Influenza and the Respiratory Microbiome

Despite the availability of vaccines, influenza causes approximately 3-5 million cases of severe illness and 400,000 deaths each year. Prevention efforts might potentially be strengthened by harnessing the host microbiome, which plays an important role in maintaining human health by promoting host immunity and colonization resistance. Although vaccines are the best available means of prevention, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- to middle-income countries. Exploring the relationship between influenza virus and the respiratory microbiome may contribute to alternative strategies of prevention. This dissertation explores the relationship between influenza virus and the respiratory microbiome. In chapter 2, we describe our current understanding of respiratory virus-bacteria interactions using systematic and targeted literature searches. We explore whether respiratory viruses can place selective pressures on bacteria in the upper respiratory tract. Further, as colonization in the upper respiratory tract is a necessary precursor for many respiratory pathogens, we explore whether virus-associated changes in the upper respiratory tract microbiome can influence the etiology of bacterial pneumonia. We found strong biological support for a link between respiratory viruses, the upper respiratory tract microbiome, and bacterial pneumonia. However, we found a lack of longitudinal studies among human populations that examined all three components. To address this knowledge gap, we used a household transmission study of influenza in Nicaragua to explore potential relationships between influenza and the respiratory microbiome. In chapter 3, we examine whether the respiratory microbiome mediates susceptibility to influenza virus infection and characterize structural changes to the respiratory microbiome during influenza virus infection. We used Dirichlet multinomial mixture models to assign nose/throat samples to bacterial community types and generalized linear mixed effects models which account for clustering by household. We found a single community type associated with decreased susceptibility to influenza. Further, we found high rates of change in the microbiome structure following influenza virus infection as well as among household contacts who were never infected with influenza during follow up. In chapter 4, we use secondary cases from the Nicaraguan household transmission study to investigate whether the respiratory microbiome impacts influenza symptomology and viral shedding. We used generalized linear mixed effects models to examine the presentation of symptoms and viral shedding. Further, we used accelerated failure time models with a generalized estimating equation approach to examine time-to-event outcomes including symptom duration, shedding duration, and time to infection. The duration of symptoms varied by bacterial community type both prior to and during influenza virus infection. Further, a community type with low diversity was associated with shorter duration of viral shedding and delayed time to infection among secondary cases. The results of these various analyses suggest the respiratory microbiome may be a potential target for reducing influenza risk, household transmission, and disease severity. In the final chapter, I review the skills I learned and the challenges I encountered during the dissertation process. Finally, I review future research directions that focus on deciphering the complex dynamics between the host, pathogen, and microbiome.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143948/1/kyuhan_1.pd

Peripheral blood mononuclear cell-converted induced pluripotent stem cells (iPSCs) from an early onset Alzheimer's patient

AbstractImprovement in transduction efficiency makes it possible to convert blood cells into induced pluripotent stem cells (iPSC). In this study, we generated an iPSC line from peripheral blood mononuclear cells (PBMC) donated by a patient who exhibited memory deficit at age 59; outcome of positron emission tomography scan is consistent with a diagnosis of Alzheimer's disease. Integration-free CytoTune-iPS Sendai Reprogramming factors which include Sendai virus particles of the four Yamanaka factors Oct4, Sox2, Klf4, and c-Myc were introduced to PBMC to convert them to iPSCs without retention of virus. Three germ layer differentiation was induced to demonstrate the pluripotency of these iPSCs

Conservative Management of Spontaneous Isolated Dissection of the Superior Mesenteric Artery

Purpose. We report the clinical outcomes of patients with spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) who were treated conservatively. Materials and Methods. A retrospective review was performed in 14 patients from 2006 to 2016 with SIDSMA. Their clinical features and computed tomographic angiography (CTA) characteristics, treatment methods, and clinical outcomes were analyzed. The mean age was 53.6 (range, 41–73) years, and the mean follow-up duration was 20.6 (range, 1–54) months. Conservative management was the primary treatment if no bowel ischemia or arterial rupture was noted. Results. The mean initial abdominal visual analog pain score was 7 (range, 5–9) in seven patients. The mean total duration of abdominal pain was 10.2 days (range, 2–42 days) in 10 patients. The mean percentage stenosis of the dissected SMA at the initial presentation was 78.8% in 14 patients. Complete obstruction of the SMA at the initial presentation was evident in 4 of the 14 patients (28.6%). Conservative management was successful in all 14 patients. None of the 14 patients developed bowel ischemia or an infarction. Abdominal pain did not recur in any patient during follow-up (mean, 20.6 months; range, 1–54 months). Conclusion. Conservative management was successful for all SIDSMA patients, even those with severe compression of the true lumen or complete obstruction of the dissected SMA

Nanopores of carbon nanotubes as practical hydrogen storage media

We report on hydrogen desorption mechanisms in the nanopores of multiwalled carbon nanotubes (MWCNTs). The as-grown MWCNTs show continuous walls that do not provide sites for hydrogen storage under ambient conditions. However, after treating the nanotubes with oxygen plasma to create nanopores in the MWCNTs, we observed the appearance of a new hydrogen desorption peak in the 300–350 K range. Furthermore, the calculations of density functional theory and molecular dynamics simulations confirmed that this peak could be attributed to the hydrogen that is physically adsorbed inside nanopores whose diameter is approximately 1 nm. Thus, we demonstrated that 1 nm nanopores in MWCNTs offer a promising route to hydrogen storage media for onboard practical applications

Guards and Culprits in the Endoplasmic Reticulum: Glucolipotoxicity and β-Cell Failure in Type II Diabetes

The endoplasmic reticulum (ER) is a cellular organelle responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. The ER participates in all branches of metabolism, linking nutrient sensing to cellular signaling. Many pathological and physiological factors perturb ER function and induce ER stress. ER stress triggers an adaptive signaling cascade, called the unfolded protein response (UPR), to relieve the stress. The failure of the UPR to resolve ER stress leads to pathological conditions such as β-cell dysfunction and death, and type II diabetes. However, much less is known about the fine details of the control and regulation of the ER response to hyperglycemia (glucotoxicity), hyperlipidemia (lipotoxicity), and the combination of both (glucolipotoxicity). This paper considers recent insights into how the response is regulated, which may provide clues into the mechanism of ER stress-mediated β-cell dysfunction and death during the progression of glucolipotoxicity-induced type II diabetes

Effect of Different Seeding Rate on Seed Production of the Rye Variety “Gogu” in Korea

The rye (Secale cereale L.) has been used as an excellent green manure crop and good forage crop in Korea. The rye is usually recommended as a winter crop for forage and green manure after either maize or rice in Korea (Heo et al., 2009). But most of its seeds are being imported from foreign countries because the seed productions have difficulty with latematuring and the heavy raining season in the ripening stage in Korea. Therefore, a new rye variety “Gogu” with an earlymaturing and high performance was bred by National Institute of Crop Science (NICS), Suwon, Korea in 2004. This study was carried out to determine the effect of seeding rate on the seed yield and agronomic characteristics of the rye variety “Gogu” in the north eastern area, Youngwol, Korea