Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants

This project was supported by grants from the ERC (no. 339367, MJ), BBSRC IBCatalyst (no. BB/M028526/1, MJ, WEH), BBSRC FoF (no. BB/M013669/1, MJ, WEH), IBioIC Exemplar (no. 2014-2-4, MJ, WEH), an AstraZeneca studentship (MJ, WEH, LT, KR), the Academy of Finland (no. 259505, DPF) and the SULSA leaders award (WEH). The authors like to thank the Aberdeen Proteomics Facility and the Aberdeen School of Natural and Computing Sciences MS Facility for LCMS analysis. Electronic supplementary information (ESI) available: Experimental section, Fig. S1–S60 and Tables S1–S3. See DOI: 10.1039/c7cc05913bPeer reviewedPublisher PD

Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 ( 2 ) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 ( Pf eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline ( 2 ) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency

Structure-Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis

Leishmaniasis is a collection of diseases caused by more than 20 Leishmania parasite species that manifest as either visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant mortality and morbidity associated with leishmaniasis, it remains a neglected tropical disease. Existing treatments have variable efficacy, significant toxicity, rising resistance, and limited oral bioavailability, which necessitates the development of novel and affordable therapeutics. Here, we report on the continued optimization of a series of imidazopyridines for visceral leishmaniasis and a scaffold hop to a series of substituted 2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism, and elimination properties

Panel cointegration of Chinese A and B shares

We study information flows in China's stock markets. By using panel data methods we test for a unit root in the price premium of domestic investors' A shares over foreign investors' B shares, as well as cointegration between the A- and B-share prices on the Shanghai and Shenzhen stock exchanges. We find that the A-share premia are nonstationary, and that the A- and B-share prices are not cointegrated up till January 2001. After February 2001, when domestic investors were allowed to trade B shares, the A-share premia become stationary and the A- and B-share prices cointegrated. One interesting result from the panel data analysis is that most firms' A and B shares are cointegrated, but not all firms. Cointegration is more likely for firms with a small A-share premium, low ratio of nontradeable shares, high growth rate and large B-share market capitalization relative to the A-share market capitalization. Our findings suggest that the relaxation of the investment restrictions decreased the segmentation between the A- and B-share markets in China.

Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder.

We have investigated a 15 year old girl with progressive external ophthalmoplegia, including bilateral ptosis and retinal rod and cone cell dysfunction with atypical retinal pigmentation, complicated by cerebellar ataxia, partial cardiac conduction block, and diabetes mellitus. In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially though to be psychosomatic. Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA. We therefore conclude that this patient has developed the Kearns-Sayre syndrome after a Pearson syndrome-like crisis in her first year of life

Role of Helicobacter pylori in conjunctival mucosa-associated lymphoid tissue lymphoma

Objective: Conjunctiva-associated lymphoid tissue is the conjunctival equivalent to mucosa-associated lymphoid tissue (MALT). Mucosa-associated lymphoid tissue lymphoma has been shown to be associated with Helicobacter pylori. In this study, the prevalence and possible role of H. pylori infection in conjunctival MALT lymphoma were evaluated. Design: Retrospective noncomparative case series. Participants: Thirteen cases of conjunctival MALT lymphoma were investigated. Five samples of conjunctival lymphoid hyperplasia and 20 biopsies of normal conjunctiva served as controls. Methods: The specimens were investigated for the presence of H. pylori with immunohistochemistry (IHC) and nested polymerase chain reaction (PCR) techniques. For each case of conjunctival MALT lymphoma, information regarding gender, age at presentation, conjunctival localization, and information of generalized MALT lymphoma were collected. Main Outcome Measures: Detection of H. pylori and patient characteristics. Results: The 13 conjunctival MALT lymphomas originated from 8 women and 5 men with an average age of 62 years (range, 25-87). Only 1 patient had evidence of systemic MALT lymphoma. H. pylon could not be identified in any of the conjunctival MALT lymphomas, in conjunctival lymphoid hyperplasia, or in normal conjunctival biopsies using IHC and PCR techniques. Conclusions: An association between H. pylori and localized conjunctival MALT lymphoma could not be verified. Antigens other than H. pylon may take part in the development of conjunctival MALT lymphoma

International physical activity questionnaire: 12-country reliability and validity,”

Background: Physical inactivity is a global concern, but diverse physical activity measures in use prevent international comparisons. The International Physical Activity Questionnaire (IPAQ) was developed as an instrument for cross-national monitoring of physical activity and inactivity. Methods: Between 1997 and 1998, an International Consensus Group developed four long and four short forms of the IPAQ instruments (administered by telephone interview or self-administration, with two alternate reference periods, either the "last 7 d" or a "usual week" of recalled physical activity). During 2000, 14 centers from 12 countries collected reliability and/or validity data on at least two of the eight IPAQ instruments. Test-retest repeatability was assessed within the same week. Concurrent (inter-method) validity was assessed at the same administration, and criterion IPAQ validity was assessed against the CSA (now MTI) accelerometer. Spearman's correlation coefficients are reported, based on the total reported physical activity. Results: Overall, the IPAQ questionnaires produced repeatable data (Spearman's clustered around 0.8), with comparable data from short and long forms. Criterion validity had a median of about 0.30, which was comparable to most other self-report validation studies. The "usual week" and "last 7 d" reference periods performed similarly, and the reliability of telephone administration was similar to the self-administered mode. Conclusions: The IPAQ instruments have acceptable measurement properties, at least as good as other established self-reports. Considering the diverse samples in this study, IPAQ has reasonable measurement properties for monitoring population levels of physical activity among 18-to 65-yr-old adults in diverse settings. The short IPAQ form "last 7 d recall" is recommended for national monitoring and the long form for research requiring more detailed assessment