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  • The American Society for Biochemistry and Molecular Biology (ASBMB)  (12)
  • BMJ Publishing Group  (11)
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  • 1
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    Cynthia Ruth Woodhall (2013)
    BMJ Publishing Group
    Details
    Publication Date: 2013-11-02
    Description: Cynthia Ruth Woodhall was brought up in the Black Country. After qualifying she undertook basic junior posts, but then specialised in paediatrics, spending an important and formative year in...
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
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    Clinical effectiveness of collaborative care for depression in UK primary care (CADET): cluster randomised controlled trial (2013)
    BMJ Publishing Group
    Details
    Publication Date: 2013-08-20
    Description: Objective To compare the clinical effectiveness of collaborative care with usual care in the management of patients with moderate to severe depression.Design Cluster randomised controlled...
    Keywords: Clinical trials (epidemiology), General practice / family medicine, UK, Drug misuse (including addiction), Anxiety disorders (including OCD and PTSD), Drugs misuse (including addiction), Mood disorders (including depression), Psychotic disorders (incl schizophrenia), Health education, Health promotion, Sociology
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 3
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    Dihydroartemisinin-piperaquine holds promise as an option for malaria prevention in pregnancy (2016)
    BMJ Publishing Group
    Details
    Publication Date: 2016-07-27
    Description: Commentary on : Kakuru A , Jagannathan P, Muhindo MK, et al .. Dihydroartemisinin-piperaquine for the prevention of malaria in pregnancy. N Engl J Med 2016 ; 374 : 928 –39. Context Malaria in pregnancy has devastating consequences for mother and fetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with treatment doses of an efficacious antimalarial during the second and third trimesters of pregnancy at predefined intervals. Sulfadoxine–pyrimethamine is currently recommended, but high-level parasite resistance threatens its efficacy. Recent trials showed that amodiaquine, mefloquine and chloroquine–azithromycin are not suitable alternatives due to poor tolerability. This trial by Kakuru et al evaluated the artemisinin-based combination therapy (ACT), dihydroartemisinin–piperaquine, for IPTp. Dihydroartemisinin–piperaquine is already recommended by WHO for treatment of malaria in the second and third trimesters. A recent comparison of four ACTs for treatment of malaria in pregnancy in Africa showed that dihydroartemisinin–piperaquine had the best efficacy and a long post-treatment prophylactic effect, which supports...
    Keywords: Epidemiologic studies, Open access, Travel medicine, Tropical medicine (infectious diseases), Pregnancy
    Print ISSN: 1356-5524
    Electronic ISSN: 1473-6810
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
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    CEACAM1 Loss and Leptin Resistance [Molecular Bases of Disease] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-05-21
    Description: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance. Consistently, mice with null mutation of Ceacam1 (Cc1−/−) exhibit impaired insulin clearance with increased lipid production in liver and redistribution to white adipose tissue, leading to visceral obesity at 2 months of age. When the mutation is propagated on the C57/BL6J genetic background, total fat mass rises significantly with age, and glucose intolerance and systemic insulin resistance develop at 6 months of age. This study was carried out to determine the mechanisms underlying the marked increase in total fat mass in 6-month-old mutants. Indirect calorimetry analysis showed that Cc1−/− mice develop hyperphagia and a significant reduction in physical activity, in particular in the early hours of the dark cycle, during which energy expenditure is only slightly lower than in wild-type mice. They also exhibit increased triglyceride accumulation in skeletal muscle, due in part to incomplete fatty acid β-oxidation. Mechanistically, hypothalamic leptin signaling is reduced, as demonstrated by blunted STAT3 phosphorylation in coronal sections in response to an intracerebral ventricular injection of leptin. Hypothalamic fatty-acid synthase activity is also elevated in the mutants. Together, the data show that the increase in total fat mass in Cc1−/− mice is mainly attributed to hyperphagia and reduced spontaneous physical activity. Although the contribution of the loss of CEACAM1 from anorexigenic proopiomelanocortin neurons in the arcuate nucleus is unclear, leptin resistance and elevated hypothalamic fatty-acid synthase activity could underlie altered energy balance in these mice.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 5
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    Mitochondrial Protection Prevents Neurodegeneration in MS [Cell Biology] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-02-27
    Description: The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 6
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    Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study (2015)
    BMJ Publishing Group
    Details
    Publication Date: 2015-07-25
    Description: Introduction Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear. Materials and methods This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan–Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives. Results After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%–8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59). Discussions Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes.
    Keywords: Breast cancer, Colon cancer, Screening (oncology), Epidemiology
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 7
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    E. coli Topoisomerase IV E and an Inhibitor Binding Mode [Protein Structure and Folding] (2016)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2016-08-20
    Description: Bacterial topoisomerases are attractive antibacterial drug targets because of their importance in bacterial growth and low homology with other human topoisomerases. Structure-based drug design has been a proven approach of efficiently developing new antibiotics against these targets. Past studies have focused on developing lead compounds against the ATP binding pockets of both DNA gyrase and topoisomerase IV. A detailed understanding of the interactions between ligand and target in a solution state will provide valuable information for further developing drugs against topoisomerase IV targets. Here we describe a detailed characterization of a known potent inhibitor containing a 9H-pyrimido[4,5-b]indole scaffold against the N-terminal domain of the topoisomerase IV E subunit from Escherichia coli (eParE). Using a series of biophysical and biochemical experiments, it has been demonstrated that this inhibitor forms a tight complex with eParE. NMR studies revealed the exact protein residues responsible for inhibitor binding. Through comparative studies of two inhibitors of markedly varied potencies, it is hypothesized that gaining molecular interactions with residues in the α4 and residues close to the loop of β1-α2 and residues in the loop of β3-β4 might improve the inhibitor potency.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 8
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    Interaction Modes of the ASC Pyrin Domain [Signal Transduction] (2012)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2012-12-08
    Description: A key process underlying an innate immune response to pathogens or cellular stress is activation of members of the NOD-like receptor family, such as NLRP3, to assemble caspase-1-activating inflammasome complexes. Activated caspase-1 processes proinflammatory cytokines into active forms that mediate inflammation. Activation of the NLRP3 inflammasome is also associated with common diseases including cardiovascular disease, diabetes, chronic kidney disease, and Alzheimer disease. However, the molecular details of NLRP3 inflammasome assembly are not established. The adaptor protein ASC plays a key role in inflammasome assembly. It is composed of an N-terminal pyrin domain (PYD) and a C-terminal caspase recruitment domain, which are protein interaction domains of the death fold superfamily. ASC interacts with NLRP3 via a homotypic PYD interaction and recruits procaspase-1 via a homotypic caspase recruitment domain interaction. Here we demonstrate that ASC PYD contains two distinct binding sites important for self-association and interaction with NLRP3 and the modulatory protein POP1. Modeling of the homodimeric ASC PYD complex formed via an asymmetric interaction using both sites resembles a type I interaction found in other death fold domain complexes. This interaction mode also permits assembly of ASC PYDs into filaments. Furthermore, a type I binding mode is likely conserved in interactions with NLRP3 and POP1, because residues critical for interaction of ASC PYD are conserved in these PYDs. We also demonstrate that ASC PYD can simultaneously self-associate and interact with NLRP3, rationalizing the model whereby ASC self-association upon recruitment to NLRP3 promotes clustering and activation of procaspase-1.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 9
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    NMR Study of the Dengue Protease [Microbiology] (2013)
    The American Society for Biochemistry and Molecular Biology (ASBMB)
    Details
    Publication Date: 2013-05-04
    Description: The dengue virus (DENV) is a mosquito-borne pathogen responsible for an estimated 100 million human infections annually. The viral genome encodes a two-component trypsin-like protease that contains the cofactor region from the nonstructural protein NS2B and the protease domain from NS3 (NS3pro). The NS2B-NS3pro complex plays a crucial role in viral maturation and has been identified as a potential drug target. Using a DENV protease construct containing NS2B covalently linked to NS3pro via a Gly4-Ser-Gly4 linker (“linked protease”), previous x-ray crystal structures show that the C-terminal fragment of NS2B is remote from NS3pro and exists in an open state in the absence of an inhibitor; however, in the presence of an inhibitor, NS2B complexes with NS3pro to form a closed state. This linked enzyme produced NMR spectra with severe signal overlap and line broadening. To obtain a protease construct with a resolved NMR spectrum, we expressed and purified an unlinked protease complex containing a 50-residue segment of the NS2B cofactor region and NS3pro without the glycine linker using a coexpression system. This unlinked protease complex was catalytically active at neutral pH in the absence of glycerol and produced dispersed cross-peaks in a 1H-15N heteronuclear single quantum correlation spectrum that enabled us to conduct backbone assignments using conventional techniques. In addition, titration with an active-site peptide aldehyde inhibitor and paramagnetic relaxation enhancement studies demonstrated that the unlinked DENV protease exists predominantly in a closed conformation in solution. This protease complex can serve as a useful tool for drug discovery against DENV.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Published by The American Society for Biochemistry and Molecular Biology (ASBMB)
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  • 10
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    Stephen Vincent Lees (2014)
    BMJ Publishing Group
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    Publication Date: 2014-02-01
    Description: Stephen Vincent Lees spent his early years in Oldham and then Parbold, near Wigan. He was educated at Bolton School. His three passions in life were medicine, motor sport, and music. His father,...
    Topics: Medicine
    Published by BMJ Publishing Group
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