NASA Tech Briefs Index, 1977, volume 2, numbers 1-4

Announcements of new technology derived from the research and development activities of NASA are presented. Abstracts, and indexes for subject, personal author, originating center, and Tech Brief number are presented for 1977

Integrative Transkingdom Analysis of the Gut Microbiome in Antibiotic Perturbation and Critical Illness

cited By 2Bacterial microbiota play a critical role in mediating local and systemic immunity, and shifts in these microbial communities have been linked to impaired outcomes in critical illness. Emerging data indicate that other intestinal organisms, including bacteriophages, viruses of eukaryotes, fungi, and protozoa, are closely interlinked with the bacterial microbiota and their host, yet their collective role during antibiotic perturbation and critical illness remains to be elucidated. We employed multi-omics factor analysis (MOFA) to systematically integrate the bacterial (16S rRNA), fungal (intergenic transcribed spacer 1 rRNA), and viral (virus discovery next generation sequencing) components of the intestinal microbiota of 33 critically ill patients with and without sepsis and 13 healthy volunteers. In addition, we quantified the absolute abundances of bacteria and fungi using 16S and 18S rRNA PCRs and characterized the short-chain fatty acids (SCFAs) butyrate, acetate, and propionate using nuclear magnetic resonance spectroscopy. We observe that a loss of the anaerobic intestinal environment is directly correlated with an overgrowth of aerobic pathobionts and their corresponding bacteriophages as well as an absolute enrichment of opportunistic yeasts capable of causing invasive disease. We also observed a strong depletion of SCFAs in both disease states, which was associated with an increased absolute abundance of fungi with respect to bacteria. Therefore, these findings illustrate the complexity of transkingdom changes following disruption of the intestinal bacterial microbiome. IMPORTANCE While numerous studies have characterized antibiotic-induced disruptions of the bacterial microbiome, few studies describe how these disruptions impact the composition of other kingdoms such as viruses, fungi, and protozoa. To address this knowledge gap, we employed MOFA to systematically integrate viral, fungal, and bacterial sequence data from critically ill patients (with and without sepsis) and healthy volunteers, both prior to and following exposure to broad-spectrum antibiotics. In doing so, we show that modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone, enabling the overgrowth of potentially invasive fungi and viruses. While numerous preclinical studies have described similar findings in vitro, we confirm these observations in humans using an integrative analytic approach. These findings underscore the potential value of multi-omics data integration tools in interrogating how different components of the microbiota contribute to disease states. In addition, our findings suggest that there is value in further studying potential adjunctive therapies using anaerobic bacteria or SCFAs to reduce fungal expansion after antibiotic exposure, which could ultimately lead to improved outcomes in the intensive care unit (ICU).Peer reviewe

Predicting and analyzing HIV-1 adaptation to broadly neutralizing antibodies and the host immune system using machine learning

Thanks to its extraordinarily high mutation and replication rate, the human immunodeficiency virus type 1 (HIV-1) is able to rapidly adapt to the selection pressure imposed by the host immune system or antiretroviral drug exposure. With neither a cure nor a vaccine at hand, viral control is a major pillar in the combat of the HIV-1 pandemic. Without drug exposure, interindividual differences in viral control are partly influenced by host genetic factors like the human leukocyte antigen (HLA) system, and viral genetic factors like the predominant coreceptor usage of the virus. Thus, a close monitoring of the viral population within the patients and adjustments in the treatment regimens, as well as a continuous development of new drug components are indispensable measures to counteract the emergence of viral escape variants. To this end, a fast and accurate determination of the viral adaptation is essential for a successful treatment. This thesis is based upon four studies that aim to develop and apply statistical learning methods to (i) predict adaptation of the virus to broadly neutralizing antibodies (bNAbs), a promising new treatment option, (ii) advance antibody-mediated immunotherapy for clinical usage, and (iii) predict viral adaptation to the HLA system to further understand the switch in HIV-1 coreceptor usage. In total, this thesis comprises several statistical learning approaches to predict HIV-1 adaptation, thereby, enabling a better control of HIV-1 infections.Dank seiner außergewöhnlich hohen Mutations- und Replikationsrate ist das humane Immundefizienzvirus Typ 1 (HIV-1) in der Lage sich schnell an den vom Immunsystem des Wirtes oder durch die antiretrovirale Arzneimittelexposition ausgeübten Selektionsdruck anzupassen. Da weder ein Heilmittel noch ein Impfstoff verfügbar sind, ist die Viruskontrolle eine wichtige Säule im Kampf gegen die HIV-1-Pandemie. Ohne Arzneimittelexposition werden interindividuelle Unterschiede in der Viruskontrolle teilweise durch genetische Faktoren des Wirts wie das humane Leukozytenantigensystem (HLA) und virale genetische Faktoren wie die vorherrschende Korezeptornutzung des Virus beeinflusst. Eine genaue Überwachung der Viruspopulation innerhalb des Patienten, gegebenfalls Anpassungen der Behandlungsschemata sowie eine kontinuierliche Entwicklung neuer Wirkstoffkomponenten sind daher unerlässliche Maßnahmen, um dem Auftreten viraler Fluchtvarianten entgegenzuwirken. Für eine erfolgreiche Behandlung ist eine schnelle und genaue Bestimmung der Anpassung einer Variante essentiell. Die Thesis basiert auf vier Studien, deren Ziel es ist statistische Lernverfahren zu entwickeln und anzuwenden, um (1) die Anpassung von HIV-1 an breit neutralisierende Antikörper, eine neuartige vielversprechende Therapieoption, vorherzusagen, (2) den Einsatz von Antikörper-basierte Immuntherapien für den klinischen Einsatz voranzutreiben, und (3) die virale Anpassung von HIV-1 an das HLA-System vorherzusagen, um den Wechsel der HIV-1 Korezeptornutzung besser zu verstehen. Zusammenfassend umfasst diese Thesis mehrere statistische Lernverfahrenansätze, um HIV Anpassung vorherzusagen, wodurch eine bessere Kontrolle von HIV-1 Infektionen ermöglicht wird

Hidden Markov Models

Hidden Markov Models (HMMs), although known for decades, have made a big career nowadays and are still in state of development. This book presents theoretical issues and a variety of HMMs applications in speech recognition and synthesis, medicine, neurosciences, computational biology, bioinformatics, seismology, environment protection and engineering. I hope that the reader will find this book useful and helpful for their own research

Detection of particles, bacteria and viruses using consumer optoelectronic components

The focus of this thesis is on the design, development and validation of two novel photonic sensors for the detection and characterisation of industrial and biological samples. The first one is a PSA in a collimated beam configuration using an innovative angular spatial filter, and a consumer electronic camera similar to that used in a smartphone. The small form factor angular spatial filter allows for the collection of diffused light from particles up to predefined discrete angles. By using angularly resolved scattering images acquired by the camera, a machine learning (ML) algorithm predicts the volume median diameter of the particles. Our system has achieved a mean absolute percentage error of only 0.72% for spherical particles in solution with sizes greater than 10 µm and at concentrations up to 40 mg mL-1. Compared to traditional laser diffraction systems, the proposed PSA is an order of magnitude smaller in size, weight and cost, and offers a promising approach to online industrial process monitoring. As light scattering is influenced by factors other than particle size, including shape, refractive index contrast and suspension concentration, the PSA can also be employed in biological applications. To this end, the second part of the thesis aims to optimise the PSA for the measurement of small (< 10 µm) particles such as microorganisms. The results demonstrate that the modified PSA in combination with ML is able to accurately classify different types of bacteria (Escherichia coli and Enterococcus sp.) and distinguish them from silica beads of comparable sizes, with an accuracy of 89%. Moreover, it can detect the concentration of bacteria in water with a limit of detection (LOD) of approximately 105 cells mL-1. The final part of the thesis is dedicated to the development of a low-cost, portable optical biosensor for the specific detection of particles smaller than bacteria, such as viruses (< 1 µm). The proposed system, which we have called flow virometry reader (FVR), is a modification of a flow cytometer and relies on measuring light emissions from fluorescent antibodies that bind to specific viral particles. An LOD of 3,834 copies mL-1 for SARS-CoV-2 in saliva can be achieved with the device. The FVR is clinically validated using 54 saliva samples in a blind test, with high sensitivity and specificity of 91.2% and 90%, respectively. These findings suggest that the FVR has the potential to be a highly viable alternative to current diagnostic methods for pandemic events, as it is faster (< 30 min) and less expensive than PCR tests, while being more sensitive than today’s COVID-19 rapid antigen tests. The photonic sensing technologies developed in the thesis show significant potential for use in a wide range of applications, including: • particulate air pollution, causing cardiovascular and respiratory problems • particulate water pollution, which affects the ecosystems of rivers, lakes and oceans • total bacterial count in environmental or bathing water • viral pandemics The technologies are particularly appealing in countries with limited resources due to their simple design, portability, short time-to-result and affordability, as well as the fact that they do not require a specialised laboratory or trained personnel to operate them.El objetivo de esta tesis es el diseño, desarrollo y validación de dos nuevos sensores fotónicos para la detección y caracterización de muestras industriales y biológicas. El primero es un PSA en configuración de haz colimado que usa un innovador filtro espacial angular y una cámara electrónica similar a la usada en móviles. El pequeño factor de tamaño del filtro angular espacial permite la detección de la luz difusa de las partículas hasta ángulos discretos predefinidos. A partir del uso de imágenes difusas angularmente resueltas obtenidas por la cámara, un algoritmo de aprendizaje automático, machine learning (ML) en inglés, puede predecir la mediana del diámetro del volumen de las partículas. Nuestro sistema ha conseguido un error absoluto medio porcentual de solamente un 0.72% para partículas esféricas en disoluciones con tamaños superiores a 10 µm y concentraciones de hasta 40 mg mL-1. En comparación a sistemas tradicionales de difracción láser, el propuesto PSA es un orden de magnitud más pequeño en tamaño, peso y coste, y ofrece un enfoque prometedor para la supervisión online de procesos industriales. Dado que la difusión de luz depende de más factores aparte del tamaño de la partícula, incluyendo la forma, el contraste del índice de refracción y la suspensión de la concentración, el PSA también puede ser empleado en aplicaciones biológicas. Con este objetivo, la segunda parte de la tesis busca optimizar el PSA para la medida de partículas pequeñas (< 10 µm) como microorganismos. Los resultados demuestran que el PSA modificado en combinación con ML es capaz de clasificar con exactitud diferentes tipos de bacterias (Escherichia coli y Enterococcus sp.) y diferéncialas de partículas de silicio con tamaños similares, con una precisión del 89%. Además, puede detectar una concentración de bacterias en agua con un límite de detección (LOD en inglés) de aproximadamente 105 células mL-1. La parte final de tesis está dedicada al desarrollo de un biosensor óptico de bajo coste y portátil para la detección especifica de partículas más pequeñas que bacterias, como virus (< 1 µm). El sistema propuesto, el cual hemos llamado flow virometry reader (FVR), es una modificación de un citómetro de flujo y se basa en la medida de emisiones de luz provenientes de anticuerpos fluorescentes que son unidos a partículas virales específicas. Con este dispositivo se puede conseguir un LOD de 3,834 copias mL-1 para el SARS-CoV-2 en saliva. El FVR ha sido validado clínicamente usando 54 muestras de saliva en un test a ciegas, con una sensibilidad y especificidad del 91.2% y 90%, respectivamente. Estos hallazgos sugieren que el FVR tiene el potencial de ser una alternativa viable a los métodos de diagnóstico actuales en escenarios de pandemias, pues es rápido (< 30 min) y menos costoso que los test por PCR, mientras que es más sensible que los actuales test de antígenos para COVID-19. Las tecnologías de detección fotónicas desarrolladas en esta tesis muestran un potencial significativo para su uso en un amplio rango de aplicaciones, incluyendo: -contaminación de aire por partículas, causantes de problemas cardiovasculares y respiratorios -contaminación de agua por partículas, el cual afecta a ecosistemas como ríos, lagos y océanos -recuento total de bacterias en aguas de baño o ambientales -pandemias víricas. Estas tecnologías son particularmente atractivas en países con recursos limitados, dado sus simples diseños, portabilidad, el poco tiempo de espera para obtener resultados y asequibilidad, así como el hecho de que estos no requieren un laboratorio especializado o un personal cualificado para operar con ellas.Postprint (published version

When Infodemic Meets Epidemic: a Systematic Literature Review

Epidemics and outbreaks present arduous challenges requiring both individual and communal efforts. Social media offer significant amounts of data that can be leveraged for bio-surveillance. They also provide a platform to quickly and efficiently reach a sizeable percentage of the population, hence their potential impact on various aspects of epidemic mitigation. The general objective of this systematic literature review is to provide a methodical overview of the integration of social media in different epidemic-related contexts. Three research questions were conceptualized for this review, resulting in over 10000 publications collected in the first PRISMA stage, 129 of which were selected for inclusion. A thematic method-oriented synthesis was undertaken and identified 5 main themes related to social media enabled epidemic surveillance, misinformation management, and mental health. Findings uncover a need for more robust applications of the lessons learned from epidemic post-mortem documentation. A vast gap exists between retrospective analysis of epidemic management and result integration in prospective studies. Harnessing the full potential of social media in epidemic related tasks requires streamlining the results of epidemic forecasting, public opinion understanding and misinformation propagation, all while keeping abreast of potential mental health implications. Pro-active prevention has thus become vital for epidemic curtailment and containment

Determining the immune response in human immunodefficiency virus infection : HIV -1 diversity as tool for epidemic monitoring

The Human Immunodeficiency Virus type 1 (HIV-1) is characterized by extensive genetic diversity at the population level but also within a single infected individual. The swift capacity of the virus to generate extensive diversity within the human host played a central role in the origin of the disease and is also key for the current global proportions of the HIV-1 pandemic. The epidemic started in Africa with multiple zoonotic transmissions of simian immunodeficiency virus (SIV) to humans. This was followed by a period of diversification and adaptation to the human population that, enhanced by the high rates of mutation and recombination of the virus, allowed the emergence of a virus capable of efficient sexual transmission among humans. The spread of the human adapted virus is estimated to have initiated from late 1950s to the early 1960s from Africa to the rest of the world. The predominance of the subtype B HIV-1 virus in Western Europe suggests that this was the first subtype to be introduced in this region. The subtype diversity pattern of HIV-1 in Portugal resembles the ones found in Central Africa being far more complex than the viral diversity patterns observed in the rest of Western Europe highlighting the relevance of in detailed studies of the Portuguese HIV-1 epidemics. In this work we have characterized the local HIV-1 epidemic of the Portuguese city of Braga in the years from 2000 to 2012. We found that the most frequent HIV-1 subtypes were G and B and by combining epidemiological and phylogenetic analysis we were able to uncover local transmission clusters of non-B and non-G subtypes among locals in association with sexual transmission networks that initiated transmission in the early 2000s. This corroborates Portugal as an early point of introduction of non-B HIV-1 subtypes in Western Europe. Having performed this characterization at the level of this local population we then focused on analyzing the duration of infection at the level of the infected patient. For this purpose we have optimized a methodology to differentiate recent from chronic infections. It was based on the study of ambiguous nucleotide calls obtained from routine HIV-1 genotyping. We found that the analysis of these ambiguities, as an expression of intra-host HIV-1 diversity, allowed the inference of the duration of infection in this study population. Subsequently, we questioned if high HIV-1 subtype diversity found in this region correlated with higher rates of transmission of drug resistance mutations. We found that the level of transmitted drug resistance in this population was similar to other European regions and independent predictors of transmitted drug resistance (TDR) could not be identified supporting the recommendation of universal viral sequencing at patient admission. This study performed in a country that is unique in Western Europe in what regards to HIV-1 diversity supported Portugal as one of the early entry-points of non-B HIV-1 subtypes in Western Europe and also reinforced the need for more efficacious local control measures targeting sexual transmission routes. We believe this study is of general importance especially in a time when several reports suggest that the prevalence of non-B subtypes in Western Europe is increasing. The knowledge herein generated also contributed for the development of method to discriminate recent from non-recent HIV-1 infections, a step of crucial importance to validate prevention strategies. Importantly, it was also shown that the higher HIV-1 subtype diversity found in this study population does not correlate with an increase in the rate of transmission of drug resistance when compared to the rest of the Western Europe.O Vírus da Imunodeficiência Humana Tipo 1 (VIH-1) é caracterizado por uma extensa diversidade genética não só a nível da população, mas também a nível individual, em cada hospedeiro. A rapidez do vírus para gerar grande diversidade dentro do hospedeiro humano desempenhou um papel central na génese da doença e é também essencial para as proporções globais atuais da pandemia do VIH-1. A epidemia começou em África, com várias transmissões zoonóticas de vírus da imunodeficiência símia (SIV) para seres humanos. Isto foi seguido por um período de diversificação e adaptação na população humana que, amplificada pelas altas taxas de mutação e de recombinação do vírus, permitiu o surgimento de uma nova espécie de vírus capaz de transmissão sexual eficiente entre os seres humanos. O início da propagação deste vírus já adaptado ao ser humano é estimada a partir do final dos anos 1950 ao início dos anos 1960, da África Central para o resto do mundo. A predominância do subtipo B do VIH-1 na Europa Ocidental sugere que este foi o primeiro subtipo a ser introduzido nesta região. O padrão de diversidade dos subtipos do VIH-1 em Portugal assemelha-se ao encontrado na África Central, sendo muito mais complexo do que os padrões de diversidade vírica observados no resto da Europa Ocidental. Este facto justifica o relevo que estudos detalhados sobre o VIH-1 em Portugal possam ter para a compreensão das epidemias de VIH-1. Neste trabalho foi caracterizada a epidemia local por VIH-1 na cidade portuguesa de Braga, entre os anos 2000 e 2012. Descobrimos que os subtipos VIH-1 mais frequentes foram G e B. Pela combinação de análise epidemiológica e filogenética pudemos demonstrar grupos de transmissão locais de subtipos não-B e não-G entre os residentes em associação com redes de transmissão sexual que iniciaram a transmissão no início da década de 2000. Isto indicia o papel de Portugal como um ponto de início da introdução de subtipos não-B do VIH-1 na Europa Ocidental. Tendo realizado esta caracterização a nível da população local, o trabalho concentrou-se na análise da duração da infeção ao nível individual. Para este efeito, aperfeiçoou-se uma metodologia para diferenciar infeção recente de infeção crónica. Baseados no estudo de posições nucleotídicas ambíguas obtidas a partir de genotipagem rotineira doVIH-1,descobrimos que a análise dessas ambiguidades, como uma expressão da diversidade intra-hospedeiro do VIH-1, permite inferir a duração da infeção nesta população em estudo. Posteriormente questionamos se a elevada diversidade do VIH-1 encontrada nesta região se poderia correlacionar com maiores taxas de transmissão de mutações de resistência aos antiretrovíricos. Descobrimos que o nível de resistência à terapêutica transmitido nesta população foi semelhante a outras regiões europeias. Não foram identificados preditores independentes de resistência transmissível aos antiretrovíricos, suportando a recomendação de sequenciamento viral universal no momento do contacto do doente com os serviços de saúde. Este estudo realizado num país que é único na Europa Ocidental no que diz respeito à diversidade do VIH-1,validoua noção de Portugal como um dos pontos de entrada iniciais de subtipos não-B do VIH-1 na Europa Ocidental e também reforçou a necessidade de medidas locais de controlo mais eficazes, que visem modos de transmissão sexual. Acreditamos que este estudo é relevante, especialmente num tempo em que vários artigos sugerem que a prevalência de subtipos não-B na Europa Ocidental está a aumentar. O conhecimento aqui gerado também contribuiu para o desenvolvimento de um método para discriminar infeções recentes pelo HIV-1 das não-recentes, um passo de importância crucial para validar as estratégias de prevenção. Relevantemente, também foi demonstrado que à maior diversidade doVIH-1 encontrada na população em estudo, não correspondeu um aumento na taxa de transmissão de resistência à terapêutica, quando comparada com o resto da Europa Ocidental