Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model’s structure and in silico “experimental” data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation

A Bispecific Antibody Based Assay Shows Potential for Detecting Tuberculosis in Resource Constrained Laboratory Settings

The re-emergence of tuberculosis (TB) as a global public health threat highlights the necessity of rapid, simple and inexpensive point-of-care detection of the disease. Early diagnosis of TB is vital not only for preventing the spread of the disease but also for timely initiation of treatment. The later in turn will reduce the possible emergence of multi-drug resistant strains of Mycobacterium tuberculosis. Lipoarabinomannan (LAM) is an important non-protein antigen of the bacterial cell wall, which is found to be present in different body fluids of infected patients including blood, urine and sputum. We have developed a bispecific monoclonal antibody with predetermined specificities towards the LAM antigen and a reporter molecule horseradish peroxidase (HRPO). The developed antibody was subsequently used to design a simple low cost immunoswab based assay to detect LAM antigen. The limit of detection for spiked synthetic LAM was found to be 5.0 ng/ml (bovine urine), 0.5 ng/ml (rabbit serum) and 0.005 ng/ml (saline) and that for bacterial LAM from M. tuberculosis H37Rv was found to be 0.5 ng/ml (rabbit serum). The assay was evaluated with 21 stored clinical serum samples (14 were positive and 7 were negative in terms of anti-LAM titer). In addition, all 14 positive samples were culture positive. The assay showed 100% specificity and 64% sensitivity (95% confidence interval). In addition to good specificity, the end point could be read visually within two hours of sample collection. The reported assay might be used as a rapid tool for detecting TB in resource constrained laboratory settings

Molecular characterization of hepatitis B virus X gene in chronic hepatitis B patients

BACKGROUND: HBV-X protein is associated with the pathogenesis of HBV related diseases, specially in hepatocellular carcinomas of chronic patients. Genetic variability of the X gene includes genotypic specific variations and mutations emerging during chronic infection. Its coding sequence overlaps important regions for virus replication, including the basal core promoter. Differences in the X gene may have implications in biological functions of the protein and thus, affect the evolution of the disease. There are controversial results about the consequences of mutations in this region and their relationship with pathogenesis. The purpose of this work was to describe the diversity of HBV-X gene in chronic hepatitis patients infected with different genotypes, according to liver disease. METHODS: HBV-X gene was sequenced from chronic hepatitis B patient samples, analyzed by phylogeny and genotyped. Nucleotide and aminoacid diversity was determined calculating intragenetic distances. Mutations at 127, 130 and 131 aminoacids were considered in relation to liver disease. RESULTS: The most prevalent genotype detected in this cohort was F (F1 and F4), followed by D and A. Most of the samples corresponding to genotypes A and F1 were HBeAg(+) and for genotypes D and F4, HBeAg(−) samples were represented in a higher percentage. Intragenetic distance values were higher in HBeAg(−) than in positive samples for all genotypes, and lower in overlapped regions, compared to single codification ones. Nucleotide and aminoacid diversities were higher in HBeAg(−), than in HBeAg(+) samples. CONCLUSIONS: Independently of the infecting genotypes, mutations at any of 127, 130 and/or 131 aminoacid positions and HBeAg(−) status were associated with mild liver disease in this cohort

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients

AimsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19.Methods and resultsThis analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P ConclusionThis study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease

Levodopa-Induced Dyskinesia Is Associated with Increased Thyrotropin Releasing Hormone in the Dorsal Striatum of Hemi-Parkinsonian Rats

Background Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition. Methodology/Principal Findings Quantitative real-time polymerase chain reaction (PCR) was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH) was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes. Conclusions/Significance TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.Morris K. Udall Center for Excellence in Parkinson’s Research at MGH/MITNational Institutes of Health (U.S.) (NIH NS38372)American Parkinson Disease Association, Inc.University of Alabama at BirminghamMassachusetts General HospitalNational Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIDDK/NIH grant R01 DK58148)National Institute of Neurological Disorders and Stroke (U.S.) (R01 NINDS/NIH grant NS045231)Stanley H. and Sheila G. Sydney FundMichael J. Fox Foundation for Parkinson's Researc

Rationale and design of XAMOS: noninterventional study of rivaroxaban for prophylaxis of venous thromboembolism after major hip and knee surgery

Alexander GG Turpie,1 André C Schmidt,2 Reinhold Kreutz,3 Michael R Lassen,4 Waheed Jama,1,2 Lorenzo Mantovani,5 Sylvia Haas61Department of Medicine, Hamilton Health Sciences, General Division, Ontario, Canada; 2Bayer Healthcare Pharmaceuticals, Global Development, Berlin, Germany; 3Institut für Klinische Pharmakologie und Toxikologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; 4Department of Orthopaedics, Spine Clinic, Clinical Trial Unit, Hørsholm Hospital, University of Copenhagen, Hørsholm, Denmark; 5Faculty of Pharmacy, Federico II University of Naples, Naples, Italy; 6Institut für Experimentelle Onkologie und Therapieforschung, TU München, GermanyAbstract: Venous thromboembolism is a frequent and potentially life-threatening complication of orthopedic surgery. Rivaroxaban is an oral direct factor Xa inhibitor, which was shown to be effective for the prevention of venous thromboembolism after elective hip and knee arthroplasty in the RECORD study program. Rivaroxaban has the potential to overcome the limitations of the current standards of care in the prevention of venous thromboembolism. XAMOS (Xarelto® in the prophylaxis of post-surgical venous thromboembolism after elective major orthopedic surgery of hip or knee) is an international, noninterventional, parallel-group study to gain insight into the safety (major bleeding, side effects) and effectiveness (prevention of symptomatic thromboembolic events) of rivaroxaban in daily clinical practice. XAMOS will follow 15,000 patients after major orthopedic surgery in approximately 200 centers worldwide, with about 7500 patients receiving rivaroxaban and about 7500 standard of care. XAMOS will supplement the clinical data obtained in the Phase III RECORD 1, 2, 3, and 4 trials in which rivaroxaban was shown to be superior for the primary efficacy endpoints, and with a safety profile similar to that of enoxaparin after hip or knee replacement surgery. XAMOS was started in 2009 and will complete recruitment and follow-up in 2011.Keywords: rivaroxaban, venous thromboembolism, effectiveness, oral anticoagulatio