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"Alexander Klose"
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Automated quantification of bioluminescence images
We developed a computer-aided analysis tool for quantitatively determining bioluminescent reporter distributions inside small animals. The core innovations are a body-fitting animal shuttle and a statistical mouse atlas, both of which are spatially aligned and scaled according to the animal’s weight, and hence provide data congruency across animals of varying size and pose. In conjunction with a multispectral bioluminescence tomography technique capitalizing on the spatial framework of the shuttle, the in vivo biodistribution of luminescent reporters can rapidly be calculated and, thus, enables operator-independent and computer-driven data analysis. We demonstrate its functionality by quantitatively monitoring a bacterial infection, where the bacterial organ burden was determined and validated with the established serial-plating method. In addition, the statistical mouse atlas was validated and compared to existing techniques providing an anatomical reference. The proposed data analysis tool promises to increase data throughput and data reproducibility and accelerate human disease modeling in mice.
Analysis of bioluminescence images of bacterial distributions in living animals is mostly manual and semiquantitative. Here, the authors present an analysis platform featuring an animal mold, a probabilistic organ atlas, and a mirror gantry to perform automatic in vivo bioluminescence quantification.
Journal Article
Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression
Animal models recapitulating COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Intranasally inoculated transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. We evaluated the clinical and virological dynamics of SARS-CoV-2 using two intranasal doses (104 and 106 PFUs), with a detailed spatiotemporal pathologic analysis of the 106 dose cohort. Despite generally mild-to-moderate pneumonia, clinical decline resulting in euthanasia or death was commonly associated with hypothermia and viral neurodissemination independent of inoculation dose. Neuroinvasion was first observed at 4 days post-infection, initially restricted to the olfactory bulb suggesting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. Absence of viremia suggests neuroinvasion occurs independently of transport across the blood-brain barrier. SARS-CoV-2 tropism was neither restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), nor inclusive of some ACE2-positive cell lineages (e.g., bronchiolar epithelium and brain vasculature). Absence of detectable ACE2 protein expression in neurons but overexpression in neuroepithelium suggest this as the most likely portal of neuroinvasion, with subsequent ACE2 independent lethal neurodissemination. A paucity of epidemiological data and contradicting evidence for neuroinvasion and neurodissemination in humans call into question the translational relevance of this model.
Journal Article
α–Intercalated cells defend the urinary system from bacterial infection
α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.
Journal Article
The Container Principle
We live in a world organized around the container. Standardized twenty- and forty-foot shipping containers carry material goods across oceans and over land; provide shelter, office space, and storage capacity; inspire films, novels, metaphors, and paradigms. Today, TEU (Twenty Foot Equivalent Unit, the official measurement for shipping containers) has become something like a global currency. A container ship, sailing under the flag of one country but owned by a corporation headquartered in another, carrying auto parts from Japan, frozen fish from Vietnam, and rubber ducks from China, offers a vivid representation of the increasing, world-is-flat globalization of the international economy. InThe Container Principle, Alexander Klose investigates the principle of the container and its effect on the way we live and think.Klose explores a series of \"container situations\" in their historical, political, and cultural contexts. He examines the container as a time capsule, sometimes breaking loose and washing up onshore to display an inventory of artifacts of our culture. He explains the \"Matryoshka principle,\" explores the history of land-water transport, and charts the three phases of container history. He examines the rise of logistics, the containerization of computing in the form of modularization and standardization, the architecture of container-like housing (citing both Le Corbusier and Malvina Reynolds's \"Little Boxes\"), and a range of artistic projects inspired by containers. Containerization, spreading from physical storage to organizational metaphors, Klose argues, signals a change in the fundamental order of thinking and things. It has become a principle.
eBook
Cell-specific image-guided transcriptomics identifies complex injuries caused by ischemic acute kidney injury in mice
The kidney’s inherent complexity has made identifying cell-specific pathways challenging, particularly when temporally associating them with the dynamic pathophysiology of acute kidney injury (AKI). Here, we combine renal cell-specific luciferase reporter mice using a chemoselective luciferin to guide the acquisition of cell-specific transcriptional changes in C57BL/6 background mice. Hydrogen peroxide generation, a common mechanism of tissue damage, was tracked using a peroxy-caged-luciferin to identify optimum time points for immunoprecipitation of labeled ribosomes for RNA-sequencing. Together, these tools revealed a profound impact of AKI on mitochondrial pathways in the collecting duct. In fact, targeting the mitochondria with an antioxidant, ameliorated not only hydrogen peroxide generation, but also significantly reduced oxidative stress and the expression of the AKI biomarker, LCN2. This integrative approach of coupling physiological imaging with transcriptomics and drug testing revealed how the collecting duct responds to AKI and opens new venues for cell-specific predictive monitoring and treatment.
Miyazaki, Gharib, Hsu et al. use a combined cell-specific luciferase reporter system and chemo-selective substrate to identify mouse tissues at risk of renal injury. The platform can be used to identify cell-specific pathophysiological events and transcriptional changes, finding potential therapeutic targets.
Journal Article
Minimizing the risk of perioperative stroke by clampless off-pump bypass surgery: a retrospective observational analysis
Objectives
Stroke is a devastating complication after coronary artery bypass grafting, occurring in 1.4% to 4.3% of patients. A major cause of stroke is cerebral embolization of aortic atheromatous debris or calcified plaques. This report analyzes the incidence of stroke in patients treated according to the clampless concept, i.e. avoiding side-clamping of the aorta, by means of off-pump coronary artery bypass surgery (OPCAB) in combination with the HEARTSTRING device.
Methods
During a period of 43 months (2005-2008), 412 consecutive patients were treated with the above-mentioned method by one single surgeon. A minimum of one proximal aortal anastomosis was performed in each patient. Altogether, 542 proximal anastomosis were applied, each created by means of the HEARTSTRING device.
Results
The mean age of patients was 67+9.7 years, the predicted mortality 5.2% (logistic EuroSCORE) and the observed mortality 1.9%. Histories of preoperative neurological disorders or cerebrovascular diseases were documented in 15% of patients. The overall incidence of postoperative stroke was 0.48% in contrast to 1.3% according to the stroke risk score.
Conclusions
In accordance to previously published data, our results show that avoiding aortic side-clamping during OPCAB reduces postoperative stroke rates. The HEARTSTRING device is a safe option for creating proximal aortic anastomosis.
Journal Article
Optical tomography with the equation of radiative transfer
Purpose - This paper sets out to give an overview about state-of-the-art optical tomographic image reconstruction algorithms that are based on the equation of radiative transfer (ERT).Design methodology approach - An objective function, which describes the discrepancy between measured and numerically predicted light intensity data on the tissue surface, is iteratively minimized to find the unknown spatial distribution of the optical parameters or sources. At each iteration step, the predicted partial current is calculated by a forward model for light propagation based on the ERT. The equation of radiative is solved with either finite difference or finite volume methods.Findings - Tomographic reconstruction algorithms based on the ERT accurately recover the spatial distribution of optical tissue properties and light sources in biological tissue. These tissues either can have small geometries large absorption coefficients, or can contain void-like inclusions.Originality value - These image reconstruction methods can be employed in small animal imaging for monitoring blood oxygenation, in imaging of tumor growth, in molecular imaging of fluorescent and bioluminescent probes, in imaging of human finger joints for early diagnosis of rheumatoid arthritis, and in functional brain imaging.
Journal Article