Magnesium-catalysed nitrile hydroboration

A β-diketiminato n-butylmagnesium complex is presented as a selective precatalyst for the reductive hydroboration of organic nitriles with pinacolborane (HBpin). Stoichiometric reactivity studies indicate that catalytic turnover ensues through the generation of magnesium aldimido, aldimidoborate and borylamido intermediates, which are formed in a sequence of intramolecular nitrile insertion and inter- and intramolecular B–H metathesis events. Kinetic studies highlight variations in mechanism for the catalytic dihydroboration of alkyl nitriles, aryl nitriles bearing electron withdrawing (Ar(EWG)CN) and aryl nitriles bearing electron donating (Ar(EDG)CN) substitution patterns. Kinetic isotope effects (KIEs) for catalysis performed with DBpin indicate that B–H bond breaking and C–H bond forming reactions are involved in the rate determining processes during the dihydroboration of alkyl nitriles and Ar(EDG)CN substrates, which display divergent first and second order rate dependences on [HBpin] respectively. In contrast, the hydroboration of Ar(EWG)CN substrates provides no KIE and HBpin is not implicated in the rate determining process during catalysis. Irrespective of these differences, a common mechanism is proposed in which the rate determining steps are deduced to vary through the establishment of several pre-equilibria, the relative positions of which are determined by the respective stabilities of the dimeric and monomeric magnesium aldimide and magnesium aldimidoborate intermediates as a result of adjustments to the basicity of the nitrile substrate. More generally, these observations indicate that homogeneous processes performed under heavier alkaline earth catalysis are likely to demonstrate previously unappreciated mechanistic diversity

Influence of Anthropogenic Pressures on the Bioactivity Potential of Sponges and Soft Corals in the Coral Reef Environment

The wealth of marine sponges and soft corals in Indonesian waters represents a rich source of natural products. However, anthropogenic pressures potentially decrease diversity in coral reefs. Presented here are trends for tropical sponge and soft coral biodiversity and their bioactivity potential under the influence of increasing anthropogenic pressures. Samples were collected along transects (near, mid, and far) at Karimunjawa and Seribu Islands Marine National Parks and environmental parameters (salinity, pH, dissolved oxygen (DO), phosphate, nitrate, and ammonia), sponge and soft coral biodiversity, and the bioactivity potential of those organisms (50% Growth Inhibition (GI50) of cancer cell lines H460-Lung, MCF7-Breast, and SF268-CNS) are compared. The environmental conditions and biodiversity were found to be significantly different between groups of sampling sites (P<0.05). Canonical Discriminant Analysis (CDA) revealed DO was the discriminant factor driving the separation between groups (90.1%). Diversity tended to be higher in the Far group with strong and significant relation to DO (R= 0.611, P<0.05) and ammonia (R = -0.812, P<0.05). The CDA also showed that an increase in bioactivity (low % GI50) of sponge and soft coral extracts was related to a canonical function (57.21%) consisting of high DO, high pH, and low nutrients. These findings indicate the production of bioactive compounds is related to diversity and complexity of coral reef systems. Therefore, strategies for marine protection by mitigating the impacts of anthropogenic pressures needs to be optimized in order to conserve the overall environment and sustain its natural bioactivity potential indefinitely

Cytotoxic Cembranes from Indonesian Specimens of the Soft Coral Nephthea sp

Methanol extracts of two specimens of the soft coral Nephthea sp. collected from the Seribu Islands, Indonesia, were active in an anticancer bioassay. One new (1) and four known diterpenes (2–5) based on the cembrane carbon skeleton were isolated from these extracts, as was arachidonic acid (8). The structures of all compounds were elucidated using NMR, including 1,1-ADEQUATE and 1D gradient selective NOESY where applicable to determine the relative stereochemistry. Spectroscopic data, including 1H and 13C NMR, UV, IR and optical rotations are reported when enough material was available and where this has not been done previously. Inhibition assays employing three cancer cell lines; SF-268 (CNS), MCF-7 (breast), and H460 (lung) were used to guide the isolation of all compounds

A New Diketopiperazine, Cyclo-(4-S-hydroxy-R-proline-R-isoleucine), from an Australian Specimen of the Sponge Stelletta sp. †

While investigating the cytotoxic activity of the methanol extract of an Australian marine sponge Stelletta sp. (Demospongiae), a new diketopiperazine, cyclo-(4-S-hydroxy-R-proline-R-isoleucine) (1), was isolated together with the known bengamides; A (2), F (3), N (4), Y (5), and bengazoles; Z (6), C4 (7) and C6 (8). The isolation and structure elucidation of the diketopiperazine (1), together with the activity of 1–8 against a panel of human and mammalian cell lines are discussed

An air-stable [Cu(NHC)(OR)] (R = C(H)(CF3)2) complex for C-H, N-H and S-H bond activation

The synthesis, isolation and full characterisation of a [Cu(IPr)(OC(H)(CF3)(2))] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) complex are reported. This new Cu(i) complex is a versatile synthon and can activate numerous X-H bonds including C-H, N-H and S-H bonds. [Cu(IPr)(OC(H)(CF3)(2))] was investigated as a pre-catalyst in several catalytic reactions

Automated de-identification of clinical free-text

ABSTRACT Objectives Increasing interest to use unstructured electronic patient records for research has attracted attention to automated de-identification methods to conduct large scale removal of Personal Identifiable Information (PII). PII mainly include identifiable information such as person names, dates (e.g., date of birth), reference numbers (e.g., hospital number, NHS number), locations (e.g., hospital names, addresses), contacts (e.g., telephone, e-mail), occupation, age, and other identity information (ethnical, religion, sexual) mentioned in a private context.  De-identification of clinical free-text remains crucial to enable large-scale data access for health research while adhering to legal (Data Protection Act 1998) and ethical obligations. Here we present a computational method developed to automatically remove PII from clinical text. Approach In order to automatically identify PII in clinical text, we have developed and validated a Natural Language Processing (NLP) method which combine knowledge- (lexical dictionaries and rules) and data-driven (linear-chain conditional random fields) techniques. In addition, we have designed a novel two-pass recognition approach that uses the output of the initial pass to create patient-level and run-time dictionaries used to identify PII mentions that lack specific contextual clues considered by the initial entity extraction modules. The labelled data used to model and validate our techniques were generated using six human annotators and two distinct types of free-text from The Christie NHS Foundation Trust: (1) clinical correspondence (400 documents) and (2) clinical notes (1,300 documents). Results The de-identification approach was developed and validated using a 60/40 percent split between the development and test datasets. The preliminary results show that our method achieves 97% and 93% token-level F1-measure on clinical correspondence and clinical notes respectively. In addition, the proposed two-pass recognition method was found particularly effective for longitudinal records. Notably, the performances are comparable to human benchmarks (using inter annotator agreements) of 97% and 90% F1 respectively. Conclusions We have developed and validated a state-of-the-art method that matches human benchmarks in identification and removal of PII from free-text clinical records. The method has been further validated across multiple institutions and countries (United States and United Kingdom), where we have identified a notable NLP challenge of cross-dataset adaption and have proposed using active learning methods to address this problem. The algorithm, including an active learning component, will be provided as open source to the healthcare community

Autophagosomal iκbα degradation plays a role in the long term control of tumor necrosis factor-α-induced nuclear factor-κb (nf-κb) activity

Transcription factor NF-kappa B is persistently activated in many chronic inflammatory diseases and cancers. The short term regulation of NF-kappa B is well understood, but little is known about the mechanisms of its long term activation. We studied the effect of a single application of TNF-alpha on NF-kappa B activity for up to 48 h in intestinal epithelial cells. Results show that NF-kappa B remained persistently activated up to 48 h after TNF-alpha and that the long term activation of NF-kappa B was accompanied by a biphasic degradation of I kappa B alpha. The first phase of I kappa B alpha degradation was proteasome-dependent, but the second was not. Further investigation showed that TNF-alpha stimulated formation of autophagosomes in intestinal epithelial cells and that I kappa B alpha co-localized with autophagosomal vesicles. Pharmacological or genetic blockade of autophagosome formation or the inhibition of lysosomal proteases decreased TNF-alpha-induced degradation of I kappa B alpha and lowered NF-kappa B target gene expression. Together, these findings indicate a role of autophagy in the control of long term NF-kappa B activity. Because abnormalities in autophagy have been linked to ineffective innate immunity, we propose that alterations in NF-kappa B may mediate this effect

Metachromins U-W: Cytotoxic merosesquiterpenoids from an Australian specimen of the sponge Thorecta reticulata

Three new merosesquiterpenoids, metachromins U, V, and W (1–3), were isolated from a specimen of the marine sponge Thorecta reticulata collected off Hunter Island, Tasmania, Australia. Structures of the new compounds were elucidated through extensive NMR investigations and comparison with literature values. The cytotoxicities of 1–3 were assessed against a panel of human tumor cell lines (SF-268, H460, MCF-7, and HT-29) and a mammalian cell line (CHO-K1). All compounds were found to have 50% growth inhibition activities in the range 2.1–130 μM, with 2 being the most active (GI50 2.1–10 μM)