Ynone Co-Coordination at a Nickel Borane Complex: An Assessment of Secondary Coordination Sphere Effects.

Secondary coordination sphere ligand effects can be used to direct or organize small molecule substrates at a metal center. Herein, we assess the bifunctional ambiphilic diphosphine, tri--butylboranyldiphosphinoethane (tbbpe) and its ability to influence stereoselective substrate coordination, while appended to nickel. This report takes a synthetic/computational approach to test the impacts and limitations associated with ligand-directed substrate coordination using [Ni(tbbpe)(η:η-COD)] (COD = 1,5-cyclooctadiene) and ynones (alkynes having an α-carbonyl group at the propargylic position) as model substrates.

Reactions of nickel boranyl compounds with pnictogen-carbon triple bonds.

The catalytic conversion of unsaturated small molecules such as nitriles into reduced products is of interest for the production of fine chemicals. In this vein, metal-ligand cooperativity has been leveraged to promote such reactivity, often conferring stability to bound substrate - a balancing act that may offer activation at the cost of turnover efficiency. This report describes the reactivity of a [(diphosphine)Ni] compound with pnictogen carbon triple bonds (R-C[triple bond, length as m-dash]E; E = N, P), where the diphosphine contains two pendant borane groups.

Bis(1-bora-4-phosphorinane) ring closure at Cp*M (M = Fe, Co) complexes.

Bis(1-bora-4-phosphorinane) metal complexes have been synthesized using a Cp*M-protecting (M = FeCl, Co, Cp* = CMe) strategy and structurally authenticated by NMR spectroscopy and single crystal X-ray diffraction. Synthesis of these scaffolds is highly sensitive to the identity of vinylphosphine precursor. This approach provides a new method for the generation of saturated ,-containing main-group ring systems.

Competitive gold/nickel transmetalation.

Transmetalation is a key method for the construction of element-element bonds. Here, we disclose the reactivity of [Ni(Ar)(I)(diphosphine)] compounds with arylgold(I) transmetalating agents, which is directly relevant to cross-coupling catalysis. Both aryl-for-iodide and unexpected aryl-for-aryl transmetalation are witnessed.

Lewis Acid-Promoted Oxidative Addition at a [Ni (diphosphine) ] Complex: The Critical Role of a Secondary Coordination Sphere.

Oxidative addition represents a critical elementary step in myriad catalytic transformations. Here, the importance of thoughtful ligand design cannot be overstated. In this work, we report the intermolecular activation of iodobenzene (PhI) at a coordinatively saturated 18-electron [Ni (diphosphine) ] complex bearing a Lewis acidic secondary coordination sphere.

Preparation of a borane-appended Co(III) hydride: evidence for metal-ligand cooperativity in O-H bond activation.

Cobalt hydrides are known to mediate a number of important chemical transformations including proton (H), hydride (H), and hydrogen-atom (H˙) transfer. Central to the tunability of such frameworks is judicious ligand design, which offers the flexibility to alter fundamental properties relevant to reactivity. Herein, we report the preparation of one such cobalt(III) hydride: [Cp*Co(PB)(H)]BPh (Cp* = CMe, PB = 1,2-bis(di(3-dicyclohexylborane)propylphosphino)ethane) that is encircled by a boron-based Lewis-acidic secondary coordination sphere.

Investigation of modified nanopore arrays using FIB/SEM tomography.

The investigation of electrochemical processes at the interface of two immiscible electrolyte solutions (ITIES) is of great interest for sensing applications, and serves as a surrogate to the study of biological transport phenomena, e.g. ion channels.

Can MRI T be used to detect early changes in 5xFAD Alzheimer's mouse brain?

Objectives: In the present study, we have tested whether MRI T relaxation time is a sensitive marker to detect early stages of amyloidosis and gliosis in the young 5xFAD transgenic mouse, a well-established animal model for Alzheimer's disease.

Materials And Methods: 5xFAD and wild-type mice were imaged in a 4.7 T Varian horizontal bore MRI system to generate T quantitative maps using the spin-echo multi-slice sequence.

Gadolinium-complexed Aβ-binding contrast agents for MRI diagnosis of Alzheimer's Disease.

MRI contrast agents, containing peptide sequences that bind β-amyloid and gadolinium ions ligated to DOTA have been synthesized for evaluation in early diagnosis of Alzheimer's Disease in transgenic mice models. A number of brain penetration modifications were incorporated and sufficient amounts of contrast agent in the brain were achieved only by addition of a cationic cell penetration sequence along with the use of microparticle assisted ultrasound activation. In the T1 mode of a MRI scan, the peptide (R2) illuminated areas of brain rich in amyloid plaques.

The elusive nature and diagnostics of misfolded Aβ oligomers.

Amyloid-beta (Aβ) peptide oligomers are believed to be the causative agents of Alzheimer's disease (AD). Though post-mortem examination shows that insoluble fibrils are deposited in the brains of AD patients in the form of intracellular (tangles) and extracellular (plaques) deposits, it has been observed that cognitive impairment is linked to synaptic dysfunction in the stages of the illness well before the appearance of these mature deposits. Increasing evidence suggests that the most toxic forms of Aβ are soluble low-oligomer ligands whose amounts better correlate with the extent of cognitive loss in patients than the amounts of fibrillar insoluble forms.

Quantitative evaluation of MRI and histological characteristics of the 5xFAD Alzheimer mouse brain.

Assessment of β-amyloid (Aβ) plaque load in Alzheimer's disease by MRI would provide an important biomarker to monitor disease progression or treatment response. Alterations in tissue structure caused by the presence of Aβ may cause localised changes that can be detected by quantitative T₁ and T₂ relaxation time measurements averaged over larger areas of tissue than that of individual plaques. We constructed depth profiles of the T₁ and T₂ relaxation times of the cerebral cortex with subjacent white matter and hippocampus in six 5xFAD transgenic and six control mice at 11 months of age.

Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2.

Background: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer's disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release.

ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele.

Ataxia telangiectasia patients, with constitutional bi-allelic ATM mutations, have a marked risk of lymphoid tumors and ATM mutation carriers have a smaller risk of cancer. Sporadic ATM mutations occur in 10-20% of chronic lymphocytic leukemia and are often associated with chromosome 11q deletions which cause loss of an ATM allele. The role of constitutional ATM mutations in the pathogenesis of chronic lymphocytic leukemia is unknown.

The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors.

NNMT (nicotinamide N-methyltransferase, E.C. 2.

Development of retro-inverso peptides as anti-aggregation drugs for β-amyloid in Alzheimer's disease.

Alzheimer's disease (AD) is a devastating degenerative disorder of the brain for which there is no cure or effective treatment. There is much evidence to suggest that β-amyloid protein (Aβ) aggregation in the brain leading to deposits is an important step in the development of AD. Recently, two peptides, RGKLVFFGR (OR1) and RGKLVFFGR-NH(2) (OR2) containing the sequence KLVFF, which is the central region (residues 16-20) of Aβ, have been found to be potent inhibitors of Aβ aggregate formation.

Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia.

Recently a mouse model of T/natural killer acute lymphoblastic leukemia was used to assess global promoter methylation across the mouse genome using the restriction landmark genomic scanning technique. One of the methylated mouse genes identified in this way was Slit2. There are three mammalian SLIT genes (SLIT1, SLIT2, SLIT3), that belong to a highly conserved family of axon guidance molecules.

The protective effects of the nutraceutical, colostrinin, against Alzheimer's disease, is mediated via prevention of apoptosis in human neurones induced by aggregated beta-amyloid.

Objective: It has previously been demonstrated that oral administration of ovine Colostrinin (CLN), a proline-rich polypeptide isolated from ovine colostrum, can effectively treat Alzheimer's disease patients. This study aims to determine whether CLN has effects on the aggregation and toxicity of synthetic beta-amyloid (Abeta), implicated as a causative agent of AD.

Design And Measurements: Using cell assays, we examined if pre-treatment of neuronal cells with CLN confers protection.

Molecular interactions of the plasma membrane calcium ATPase 2 at pre- and post-synaptic sites in rat cerebellum.

The plasma membrane calcium extrusion mechanism, PMCA (plasma membrane calcium ATPase) isoform 2 is richly expressed in the brain and particularly the cerebellum. Whilst PMCA2 is known to interact with a variety of proteins to participate in important signalling events [Strehler EE, Filoteo AG, Penniston JT, Caride AJ (2007) Plasma-membrane Ca(2+) pumps: structural diversity as the basis for functional versatility. Biochem Soc Trans 35 (Pt 5):919-922], its molecular interactions in brain synapse tissue are not well understood.

Galantamine inhibits beta-amyloid aggregation and cytotoxicity.

The ability of galantamine (Reminyl) to inhibit the aggregation and toxicity of the beta-amyloid peptide (Abeta) was investigated. Galantamine showed concentration-dependent inhibition of aggregation of both Abeta 1-40 and Abeta 1-42, as determined by an ELISA method. Electron microscope studies of Abeta 1-40 incubated in the presence of galantamine revealed fibrils that were disordered and clumped in appearance.

Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers.

Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome.

Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients.

Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours. ATM mutations have been found in a number of adult lymphoid malignancies but there is no data on the occurrence of ATM mutations in multiple myeloma tumours. The purpose of our work was to investigate the occurrence of ATM mutations in multiple myeloma and to this end we screened 45 sporadic cases for ATM mutations using denaturing high-performance liquid chromatography analysis and DNA sequencing.

HLA homology within the C5 domain promotes peptide binding by HIV type 1 gp120.

The mechanisms by which HIV-1 induces chronic pathogenic immune activation associated with disease progression remain unclear despite many years of AIDS research. One proposal suggests that sequence and structural mimicry between gp120 and HLA may endow HIV with the capacity to arouse alloreactive and autoimmune responses within the susceptible host, fueling disease progression in a manner similar to graft-versus-host disease (GVHD). Both gp120 and HLA share a common functional interaction with CD4 but also demonstrate peptide binding properties.