Electronic Structures of Nitridomanganese(V) Complexes

The single-crystal polarized absorption and circular dichroism spectra of the nitridomanganese(V) complexes (salen)Mn⋮N (1), (1S,2S-(−)-saldpen)Mn⋮N (2), and (1R,2R-(+)-saldpen)Mn⋮N (3) have been measured [salen = N,N‘-ethylenebis(salicylideneaminato) dianion, 1S,2S-(−)-saldpen = N,N‘-(1S,2S-(−)-diphenyl)ethylenebis(salicylideneaminato) dianion, and 1R,2R-(+)-saldpen = N,N‘-(1R,2R-(+)-diphenyl)ethylenebis(salicylideneaminato) dianion]. As revealed by X-ray crystal structure analyses, these molecules have a distorted square-pyramidal geometry with a short Mn⋮N bond distance (1.52(3) Å for 2). The Cs compounds have a low-spin^ 1A‘[a‘(x^2 − y^2)]^2 ground state. The lowest absorption system (∼600 nm) consists of two components that are separated by approximately 4000 cm^(-1); these are assigned to ^1A‘ → ^1A‘[a‘(x^2 − y^2)a‘(yz)] (14 900 cm^(-1)) and ^1A‘ → ^1A‘‘[a‘(x^2 − y^2)a‘‘(xz)] (18 900 cm^(-1)) transitions

Structures of Ruthenium-modified Pseudomonas aeruginosa Azurin and [Ru(2,2’-bipyridine)_2(imidazole)_2)]SO_4•10H_2O

The crystal structure of Ru(2,2'-bipyridine)_2(imidazole)(His83)azurin (RuAz) has been determined to 2.3 Å ¬resolution by X-ray crystallography. The spectroscopic and thermodynamic properties of both the native protein and [Ru(2,2'-bipyridine)_2(imidazole)_2]^(2+) are maintained in the modified protein. Dark-green RuAz crystals grown from PEG 4000, LiNO_3, CuCl_2 and Tris buffer are monoclinic, belong to the space group C2 and have cell parameters a = 100.6, b = 35.4, c = 74.7 Å and β = 106.5°. In addition, [Ru(2,2'-bipyridine)_2(imidazole)_2]SO_4•10H_2O was synthesized, crystallized and structurally characterized by X-ray crystallography. Red-brown crystals of this complex are monoclinic, space group P2_1/n, unit-cell parameters a = 13.230 (2), b = 18.197 (4), c = 16.126 (4) Å, β = 108.65 (2)°. Stereochemical parameters for the refinement of Ru(2,2'-bipyridine)_2(imidazole)(His83) were taken from the atomic coordinates of [Ru(2,2'-bipyridine)_2(imidazole)_2]^(2+). The structure of RuAz confirms that His83 is the only site of chemical modification and that the native azurin structure is not perturbed significantly by the ruthenium label

Electronic Structures of Nitridomanganese(V) Complexes

The single-crystal polarized absorption and circular dichroism spectra of the nitridomanganese(V) complexes (salen)Mn⋮N (1), (1S,2S-(−)-saldpen)Mn⋮N (2), and (1R,2R-(+)-saldpen)Mn⋮N (3) have been measured [salen = N,N‘-ethylenebis(salicylideneaminato) dianion, 1S,2S-(−)-saldpen = N,N‘-(1S,2S-(−)-diphenyl)ethylenebis(salicylideneaminato) dianion, and 1R,2R-(+)-saldpen = N,N‘-(1R,2R-(+)-diphenyl)ethylenebis(salicylideneaminato) dianion]. As revealed by X-ray crystal structure analyses, these molecules have a distorted square-pyramidal geometry with a short Mn⋮N bond distance (1.52(3) Å for 2). The Cs compounds have a low-spin^ 1A‘[a‘(x^2 − y^2)]^2 ground state. The lowest absorption system (∼600 nm) consists of two components that are separated by approximately 4000 cm^(-1); these are assigned to ^1A‘ → ^1A‘[a‘(x^2 − y^2)a‘(yz)] (14 900 cm^(-1)) and ^1A‘ → ^1A‘‘[a‘(x^2 − y^2)a‘‘(xz)] (18 900 cm^(-1)) transitions

Altered countermovement jump force profile and muscle- tendon unit kinematics following combined ballistic training

Combined heavy- and light-load ballistic training is often employed in high-performance sport to improve athletic performance and is accompanied by adaptations in muscle architecture. However, little is known about how training affects muscle-tendon unit (MTU) kinematics during the execution of a sport-specific skill (e.g., jumping), which could improve our understanding of how training improves athletic performance. The aim of this study was to investigate vastus lateralis (VL) MTU kinematics during a countermovement jump (CMJ) following combined ballistic training. Eighteen young, healthy males completed a 10-week program consisting of weightlifting derivatives, plyometrics, and ballistic tasks under a range of loads. Ultrasonography of VL and force plate measurements during a CMJ were taken at baseline, mid-test, and post-test. The training program improved CMJ height by 11 ± 13%. During the CMJ, VL's MTU and series elastic element (SEE) length changes and velocities increased from baseline to post-test, but VL's fascicle length change and velocity did not significantly change. It is speculated that altered lower limb coordination and increased force output of the lower limb muscles during the CMJ allowed more energy to be stored within VL's SEE. This may have contributed to enhanced VL MTU work during the propulsion phase and an improved CMJ performance following combined ballistic training

iPSC-derived myelinoids to study myelin biology of humans

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (“myelinoids”) and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination—both at the level of individual oligodendrocytes and globally across whole myelinoids—and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

BACKGROUND: No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". METHODS/DESIGN: MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. RESULTS: Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. CONCLUSIONS: In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00395200).RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART):a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259

A rapidly-reversible absorptive and emissive vapochromic Pt(II) pincer-based chemical sensor

Selective, robust and cost-effective chemical sensors for detecting small volatile-organic compounds (VOCs) have widespread applications in industry, healthcare and environmental monitoring. Here we design a Pt(II) pincer-type material with selective absorptive and emissive responses to methanol and water. The yellow anhydrous form converts reversibly on a subsecond timescale to a red hydrate in the presence of parts-per-thousand levels of atmospheric water vapour. Exposure to methanol induces a similarly-rapid and reversible colour change to a blue methanol solvate. Stable smart coatings on glass demonstrate robust switching over 104 cycles, and flexible microporous polymer membranes incorporating microcrystals of the complex show identical vapochromic behaviour. The rapid vapochromic response can be rationalised from the crystal structure, and in combination with quantum-chemical modelling, we provide a complete microscopic picture of the switching mechanism. We discuss how this multiscale design approach can be used to obtain new compounds with tailored VOC selectivity and spectral responses

Fish Oil and Fenofibrate for the Treatment of Hypertriglyceridemia in HIV-Infected Subjects on Antiretroviral Therapy: Results of ACTG A5186

Fish oil has been shown to reduce serum triglyceride (TG) concentrations. In HIV-infected patients on antiretroviral therapy, high TG concentrations likely contribute to increased risk of cardiovascular disease. AIDS Clinical Trials Group A5186 examined the safety and efficacy of fish oil plus fenofibrate in subjects not achieving serum TG levels ≤200 mg/dL with either agent alone

Localized Populations of CD8low/− MHC Class I Tetramer+ SIV-Specific T Cells in Lymphoid Follicles and Genital Epithelium

CD8 T cells play an important role in controlling viral infections. We investigated the in situ localization of simian immunodeficiency virus (SIV)-specific T cells in lymph and genital tissues from SIV-infected macaques using MHC-class I tetramers. The majority of tetramer-binding cells localized in T cell zones and were CD8+. Curiously, small subpopulations of tetramer-binding cells that had little to no surface CD8 were detected in situ both early and late post-infection, and in both vaginally and rectally inoculated macaques. These tetramer+CD8low/− cells were more often localized in apparent B cell follicles relative to T cell zones and more often found near or within the genital epithelium than the submucosa. Cells analyzed by flow cytometry showed similar populations of cells. Further immunohistological characterization revealed small populations of tetramer+CD20− cells inside B cell follicles and that tetramer+ cells did not stain with γδ-TCR nor CD4 antibodies. Negative control tetramer staining indicated that tetramer+CD8low/− cells were not likely NK cells non-specifically binding to MHC tetramers. These findings have important implications for SIV-specific and other antigen-specific T cell function in these specific tissue locations, and suggest a model in which antigen-specific CD8+ T cells down modulate CD8 upon entering B cell follicles or the epithelial layer of tissues, or alternatively a model in which only antigen-specific CD8 T cells that down-modulate CD8 can enter B cell follicles or the epithelium