Host-specific differences in the membrane fusion activity of influenza A viruses

The transmission of influenza A viruses from avian to other species involves numerous adaptive processes to overcome the species barrier. One major determinant of host-range restriction is the viral hemagglutinin (HA). HA plays a crucial role in virus entry into the host cell by mediating receptor-binding and membrane fusion. Virus adaptation to mammals results in alteration of receptor-binding specificity. There is growing evidence that the HA-mediated membrane fusion activity contributes to host range restriction as well. This study aimed to identify host specific differences in membrane fusion properties and to characterise potential alterations during interspecies transmission. In the first part of the thesis Eurasian avian-like swine viruses that emerged by transmission of an avian H1N1 virus in pigs in the late 1970s in Europe were shown to have a higher pH optimum of HA-mediated fusion (pH 5.1-5.4) and a decreased HA stability when compared to avian precursors (pH 4.9-5.2). These results indicate that this avian-to-swine transmission was accompanied by changes in HA stability. Sequence comparison revealed eight amino acid substitutions that separate the HA of early avian-like swine viruses from their putative avian precursor. Furthermore, mutations in one of these positions contribute to the low stability phenotype. In agreement with natural avian-to-swine transmission, experimental adaptation of a potential avian precursor of the avian-like swine lineage to pigs resulted in a decreased HA stability. This states the first formal proof that viral membrane fusion and stability properties change during interspecies transmission. The second part of the thesis investigated differences in membrane fusion activity among different avian virus species. Comparison of H7 viruses from wild birds and domestic poultry suggests that Eurasian H7 poultry viruses have a higher pH optimum of membrane fusion (pH 6.2) and thus possess a lower stability than H7 viruses from wild birds (pH 5.2). Moreover, all tested Eurasian H7 viruses express a lower HA stability than HAs from other subtypes (H2, H3, H4, H5, H13, H14 und H16). Previous studies indicate that H5 viruses with low HA stability replicate but do not transmit via respiratory droplets in the ferret model (Imai et al., 2012; Herfst et al., 2012). Thus, it is feasible, that H7 viruses originated from poultry are restricted in ferrets and humans to similar extend. In the last part, fusion properties of human pandemic and zoonotic viruses were studied. HAs of pandemic viruses from the last century initiated fusion in a narrow pH range between pH 5.0 and 5.2. In contrast, the swine-origin 2009 pandemic virus HA starts to fuse at a pH 0.2 units higher, which might be due to the swine origin of this HA. This further suggests that fusion characteristics continue to adapt in the course of subsequent circulation. The pH optimum of fusion of a zoonotic human H7N9 (2013) virus represents an intermediate in that it is lower when compared to putative ancestors circulating in wild birds, but still higher than that of typical human-adapted viruses. This may account for limited human-to-human transmission observed for this virus. In order to further investigate which changes in HA are needed for the emergence of avian viruses in humans, HA substitutions separating the 1968 Hong Kong pandemic virus HA from the putative avian precursor were examined. In addition to the well-known switch in receptor specificity, binding avidity changed prior to or during the emergence in humans. In this study, no difference in viral stability was observed between the pandemic virus and the putative avian precursor. This indicates that the avian ancestor was already sufficiently stable to facilitate replication and transmission in humans. In sum, this study shows that membrane fusion properties vary between host species and alter during influenza A virus emergence in new hosts. This suggests HA-mediated fusion and HA stability to act as host range restriction factors. Alterations in membrane fusion activity and viral stability may not be essential for initial infection of new host individuals. However, an optimal stability seems to be necessary to facilitate transmission within populations of new host species

Reconstructing Human Motion

This thesis presents methods for reconstructing human motion in a variety of applications and begins with an introduction to the general motion capture hardware and processing pipeline. Then, a data-driven method for the completion of corrupted marker-based motion capture data is presented. The approach is especially suitable for challenging cases, e.g., if complete marker sets of multiple body parts are missing over a long period of time. Using a large motion capture database and without the need for extensive preprocessing the method is able to fix missing markers across different actors and motion styles. The approach can be used for incrementally increasing prior-databases, as the underlying search technique for similar motions scales well to huge databases. The resulting clean motion database could then be used in the next application: a generic data-driven method for recognizing human full body actions from live motion capture data originating from various sources. The method queries an annotated motion capture database for similar motion segments, able to handle temporal deviations from the original motion. The approach is online-capable, works in realtime, requires virtually no preprocessing and is shown to work with a variety of feature sets extracted from input data including positional data, sparse accelerometer signals, skeletons extracted from depth sensors and even video data. Evaluation is done by comparing against a frame-based Support Vector Machine approach on a freely available motion database as well as a database containing Judo referee signal motions. In the last part, a method to indirectly reconstruct the effects of the human heart's pumping motion from video data of the face is applied in the context of epileptic seizures. These episodes usually feature interesting heart rate patterns like a significant increase at seizure start as well as seizure-type dependent drop-offs near the end. The pulse detection method is evaluated for applicability regarding seizure detection in a multitude of scenarios, ranging from videos recorded in a controlled clinical environment to patient supplied videos of seizures filmed with smartphones

If motion sounds: Movement sonification based on inertial sensor data

Within last years, movement sonification turned out to be an appropriate support for motor perception and motor control that can display physical motion in a very rich and direct way. But how should movement sonification be configured to support motor learning? The appropriate selection of movement parameters and their transformation into characteristic motion features is essential for an auditory display to become effective. In this paper, we introduce a real-time sonification framework for all common MIDI environments based on acceleration and orientation data from inertial sensors. Fundamental processing steps to transform motion information into meaningful sound will be discussed. The proposed framework of inertial motion capturing, kinematic parameter selection and possible kinematic acoustic mapping provides a basis for mobile real-time movement sonification which is a prospective powerful training tool for rehabilitation and sports and offers a broad variety of application possibilities.EU/EFRE/W2-8011866

Analysis of ceiling effects occurring with speech recognition tests in adult cochlear-implanted patients

This article presents a simple method of analysing speech test scores which are biased through ceiling effects. Eighty postlingually deafened adults implanted with a MED-EL COMBI 40/40+ cochlear implant (CI) were administered a numbers test and a sentence test at initial device activation and at 1, 3, 6, 12 and 24 months thereafter. As a measure for speech recognition performance, the number of patients who scored at the `ceiling level' (i.e. at least 95% correct answers) was counted at each test interval. Results showed a quick increase in this number soon after device activation as well as a continuous improvement over time ( numbers test: 1 month: 51%; 6 months: 73%; 24 months: 88%; sentence test: 1 month: 33%; 6 months: 49%; 24 months: 64%). The new method allows for the detection of speech recognition progress in CI patient samples even at late test intervals, where improvement curves based on averaged scores are usually assuming a flat shape. Copyright (C) 2004 S. Karger AG, Basel

Monocyte, Lymphocyte and Neutrophil Ratios – Easy-to-Use Biomarkers for the Diagnosis of Pediatric Tuberculosis

Background: The neutrophil-to-lymphocyte-ratio (NLR), neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) and monocyte-to-lymphocyte-ratio (MLR) may have diagnostic potential for tuberculosis (TB). Methods: Data of two prospective multicenter studies in Switzerland were used, which included children <18 years with TB exposure, infection or disease or with febrile non-TB lower-respiratory-tract infection (nTB-LRTI). Results: Of the 389 children included 25 (6.4%) had TB disease, 12 (3.1%) TB infection, 28 (7.2%) were healthy TB exposed and 324 (83.3%) nTB-LRTI. Median (IQR) NLR was highest with 2.0 (1.2, 2.2) in children with TB disease compared to TB exposed [0.8 (0.6, 1.3); P = 0.002] and nTB-LRTI [0.3 (0.1, 1.0); P < 0.001]. Median (IQR) NMLR was highest with 1.4 (1.2, 1.7) in children with TB disease compared to healthy exposed [0.7 (0.6, 1.1); P = 0.003] and children with nTB-LRTI [0.2 (0.1, 0.6); P < 0.001). Receiver operating characteristic curves to detect TB disease compared to nTB-LRTI for NLR and NMLR had an area under the curve of 0.82 and 0.86, the sensitivity of 88% and 88%, and specificity of 71% and 76%, respectively. Conclusion: NLR and NMLR are promising, easy-to-obtain diagnostic biomarkers to differentiate children with TB disease from other lower respiratory tract infections. These results require validation in a larger study and in settings with high and low TB endemicity