Correlation of intrinsic DNA curvature with DNA property periodicity

AbstractTwelve di- and trinucleotide parameter sets representing various structural, thermodynamic or bendability-related properties of DNA were tested in the prediction of DNA curvature applying Fourier analysis on curved and straight, A/T-type or G/C-type DNA sequence motifs. The best predictions were obtained with a new consensus bendability scale created by combining a nucleosome-based and a deoxyribonuclease I-based parameter set. Geometry calculations on the same sequences showed that the helical parameters derived from NMR structures can correctly predict curvature, as distinct from the parameters derived from X-ray crystallographic analysis

Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections

11 páginas, 5 figuras, 1 tablaPolyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0-5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient's drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.The authors were supported by projects SAF2016-77346-R and PID2019-104477RB-I00 awarded to IC and the grant BES-2017-079656 awarded to MM by the Spanish Ministry of Economy and Competitiveness and Ministry of Science, the ERC project 638553-TBACCELERATE awarded to IC, Spanish Government-FEDER Funds through CV contract CPII18/00031 and grant PI16/01511, and Generalitat Valencia Grant to I.C. (code PROMETEO/2020/012). The grant providers played no part in study design, data collection, and analysis, or the preparation of the manuscript.Peer reviewe

Predictive capabilities of baseline radiological findings for early and late disease outcomes within sensitive and multi-drug resistant tuberculosis cases

Purpose: This study compares performance of Timika Score to standardized, detailed radiologist observations of Chest X rays (CXR) for predicting early infectiousness and subsequent treatment outcome in drug sensitive (DS) or multi-drug resistant (MDR) tuberculosis cases. It seeks improvement in prediction of these clinical events through these additional observations. Method: This is a retrospective study analyzing cases from the NIH/NIAID supported TB Portals database, a large, trans-national, multi-site cohort of primarily drug-resistant tuberculosis patients. We analyzed patient records with sputum microscopy readings, radiologist annotated CXR, and treatment outcome including a matching step on important covariates of age, gender, HIV status, case definition, Body Mass Index (BMI), smoking, drug use, and Timika Score across resistance type for comparison. Results: 2142 patients with tuberculosis infection (374 with poor outcome and 1768 with good treatment outcome) were retrospectively reviewed. Bayesian ANOVA demonstrates radiologist observations did not show greater predictive ability for baseline infectiousness (0.77 and 0.74 probability in DS and MDR respectively); however, the observations provided superior prediction of treatment outcome (0.84 and 0.63 probability in DS and MDR respectively). Estimated lung abnormal area and cavity were identified as important predictors underlying the Timika Score’s performance. Conclusions: Timika Score simplifies the usage of baseline CXR for prediction of early infectiousness of the case and shows comparable performance to using detailed, standardized radiologist observations. The score’s utility diminishes for treatment outcome prediction and is exceeded by the usage of the detailed observations although prediction performance on treatment outcome decreases especially in MDR TB cases

Performance of Qure.ai automatic classifiers against a large annotated database of patients with diverse forms of tuberculosis.

Availability of trained radiologists for fast processing of CXRs in regions burdened with tuberculosis always has been a challenge, affecting both timely diagnosis and patient monitoring. The paucity of annotated images of lungs of TB patients hampers attempts to apply data-oriented algorithms for research and clinical practices. The TB Portals Program database (TBPP, https://TBPortals.niaid.nih.gov) is a global collaboration curating a large collection of the most dangerous, hard-to-cure drug-resistant tuberculosis (DR-TB) patient cases. TBPP, with 1,179 (83%) DR-TB patient cases, is a unique collection that is well positioned as a testing ground for deep learning classifiers. As of January 2019, the TBPP database contains 1,538 CXRs, of which 346 (22.5%) are annotated by a radiologist and 104 (6.7%) by a pulmonologist-leaving 1,088 (70.7%) CXRs without annotations. The Qure.ai qXR artificial intelligence automated CXR interpretation tool, was blind-tested on the 346 radiologist-annotated CXRs from the TBPP database. Qure.ai qXR CXR predictions for cavity, nodule, pleural effusion, hilar lymphadenopathy was successfully matching human expert annotations. In addition, we tested the 12 Qure.ai classifiers to find whether they correlate with treatment success (information provided by treating physicians). Ten descriptors were found as significant: abnormal CXR (p = 0.0005), pleural effusion (p = 0.048), nodule (p = 0.0004), hilar lymphadenopathy (p = 0.0038), cavity (p = 0.0002), opacity (p = 0.0006), atelectasis (p = 0.0074), consolidation (p = 0.0004), indicator of TB disease (p = < .0001), and fibrosis (p = < .0001). We conclude that applying fully automated Qure.ai CXR analysis tool is useful for fast, accurate, uniform, large-scale CXR annotation assistance, as it performed well even for DR-TB cases that were not used for initial training. Testing artificial intelligence algorithms (encapsulating both machine learning and deep learning classifiers) on diverse data collections, such as TBPP, is critically important toward progressing to clinically adopted automatic assistants for medical data analysis

Protein Engineering of \u3ci\u3ede Novo\u3c/i\u3e Protein with Predesigned Structure and Activity

Thede novo protein albebetin has been engineered (J. Mol. Biol. 1992,225, 927–931) to form a predesigned tertiary fold that has not yet been observed in natural proteins. Analysis of albebetin expressed in a cell-free system and inEscherichia coli revealed its compactness, relative stability, and the secondary structure close to the predesigned one. The blast-transforming biological activity of human interferon was grafted to albebetin by attachment of an eight amino acid interferon fragment to the N-terminus of albebetin next to its first methionine residue. The chimeric protein was expressed in a wheat germ cell-free translation system and tested for its structural properties, receptor binding, and biological activity. According to the tests, albebetin incorporating the active interferon fragment has a compact and relatively stable structure, and binds the murine thymocyte recep or effectively. It activates the blast transformation reaction of thymo yte cells even more efficiently than human interferon at low concentrations

The SBASE protein domain library, release 5.0: a collection of annotated protein sequence segments.

SBASE 5.0 is the fifth release of SBASE, a collection of annotated protein domain sequences that represent various structural, functional, ligand-binding and topogenic segments of proteins. SBASE was designed to facilitate the detection of functional homologies and can be searched with standard database-search programs. The present release contains over 79863 entries provided with standardized names and is cross-referenced to all major sequence databases and sequence pattern collections. The information is assigned to individual domains rather than to entire protein sequences, thus SBASE contains substantially more cross-references and links than do the protein sequence databases. The entries are clustered into >16 000 groups in order to facilitate the detection of distant similarities. SBASE 5.0 is freely available by anonymous 'ftp' file transfer from <ftp.icgeb.trieste.it >. Automated searching of SBASE with BLAST can be carried out with the WWW-server <http://www.icgeb.trieste.it/sbase/ >. and with the electronic mail server <[email protected] >which now also provides a graphic representation of the homologies. A related WWW-server <http://www.abc.hu/blast.html > and e-mail server <[email protected] > predicts SBASE domain homologies on the basis of SWISS-PROT searches

Radiologist observations of computed tomography (CT) images predict treatment outcome in TB Portals, a real-world database of tuberculosis (TB) cases.

The TB Portals program provides a publicly accessible repository of TB case data containing multi-modal information such as case clinical characteristics, pathogen genomics, and radiomics. The real-world resource contains over 3400 TB cases, primarily drug resistant cases, and CT images with radiologist annotations are available for many of these cases. The breadth of data collected offers a patient-centric view into the etiology of the disease including the temporal context of the available imaging information. Here, we analyze a cohort of new TB cases with available radiologist observations of CTs taken around the time of initial registration of the case into the database and with available follow up to treatment outcome of cured or died. Follow up ranged from 5 weeks to a little over 2 years consistent with the longest treatment regimens for drug resistant TB and cases were registered within the years 2008 to 2019. The radiologist observations were incorporated into machine learning pipelines to test various class balancing strategies on the performance of predictive models. The modeling results support that the radiologist observations are predictive of treatment outcome. Moreover, inferential statistical analysis identifies markers of TB disease spread as having an association with poor treatment outcome including presence of radiologist observations in both lungs, swollen lymph nodes, multiple cavities, and large cavities. While the initial results are promising, further data collection is needed to incorporate methods to mitigate potential confounding such as including additional model covariates or matching cohorts on covariates of interest (e.g. demographics, BMI, comorbidity, TB subtype, etc.). Nonetheless, the preliminary results highlight the utility of the resource for hypothesis generation and exploration of potential biomarkers of TB disease severity and support these additional data collection efforts

The \u3cem\u3ede Novo\u3c/em\u3e Protein with Grafted Biological Function: Transferring of Interferon Blast-transforming Activity to Albebetin

The de novo protein albebetin has been designed recently to form a predetermined tertiary fold that has not yet been observed in natural proteins. An eight amino acid fragment (131–138) of human interferon α2 carrying the blasttransforming activity of the protein was attached to the N-terminus of albebetin next to its initiatory methionine residue. The gene of chimeric protein was expressed in a wheat germ cell-free translation system and synthesized protein was tested for its compactness and stability. Its ability for receptor binding was also studied. We have shown that albebetin with attached octapeptide is practically as compact as natural proteins of corresponding molecular weight and possesses high stability toward the urea-induced unfolding. It binds murine thymocyte receptor at a high affinity and activates the thymocyte blast transformation efficiently at a concentration of 10-11 M