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1.  Outcomes of high volume cataract surgeries in a developing country 
The British Journal of Ophthalmology  2005;89(9):1079-1083.
Aim: To analyse the outcome of high volume cataract surgery in a developing country, community based, high volume eye hospital.
Methods: In a non-comparative interventional case series, the authors reviewed the surgical outcomes of 593 patients with cataract operated upon by three high volume surgeons on six randomly selected days. There were 318 female (54%) and 275 male (46%) patients. Their mean age was 59.57 (SD 10.13) years. The majority of the patients underwent manual small incision cataract surgery (manual SICS). Extracapsular cataract extraction with posterior chamber intraocular lens (ECCE-PCIOL) and intracapsular cataract extraction (ICCE) were also done on a few patients as clinically indicated.
Results: Best corrected visual acuity of ⩾6/18 was achieved in 94% of the 520 patients who could be followed up on the 40th postoperative day (88% follow up rate). Intraoperative and immediate postoperative complications as defined by OCTET occurred in 11 (1.9%) and 75 (12.6%) patients, respectively. Average surgical time of 3.75 minutes per case (16–18 cases per hour) was achieved. Statistically significant risk factors for outcomes were found to be age >60, sex, and surgeon.
Conclusion: High volume surgery using appropriate techniques and standardised protocols does not compromise quality of outcomes.
PMCID: PMC1772816  PMID: 16113352
cataract surgery; developing country
2.  Imaging of hepatocellular carcinoma: diagnosis, staging and treatment monitoring 
Cancer Imaging  2013;12(3):530-547.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Imaging is important for establishing a diagnosis of HCC. Several imaging modalities including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and angiography are used in evaluating patients with chronic liver disease and suspected HCC. CT, MRI and contrast-enhanced US have replaced biopsy for diagnosis of HCC. Dynamic multiphase contrast-enhanced CT or MRI is the current standard for imaging diagnosis of HCC. Functional imaging techniques such as perfusion CT and diffusion-weighted MRI provide additional information about tumor angiogenesis that may be useful for treatment. Techniques evaluating tissue mechanical properties such as magnetic resonance elastography, and acoustic radiation force impulse imaging are being explored for characterizing liver lesions. The role of PET in the evaluation of HCC is evolving with promise seen especially with the use of a hepatocyte-specific PET tracer. Imaging is also critical for assessment of treatment response and detection of recurrence following locoregional treatment. Knowledge of the post-treatment appearance of HCC is essential for correct interpretation. This review article provides an overview of the role of imaging in the diagnosis, staging and post-treatment follow-up of HCC.
PMCID: PMC3666429  PMID: 23400006
Hepatocellular carcinoma; CT; MRI; diagnosis; locoregional treatment
3.  Gastric carcinoma: imaging diagnosis, staging and assessment of treatment response 
Cancer Imaging  2013;13(2):212-227.
Gastric carcinoma (GC) is one of the most common causes of cancer-related death worldwide. Surgical resection is the only cure available and is dependent on the GC stage at presentation, which incorporates depth of tumor invasion, extent of lymph node and distant metastases. Accurate preoperative staging is therefore essential for optimal surgical management with consideration of preoperative and/or postoperative chemotherapy. Multidetector computed tomography (MDCT) with its ability to assess tumor depth, nodal disease and metastases is the preferred technique for staging GC. Endoscopic ultrasonography is more accurate for assessing the depth of wall invasion in early cancer, but is limited in the assessment of advanced local or stenotic cancer and detection of distant metastases. Magnetic resonance imaging (MRI), although useful for staging, is not proven to be effective. Positron emission tomography (PET) is most useful for detecting and characterizing distant metastases. Both MDCT and PET are useful for assessment of treatment response following preoperative chemotherapy and for detection of recurrence after surgical resection. This review article discusses the usefulness of imaging modalities for detecting, staging and assessing treatment response for GC and the potential role of newer applications including CT volumetry, virtual gastroscopy and perfusion CT in the management of GC.
PMCID: PMC3667568  PMID: 23722535
Gastric carcinoma; computed tomography; endoscopic ultrasonography; magnetic resonance imaging; positron emission tomography
4.  Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib 
Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit.
Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15); paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment.
There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients; some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS.
Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0405-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4332724
Regorafenib; Colorectal carcinoma; Pharmacodynamics; Plasma cell-free DNA
7.  All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins 
Nature methods  2014;11(8):825-833.
All-optical electrophysiology—spatially resolved simultaneous optical perturbation and measurement of membrane voltage—would open new vistas in neuroscience research. We evolved two archaerhodopsin-based voltage indicators, QuasAr1 and 2, which show improved brightness and voltage sensitivity, microsecond response times, and produce no photocurrent. We engineered a novel channelrhodopsin actuator, CheRiff, which shows improved light sensitivity and kinetics, and spectral orthogonality to the QuasArs. A co-expression vector, Optopatch, enabled crosstalk-free genetically targeted all-optical electrophysiology. In cultured neurons, we combined Optopatch with patterned optical excitation to probe back-propagating action potentials in dendritic spines, synaptic transmission, sub-cellular microsecond-timescale details of action potential propagation, and simultaneous firing of many neurons in a network. Optopatch measurements revealed homeostatic tuning of intrinsic excitability in human stem cell-derived neurons. In brain slice, Optopatch induced and reported action potentials and subthreshold events, with high signal-to-noise ratios. The Optopatch platform enables high-throughput, spatially resolved electrophysiology without use of conventional electrodes.
PMCID: PMC4117813  PMID: 24952910
8.  Recurrent gene loss correlates with the evolution of stomach phenotypes in gnathostome history 
The stomach, a hallmark of gnathostome evolution, represents a unique anatomical innovation characterized by the presence of acid- and pepsin-secreting glands. However, the occurrence of these glands in gnathostome species is not universal; in the nineteenth century the French zoologist Cuvier first noted that some teleosts lacked a stomach. Strikingly, Holocephali (chimaeras), dipnoids (lungfish) and monotremes (egg-laying mammals) also lack acid secretion and a gastric cellular phenotype. Here, we test the hypothesis that loss of the gastric phenotype is correlated with the loss of key gastric genes. We investigated species from all the main gnathostome lineages and show the specific contribution of gene loss to the widespread distribution of the agastric condition. We establish that the stomach loss correlates with the persistent and complete absence of the gastric function gene kit—H+/K+-ATPase (Atp4A and Atp4B) and pepsinogens (Pga, Pgc, Cym)—in the analysed species. We also find that in gastric species the pepsinogen gene complement varies significantly (e.g. two to four in teleosts and tens in some mammals) with multiple events of pseudogenization identified in various lineages. We propose that relaxation of purifying selection in pepsinogen genes and possibly proton pump genes in response to dietary changes led to the numerous independent events of stomach loss in gnathostome history. Significantly, the absence of the gastric genes predicts that reinvention of the stomach in agastric lineages would be highly improbable, in line with Dollo's principle.
PMCID: PMC3866411  PMID: 24307675
stomach; gene loss; proton pump; pepsinogen; gene duplication; gnathostomes
9.  Designer synthetic media for studying microbial-catalyzed biofuel production 
The fermentation inhibition of yeast or bacteria by lignocellulose-derived degradation products, during hexose/pentose co-fermentation, is a major bottleneck for cost-effective lignocellulosic biorefineries. To engineer microbial strains for improved performance, it is critical to understand the mechanisms of inhibition that affect fermentative organisms in the presence of major components of a lignocellulosic hydrolysate. The development of a synthetic lignocellulosic hydrolysate (SH) media with a composition similar to the actual biomass hydrolysate will be an important advancement to facilitate these studies. In this work, we characterized the nutrients and plant-derived decomposition products present in AFEX™ pretreated corn stover hydrolysate (ACH). The SH was formulated based on the ACH composition and was further used to evaluate the inhibitory effects of various families of decomposition products during Saccharomyces cerevisiae 424A (LNH-ST) fermentation.
The ACH contained high levels of nitrogenous compounds, notably amides, pyrazines, and imidazoles. In contrast, a relatively low content of furans and aromatic and aliphatic acids were found in the ACH. Though most of the families of decomposition products were inhibitory to xylose fermentation, due to their abundance, the nitrogenous compounds showed the most inhibition. From these compounds, amides (products of the ammonolysis reaction) contributed the most to the reduction of the fermentation performance. However, this result is associated to a concentration effect, as the corresponding carboxylic acids (products of hydrolysis) promoted greater inhibition when present at the same molar concentration as the amides.
Due to its complexity, the formulated SH did not perfectly match the fermentation profile of the actual hydrolysate, especially the growth curve. However, the SH formulation was effective for studying the inhibitory effect of various compounds on yeast fermentation.
The formulation of SHs is an important advancement for future multi-omics studies and for better understanding the mechanisms of fermentation inhibition in lignocellulosic hydrolysates. The SH formulated in this work was instrumental for defining the most important inhibitors in the ACH. Major AFEX decomposition products are less inhibitory to yeast fermentation than the products of dilute acid or steam explosion pretreatments; thus, ACH is readily fermentable by yeast without any detoxification.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-014-0179-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4311453  PMID: 25642283
Synthetic hydrolysate; Lignocellulose; AFEX; Yeast fermentation inhibition; Amides inhibition; Carboxylic acids inhibition; Pretreatment decomposition products; Hydrolysate composition
10.  Single-nucleotide polymorphism identification and genotyping in Camelina sativa 
Molecular Breeding  2015;35:35.
Camelina sativa, a largely relict crop, has recently returned to interest due to its potential as an industrial oilseed. Molecular markers are key tools that will allow C. sativa to benefit from modern breeding approaches. Two complementary methodologies, capture of 3′ cDNA tags and genomic reduced-representation libraries, both of which exploited second generation sequencing platforms, were used to develop a low density (768) Illumina GoldenGate single nucleotide polymorphism (SNP) array. The array allowed 533 SNP loci to be genetically mapped in a recombinant inbred population of C. sativa. Alignment of the SNP loci to the C. sativa genome identified the underlying sequenced regions that would delimit potential candidate genes in any mapping project. In addition, the SNP array was used to assess genetic variation among a collection of 175 accessions of C. sativa, identifying two sub-populations, yet low overall gene diversity. The SNP loci will provide useful tools for future crop improvement of C. sativa.
Electronic supplementary material
The online version of this article (doi:10.1007/s11032-015-0224-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4300397  PMID: 25620879
Camelina sativa; Reduced representation; SNP; Genetic mapping; Diversity; Polyploidy
11.  Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation 
Clinical Medicine Insights. Cardiology  2015;8(Suppl 3):13-21.
Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease. The combination of positron emission tomography (PET)/computed tomography (CT) has proven to be promising for the evaluation of atherosclerotic plaques and inflammation within the vessel walls. The utilization of the radiopharmaceutical tracer, 18F-fluorodeoxyglucose (18F-FDG), with PET/CT is invaluable in understanding the pathophysiological state involved in atherosclerosis. In this review, we will discuss the use of 18F-FDG-PET/CT imaging for the evaluation of atherosclerosis and inflammation both in preclinical and clinical studies. The potential of more specific novel tracers will be discussed. Finally, we will touch on the potential benefits of using the newly introduced combined PET/magnetic resonance imaging (MRI) for non-invasive imaging of atherosclerosis.
PMCID: PMC4294600
atherosclerosis; plaque; inflammation; positron emission tomography; computed tomography; 18F-FDG
12.  Accuracy of Brief Screening Tools for Identifying Postpartum Depression Among Adolescent Mothers 
Pediatrics  2014;133(1):e45-e53.
To evaluate the accuracy of the Edinburgh Postnatal Depression Scale (EPDS) and 3 subscales for identifying postpartum depression among primiparous adolescent mothers.
Mothers enrolled in a randomized controlled trial to prevent postpartum depression completed a psychiatric diagnostic interview and the 10-item EPDS at 6 weeks, 3 months, and 6 months postpartum. Three subscales of the EPDS were assessed as brief screening tools: 3-item anxiety subscale (EPDS-3), 7-item depressive symptoms subscale (EPDS-7), and 2-item subscale (EPDS-2) that resemble the Patient Health Questionnaire-2. Receiver operating characteristic curves and the areas under the curves for each tool were compared to assess accuracy. The sensitivities and specificities of each screening tool were calculated in comparison with diagnostic criteria for a major depressive disorder. Repeated-measures longitudinal analytical techniques were used.
A total of 106 women contributed 289 postpartum visits; 18% of the women met criteria for incident postpartum depression by psychiatric diagnostic interview. When used as continuous measures, the full EPDS, EPDS-7, and EPDS-2 performed equally well (area under the curve >0.9). Optimal cutoff scores for a positive depression screen for the EPDS and EPDS-7 were lower (≥9 and ≥7, respectively) than currently recommended cutoff scores (≥10). At optimal cutoff scores, the EPDS and EPDS-7 both had sensitivities of 90% and specificities of >85%.
The EPDS, EPDS-7, and EPDS-2 are highly accurate at identifying postpartum depression among adolescent mothers. In primary care pediatric settings, the EPDS and its shorter subscales have potential for use as effective depression screening tools.
PMCID: PMC3876181  PMID: 24344102
teenage; pregnancy; screening; postpartum depression; validity
13.  Acanthamoeba, fungal, and bacterial keratitis: a comparison of risk factors and clinical features 
American journal of ophthalmology  2013;157(1):10.1016/j.ajo.2013.08.032.
To determine risk factors and clinical signs that may differentiate between bacterial, fungal, and acanthamoeba keratitis among patients presenting with presumed infectious keratitis.
Hospital-based cross-sectional study.
We examined the medical records of 115 patients with laboratory-proven bacterial keratitis, 115 patients with laboratory-proven fungal keratitis, and 115 patients with laboratory-proven acanthamoeba keratitis seen at Aravind Eye Hospital, Madurai, India, from 2006–2011. Risk factors and clinical features of the three organisms were compared using multinomial logistic regression.
Of 95 patients with bacterial keratitis, 103 patients with fungal keratitis, and 93 patients with acanthamoeba keratitis who had medical records available for review, 287 (99%) did not wear contact lenses. Differentiating features were more common for acanthamoeba keratitis than for bacterial or fungal keratitis. Compared to patients with bacterial or fungal keratitis, patients with acanthamoeba keratitis were more likely to be younger and to have a longer duration of symptoms, and to have a ring infiltrate or disease confined to the epithelium.
Risk factors and clinical examination findings can be useful for differentiating acanthamoeba keratitis from bacterial and fungal keratitis.
PMCID: PMC3865075  PMID: 24200232
risk factors; disease attributes; India; corneal ulcer
14.  2′-Hydroxy ceramide in membrane homeostasis and cell signaling 
Ceramide is a precursor of complex sphingolipids and also plays important roles in cell signaling. With the advances in lipid analytical technologies, the structural diversity of ceramide species have become evident, and the complexity of cellular metabolism and function associated with distinct ceramide species is beginning to be revealed. One of the common structural variations of ceramide is 2′-hydroxylation of the N-acyl chain. Fatty acid 2-hydroxylase (FA2H) is one of the enzymes that introduce the hydroxyl group during de novo synthesis of ceramide. FA2H is essential for the normal functioning of the nervous system, as evidenced by demyelinating disorder associated with FA2H mutations in humans and mice. Studies of Fa2h mutant mice indicate that lack of 2′-hydroxy galactosylceramide in the myelin membrane results in loss of long-term stability of myelin and eventual demyelination. FA2H also regulates differentiation of various cell types (epidermal keratinocytes, schwannoma cells, adipocytes). When provided exogenously, ceramide induces apoptosis in many cell types. Interestingly, the effective concentration of 2′-hydroxy ceramide that induces apoptosis is significantly lower compared to non-hydroxy ceramide, and cells die much more rapidly, suggesting that 2′-hydroxy ceramide can mediate proapoptotic signaling distinct from non-hydroxy ceramide. Collectively, current evidence clearly shows that 2′-hydroxy ceramide and 2′-hydroxy complex sphingolipids have unique functions in membrane homeostasis and cell signaling that could not be substituted by non-hydroxy counterparts.
PMCID: PMC3946364  PMID: 24139861
Ceramide; 2-hydroxy-ceramide; sphingolipids; 2-hydroxy-sphingolipids
15.  The structure of dynamic GPCR signaling networks 
G protein coupled receptors (GPCRs) stimulate signaling networks that control a variety of critical physiological processes. Static information on the map of interacting signaling molecules at the basis of many cellular processes exists, but little is known about the dynamic operation of these networks. Here we focus on two questions. Firstly, is the network architecture underlying GPCR activated cellular processes unique in comparison to others such as transcriptional networks? We discuss how spatially localized GPCR signaling requires uniquely organized networks to execute polarized cell responses. Secondly, what approaches overcome challenges in deciphering spatiotemporally dynamic networks that govern cell behavior? We focus on recently developed microfluidic and optical approaches that allow GPCR signaling pathways to be triggered and perturbed with spatially and temporally variant input while simultaneously visualizing molecular and cellular responses. When integrated with mathematical modeling, these approaches can help identify design principles that govern cell responses to extracellular signals. We outline why optical approaches that allow the behavior of a selected cell to be orchestrated continually are particularly well suited for probing network organization in single cells.
PMCID: PMC4007319  PMID: 24741711
17.  Autopsy study of febrile deaths during monsoon at a tertiary care institute in India: Is malaria still a challenge? 
To utilise an autopsy-based approach to study the febrile deaths and deaths due to malaria during monsoon period of three years at a tertiary care teaching hospital in Mumbai, India.
Materials and Methods:
All autopsies done at the hospital during monsoon period from 2005 to 2007 when fever was the main presenting symptom were included in the study. Monsoon period was defined from June to September. A study on the duration of hospital stay of malaria deaths was also attempted.
There were 202 autopsies of febrile illness during the study period. Malaria resulted in 20.8% of the deaths besides other causes. A majority of deaths had intrapulmonary haemorrhages as the only pathological finding. Incidence of malaria deaths was more during monsoon period than the non-monsoon period. Plasmodium falciparum was the most common species responsible for malaria deaths while cerebral malaria was the most common mode of death. In 27% of the cases, post-mortem examination helped to arrive at the correct final diagnosis. In 88.1% of the cases, malaria deaths occurred within the first 24 hours of admission to the hospital.
The study reiterates the fact that malaria remains a preventable but major cause of death in India, predominantly during the monsoon period. The study also emphasises the importance of developing treatment protocols for malaria during such crucial times besides reinforcing the existing preventive measures.
PMCID: PMC4314863  PMID: 25657486
Autopsy; cerebral malaria; death; fever; malaria; monsoon rains
18.  Oral Lichenoid Lesions - A Review and Update 
Oral lichenoid lesions or reactions (OLLs/OLRs) are clinical and histological contemporaries of the classical oral lichen planus (OLP) that have generated a lot of debate in literature. In contrast to the idiopathic nature of OLP, OLLs are often associated with a known identifiable inciting factor. A superficial examination of these lesions clinically and histologically often reveals many similarities with OLP, but recent data indicate that distinguishable features do exist and form the basis of most classifications.
Aims and Objectives:
This paper attempts to collate available data in English literature on OLLs, highlight distinguishing features clinically and histologically and reflect on the malignant transformation potential and treatment modalities of the condition.
Materials and Methods:
A comprehensive search of medical and dental databases including PubMed, Ovid, Cochrane, Pubget, Researchgate, and non-medical search engines were utilized for the review. The search words included “oral lichen planus”, “oral lichenoid lesions”, “oral drug reactions”, “lichenoid dysplasia”, and “adverse effects of dental materials”.
Review Results:
OLLs seem to grossly underrated and most cases were clubbed as OLP. Definite clinical and histological features were uncovered to establish the identity of this lesion. Associations with dental restorative materials, drugs, and medications have been conclusively proven in the etiology of this condition. Specific markers are being utilized to diagnose the condition and monitor its progress.
Substantial differentiating features were uncovered to delineate OLLs as a separate entity with definite etiology, pathogenesis, and a high malignant transformation rate compared with OLP.
PMCID: PMC4318020  PMID: 25657414
Drug association; literature review.malignant transformation; oral lichenoid lesions; oral lichen planus; oral lichenoid reactions
20.  A framework for feature extraction from hospital medical data with applications in risk prediction 
BMC Bioinformatics  2014;15(1):425.
Feature engineering is a time consuming component of predictive modeling. We propose a versatile platform to automatically extract features for risk prediction, based on a pre-defined and extensible entity schema. The extraction is independent of disease type or risk prediction task. We contrast auto-extracted features to baselines generated from the Elixhauser comorbidities.
Hospital medical records was transformed to event sequences, to which filters were applied to extract feature sets capturing diversity in temporal scales and data types. The features were evaluated on a readmission prediction task, comparing with baseline feature sets generated from the Elixhauser comorbidities. The prediction model was through logistic regression with elastic net regularization. Predictions horizons of 1, 2, 3, 6, 12 months were considered for four diverse diseases: diabetes, COPD, mental disorders and pneumonia, with derivation and validation cohorts defined on non-overlapping data-collection periods.
For unplanned readmissions, auto-extracted feature set using socio-demographic information and medical records, outperformed baselines derived from the socio-demographic information and Elixhauser comorbidities, over 20 settings (5 prediction horizons over 4 diseases). In particular over 30-day prediction, the AUCs are: COPD—baseline: 0.60 (95% CI: 0.57, 0.63), auto-extracted: 0.67 (0.64, 0.70); diabetes—baseline: 0.60 (0.58, 0.63), auto-extracted: 0.67 (0.64, 0.69); mental disorders—baseline: 0.57 (0.54, 0.60), auto-extracted: 0.69 (0.64,0.70); pneumonia—baseline: 0.61 (0.59, 0.63), auto-extracted: 0.70 (0.67, 0.72).
The advantages of auto-extracted standard features from complex medical records, in a disease and task agnostic manner were demonstrated. Auto-extracted features have good predictive power over multiple time horizons. Such feature sets have potential to form the foundation of complex automated analytic tasks.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0425-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4310185  PMID: 25547173
Feature extraction; Risk prediction; Hospital data
21.  The Grafting of Universal T-Helper Epitopes Enhances Immunogenicity of HIV-1 Tat Concurrently Improving Its Safety Profile 
PLoS ONE  2014;9(12):e114155.
Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat-based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T-lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross-reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines.
PMCID: PMC4273983  PMID: 25531437
22.  Effect on β-galactosidase synthesis and burden on growth of osmotic stress in Escherichia coli 
SpringerPlus  2014;3:748.
Osmotic Shock is known to negatively affect growth rate along with an extended lag phase. The reduction in growth rate can be characterized as burden due to the osmotic stress. Studies have shown that production of unnecessary protein also burdens cellular growth. This has been demonstrated by growing Escherichia coli on glycerol in the presence of Isopropyl-β-D-1-thiogalactopyranoside (IPTG) to induce β-galactosidase synthesis which does not offer any benefit towards growth. The trade off between osmotic stress and burden on growth due to unnecessary gene expression has not been enumerated. The influence of osmotic stress on β-galactosidase synthesis and activity is not clearly understood. Here, we study the effect of salt concentration on β-galactosidase activity and burden on growth due to unnecessary gene expression in E.coli. We characterize the burden on growth in presence of varying concentrations of salt in the presence of IPTG using three strains, namely wild type, ∆lacI and ∆lacIlacZ mutant strains. We demonstrate that the salt concentrations, sensitively inhibits enzyme synthesis thereby influencing the burden on growth. In a wild type strain, addition of lactose into the medium demonstrated growth benefit at low salt concentration but not at higher concentrations. The extent of burden due to osmotic shock was higher in a lactose M9 medium than in a glycerol M9 medium. A linear relationship was observed between enzyme activity and burden on growth in various media types studied.
PMCID: PMC4320194
Escherichia coli; Osmotic stress; Unnecessary Gene Expression; IPTG; Growth rate
23.  Lignin triggers irreversible cellulase loss during pretreated lignocellulosic biomass saccharification 
Biotechnology for Biofuels  2014;7(1):175.
Non-productive binding of enzymes to lignin is thought to impede the saccharification efficiency of pretreated lignocellulosic biomass to fermentable sugars. Due to a lack of suitable analytical techniques that track binding of individual enzymes within complex protein mixtures and the difficulty in distinguishing the contribution of productive (binding to specific glycans) versus non-productive (binding to lignin) binding of cellulases to lignocellulose, there is currently a poor understanding of individual enzyme adsorption to lignin during the time course of pretreated biomass saccharification.
In this study, we have utilized an FPLC (fast protein liquid chromatography)-based methodology to quantify free Trichoderma reesei cellulases (namely CBH I, CBH II, and EG I) concentration within a complex hydrolyzate mixture during the varying time course of biomass saccharification. Three pretreated corn stover (CS) samples were included in this study: Ammonia Fiber Expansiona (AFEX™-CS), dilute acid (DA-CS), and ionic liquid (IL-CS) pretreatments. The relative fraction of bound individual cellulases varied depending not only on the pretreated biomass type (and lignin abundance) but also on the type of cellulase. Acid pretreated biomass had the highest levels of non-recoverable cellulases, while ionic liquid pretreated biomass had the highest overall cellulase recovery. CBH II has the lowest thermal stability among the three T. reesei cellulases tested. By preparing recombinant family 1 carbohydrate binding module (CBM) fusion proteins, we have shown that family 1 CBMs are highly implicated in the non-productive binding of full-length T. reesei cellulases to lignin.
Our findings aid in further understanding the complex mechanisms of non-productive binding of cellulases to pretreated lignocellulosic biomass. Developing optimized pretreatment processes with reduced or modified lignin content to minimize non-productive enzyme binding or engineering pretreatment-specific, low-lignin binding cellulases will improve enzyme specific activity, facilitate enzyme recycling, and thereby permit production of cheaper biofuels.
PMCID: PMC4272552  PMID: 25530803
Cellulosic biofuels; Cellulase adsorption; Enzymatic saccharification; Lignin; Non-specific enzyme binding
24.  Direct Metal Laser Sintering: A Digitised Metal Casting Technology 
Dental technology is undergoing advancements at a fast pace and technology is being imported from various other fields. One such imported technology is direct metal laser sintering technology for casting metal crowns. This article will discuss the process of laser sintering for making metal crowns and fixed partial dentures with a understanding of their pros and cons.
PMCID: PMC3792306  PMID: 24431766
Metal laser sintering; 3D printing technology; Laser sintered crowns
25.  The Complementary Roles of Dynamic Contrast Enhanced MRI and 18F-Fluorodeoxyglucose PET/CT for Imaging of Carotid Atherosclerosis 
European journal of nuclear medicine and molecular imaging  2013;40(12):10.1007/s00259-013-2518-4.
Inflammation and neovascularization in vulnerable atherosclerotic plaques are key risk factors for severe clinical events. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) are two non-invasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. Here, we study the relationship between DCE-MRI and 18F-FDG PET in the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD equivalent, recruited as a substudy of the dal-PLAQUE trial (NCT00655473).
The dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and 18F-FDG PET. Only baseline imaging and biomarkers data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and 18F-FDG PET data. As secondary endpoints, we evaluated the relationship between a) PET data and whole vessel anatomical MRI data, and b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model.
We found a significant inverse relationship between several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI with DCEMRI or 18F-FDG PET metrics.
In this study we observed a significant, weak inverse relationship between inflammation measured as 18F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. 18F-FDG PET and DCE-MRI may have complementary roles in identifying subjects at high risk for cardiovascular events in future clinical practice.
PMCID: PMC3823642  PMID: 23942908
DCE-MRI; PET/CT; atherosclerosis; inflammation; neovascularization

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