absorption. Solutions of the complex in THF display nonlinear absorption of 5 ns, 1064 nm pulses in a process that is believed to involve a combination of two-photon absorption and reverse saturable absorption.

This manuscript reports the synthesis and photophysical investigation of two hexa-peri-hexabenzocoronenes (HBCs) that are functionalized with platinum(II) acetylide units of the type trans-(Ar-CC-)2Pt(PBu3)2. In one complex, the platinum is directly linked to the HBC chromophore by an ethynyl spacer, whereas in the second, the platinum is separated from the HBC via a 1,4-phenylene ethynylene spacer. The Pt-acetylide units introduce strong spin-orbit coupling into the HBC chromophore, giving rise to high yields of the triplet excited state along with moderately intense phosphorescence at ambient temperature. On the basis of emission spectroscopy, the triplet state of the HBC chromophore is located at 2.14 eV and the S-T splitting is 0.6 eV. The triplet-triplet absorption and radical cation absorption spectra of the Pt-HBCs are determined by laser flash photolysis. Aggregation of the Pt-HBCs in a poor solvent such as hexane leads to quenching of the triplet state, but spectroscopy provides no evidence for the formation of a triplet excimer, even under conditions where the molecules are strongly aggregated.

A series of platinum-containing organometallic dimer complexes has been synthesized and the photophysical properties have been investigated under one- and two-photon (2PA) absorption conditions. The complexes have the general structure [DPAF-C[triple bond]C-Pt(PBu(3))(2)-C[triple bond]C-Ar-C[triple bond]C-Pt(PBu(3))(2)-C[triple bond]C-DPAF], where Ar is a pi-conjugated unit, Bu = n-butyl, and DPAF = diphenylamino-2,7-fluorenylene. The core Ar units include 1,4-phenylene, 2,5-thienylene, 5,5'-(2,2'-bithienylene), 2,5-(3,4-ethylenedioxythiophene, 2,1,3-benzothiadiazole, and 4,7-dithien-2-yl-2,1,3-benzothiadiazole. Absorption and photoluminescence spectroscopy indicates that the complexes feature low-lying excited states based on both the core [-Pt(PBu(3))(2)-C[triple bond]C-Ar-C[triple bond]C-Pt(PBu(3))(2)-] chromophore as well as the DPAF units. Photoexcitation of the complexes produces a singlet state excited state, which rapidly undergoes intersystem crossing to afford a triplet state that has a lifetime in the microsecond time domain. In most cases, the lowest energy triplet state is localized on the core chromophore. Femtosecond 2PA spectra are measured along with triplet-triplet absorption spectra and nanosecond intensity-dependent transmission for solutions of the complexes. Each of the complexes features a 2PA absorption band in the near-infrared region (lambda approximately 700-750 nm) with a cross section 50-200 GM that is ascribed to the DPAF chromophore. The complexes also feature broad triplet-triplet absorption throughout the visible and near-infrared regions (lambda approximately 500-800 nm, (TT) approximately 5-10 x 10(4) M(-1) cm(-1)). Each of the complexes exhibits efficient nonlinear absorption of nanosecond pulses in the near-infrared region (600-800 nm), and we demonstrate that effect is most efficient in the chromophores where the 2PA cross section maxima coincides spectrally with the excited triplet state absorption.

We report a novel isoform of non-muscle myosin II-C (NM II- Mammalian non-muscle myosin IIs (NM IIs)2 belong to the conventional Class II myosins and are hexameric proteins composed of two heavy chains and two pairs of light chains, referred as the 20-kDa regulatory myosin light chain (MLC 20 ) and the 17-kDa essential myosin light chain (MLC 17 ). These myosins self-associate through their tail regions to form bipolar filaments that pull on actin filaments to produce force to drive important cellular functions such as cytokinesis, cell polarity, and cell migration (1-4). Three isoforms of the non-muscle myosin heavy chain (NMHC), II-A, II-B, and II-C, have been identified in vertebrates. They are products of three different genes, MYH9 (5, 6), MYH10 (6), and MYH14 (7, 8), respectively, in humans. It is well established that the enzymatic activity of these myosins is regulated by phosphorylation of MLC 20 , which is catalyzed by a number of enzymes, including myosin light chain kinase (MLCK), and Rho kinase (9 -14).Alternative splicing of pre-mRNA of NMHC II genes generates multiple mRNAs to enhance protein diversity in the NM II family. Work from this laboratory and others (8,(15)(16)(17)(18) has established that both NMHC II-B and II-C undergo alternative splicing to generate several isoforms. In the case of NMHC II-B, 10 amino acids are incorporated into loop 1 at amino acid 212 (NMHC II-B1), and 21 amino acids are inserted into loop 2 at amino acid 622 (NMHC II-B2; see Ref. 15). These isoforms have been expressed as proteins, and their biochemical and functional importance has been studied extensively (19 -22). Recently, it has been reported that baculovirus-expressed heavy meromyosin (HMM) II-B2 lacks actin-activated MgATPase activity and cannot propel actin filaments in an in vitro motility assay following MLC 20 phosphorylation (22) even though HMM II-B0 and II-B1 show normal phosphorylation-dependent activities (21). These two inserted isoforms (NM II-B1 and NM II-B2) are only expressed in neuronal tissues, and the results of ablating each of them and NM II-B in mice have been reported (23)(24)(25).For NMHC II-C, an alternative exon encoding 8 amino acids is incorporated into loop 1 at amino acid 227 (NMHC II-C1) at a location homologous to that of the B1 insert. Unlike NMHC II-B1, which is only expressed in neuronal tissue, NMHC II-C1 is found in a variety of tissues such as liver, kidney, testes, brain, and lung (8). The presence of the C1 insert in baculovirusexpressed HMM II-C1 increases both the actin-activated MgATPase activity and in vitro motility of HMM II-C1 compared with HMM II-C0, the noninserted form. The activity of both HMM II-C0 and HMM II-C1 is dependent on MLC 20 phosphorylation (26). NM II-C1 has been shown to be expressed in a number of tumor cell lines, and decreasing its expression using small interfering RNA delays a late step in cytokinesis in the lung tumor cell line A549 (27).In this study, we report that an exon encoding 41 amino acids can be incorporated into loop 2 near the ...