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author:("Haq, imrad")
2.  Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB 
Human Molecular Genetics  2013;22(22):4616-4626.
Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded protein response. We use both cell lines and Drosophila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is degraded by UBE2g2 (E2) and gp78 (E3) ligases. The degradation of G392E neuroserpin results from SREBP-dependent activation of the cholesterol biosynthetic pathway in cells that express polymers of neuroserpin (G392E). Inhibition of HMGCoA reductase, the limiting enzyme of the cholesterol biosynthetic pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neurones. Our data reveal a reciprocal relationship between cholesterol biosynthesis and the clearance of mutant neuroserpin. This represents the first description of a link between sterol metabolism and modulation of the proteotoxicity mediated by the EOR.
doi:10.1093/hmg/ddt310
PMCID: PMC3889810  PMID: 23814041
3.  Reactive centre loop mutants of α-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway 
Bioscience Reports  2013;33(3):e00046.
The common severe Z mutation (E342K) of α1-antitrypsin forms intracellular polymers that are associated with liver cirrhosis. The native fold of this protein is well-established and models have been proposed from crystallographic and biophysical data for the stable inter-molecular configuration that terminates the polymerization pathway. Despite these molecular ‘snapshots’, the details of the transition between monomer and polymer remain only partially understood. We surveyed the RCL (reactive centre loop) of α1-antitrypsin to identify sites important for progression, through intermediate states, to polymer. Mutations at P14P12 and P4, but not P10P8 or P2P1′, resulted in a decrease in detectable polymer in a cell model that recapitulates the intracellular polymerization of the Z variant, consistent with polymerization from a near-native conformation. We have developed a FRET (Förster resonance energy transfer)-based assay to monitor polymerization in small sample volumes. An in vitro assessment revealed the position-specific effects on the unimolecular and multimolecular phases of polymerization: the P14P12 region self-inserts early during activation, while the interaction between P6P4 and β-sheet A presents a kinetic barrier late in the polymerization pathway. Correspondingly, mutations at P6P4, but not P14P12, yield an increase in the overall apparent activation energy of association from ~360 to 550 kJ mol−1.
doi:10.1042/BSR20130038
PMCID: PMC3691886  PMID: 23659468
cirrhosis; emphysema; FRET; intermediate; polymerization; serpin; ANS, 8-anilinonaphthalene-1-sulfonic acid; bis-ANS, 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid; FRET, Förster resonance energy transfer; NTA, nitrilotriacetic acid; RCL, reactive centre loop; SI, stoichiometry of inhibition; Tm,midpoint of thermal denaturation
4.  A 43-year-old woman on triptorelin presenting with pseudotumor cerebri: a case report 
Introduction
To the best of our knowledge, this is the first time triptorelin has been reported to cause benign intracranial hypertension.
Case presentation
A 43-year-old Caucasian woman who suffered from chronic menorrhagia was started on triptorelin, a gonadotrophin-releasing hormone analogue. Three days later, she developed gradually worsening headaches accompanied by bilateral visual disturbance. Examination revealed bilateral papilledema and enlarged blind spots on her visual fields. A diagnosis of benign intracranial hypertension was made and confirmed on magnetic resonance imaging.
Conclusion
We recommend that patients at high risk (women who are overweight and of reproductive age) who are using any gonadotrophin-releasing hormone analogue (for example, triptorelin) should be periodically monitored for the possible development of benign intracranial hypertension.
doi:10.1186/1752-1947-6-122
PMCID: PMC3410770  PMID: 22554236
5.  Light through the dark ages: The Arabist contribution to Western ophthalmology 
Oman Journal of Ophthalmology  2012;5(2):75-78.
Europe in the Middle Ages had descended into a dark period, and none more so than in the field of medicine. The rich heritage of the pagan Greeks had largely been ignored or forgotten by medieval Europe, and instead it was the early Arabist world that embraced and developed the Hellenistic medical teachings, emerging not only as guardians of the classical learning still existent, but also as pioneers and innovators, restricted only by the development in the associated fields. The Kahhal (), or Oculist or Eye Specialist, had a privileged place in royal households, especially during the Abbasid period, in contrast to the time of Galen, whose writings referred to ophthalmologists in a rather derogatory manner. This elevated standing in the medical profession allowed Arabist scholars to cultivate remarkably erudite techniques and exceptional texts, which were used until very recently.
doi:10.4103/0974-620X.99367
PMCID: PMC3441032  PMID: 22993459
Arabist; medicine; ophthalmology; surgery
6.  Fungal Recognition Enhances Mannose Receptor Shedding through Dectin-1 Engagement* 
The Journal of Biological Chemistry  2011;286(10):7822-7829.
The mannose receptor (MR) is an endocytic type I membrane molecule with a broad ligand specificity that is involved in both hemostasis and pathogen recognition. Membrane-anchored MR is cleaved by a metalloproteinase into functional soluble MR (sMR) composed of the extracellular domains of intact MR. Although sMR production was initially considered a constitutive process, enhanced MR shedding has been observed in response to the fungal pathogen Pneumocystis carinii. In this work, we have investigated the mechanism mediating enhanced MR shedding in response to fungi. We show that other fungal species, including Candida albicans and Aspergillus fumigatus, together with zymosan, a preparation of the cell wall of Saccharomyces cerevisiae, mimic the effect of P. carinii on sMR production and that this effect takes place mainly through β-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate β-glucan requires expression of dectin-1. Our data, obtained using specific inhibitors, are consistent with the canonical Syk-mediated pathway triggered by dectin-1 being mainly responsible for inducing MR shedding, with Raf-1 being partially involved. As in the case of steady-state conditions, MR shedding in response to C. albicans and β-glucan particles requires metalloprotease activity. The induction of MR shedding by dectin-1 has clear implications for the role of MR in fungal recognition, as sMR was previously shown to retain the ability to bind fungal pathogens and can interact with numerous host molecules, including lysosomal hydrolases. Thus, MR cleavage could also impact on the magnitude of inflammation during fungal infection.
doi:10.1074/jbc.M110.185025
PMCID: PMC3048669  PMID: 21205820
ADAM; ADAMTS; Fungi; Inflammation; Lectin; Macrophage; Metalloprotease; Mouse; Shedding
7.  Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population 
BMC Medical Genetics  2010;11:7.
Background
Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.
Methods
To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.
Results
Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.
Conclusions
Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.
doi:10.1186/1471-2350-11-7
PMCID: PMC2820470  PMID: 20078883
8.  Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease 
Thorax  2012;68(7):670-676.
Background
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality. The most widely used marker of disease severity and progression is FEV1. However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD. Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD. Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.
Methods
Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.
Results
There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality. Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity. The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear. Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.
Conclusions
Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality.
doi:10.1136/thoraxjnl-2012-201871
PMCID: PMC3711372  PMID: 22744884
Fibrinogen; inflammation; COPD; biomarker

Results 1-8 (8)