PaperPlayer biorxiv pathology

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.25.218149v1?rss=1

Authors: Kallenberg, D., Tripathi, V., Javaid, F., Pilotti, C., George, J., Davis, S., Blackburn, J. W., O'Connor, M., Dowsett, L., Bowers, C., Liyanage, S. E., Gourlaouen, M., Hoeh, A., Mota, F., Selwood, D., Bainbridge, J., Chudasama, V., Greenwood, J., Moss, S. E.

Abstract:

Pathological angiogenesis contributes to morbidity in a number of diseases including cancer, diabetic retinopathy and the neovascular form of age-related macular degeneration, leading to significant efforts to develop effective anti-angiogenic therapeutics for these conditions. The field is dominated by inhibitors of vascular endothelial growth factor (VEGF), yet angiogenesis can also be driven and modified by other factors. We have previously demonstrated that leucine-rich alpha-2-glycoprotein 1 (LRG1) contributes to abnormal vessel growth by activating a TGF-beta switch. Here we report the development and characterisation of a function-blocking fully humanised IgG4 and its Fab fragment, that bind to LRG1 with high affinity and specificity and inhibit vascular leakage in the mouse model of laser-induced choroidal neovascularisation. In summary, we have developed a therapeutic antibody that targets a VEGF-independent signalling axis, which may be effective in a number of conditions either as monotherapy or in combination with other vascular targeted therapies.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.22.213959v1?rss=1

Authors: McAloose, D., Laverack, M., Wang, L., Killian, M. L., Caserta, L. C., Mitchell, P. K., Queen, K., Mauldin, M. R., Cronk, B. D., Bartlett, S. L., Sykes, J. M., Zec, S., Ingerman, K., Stokol, T., Frederikson, R., Delaney, M. A., Ivancic, M., Jenkins-Moore, M., Mozingo, K., Franzen, K., Hines Bergeson, N., Goodman, L., Wang, H., Wang, S., Yuan, F., Fang, Y., Olmstead, C., McCann, C., Thomas, P., Goodrich, E., Elvinger, F., Slavinski, S., Smith, D. C., Calle, P. P., Terio, K., Torchetti, M. K., Diel, D. G.

Abstract:

We describe the first cases of natural SARS-CoV-2 infection detected in animals in the United States. In March 2020, four tigers and three lions at the Bronx Zoo developed mild respiratory signs. SARS-CoV-2 RNA was detected by rRT-PCR in respiratory secretions and/or feces from all seven affected animals; viral RNA and/or antibodies were detected in their keepers. SARS-CoV-2 was isolated from respiratory secretions or feces from three affected animals; in situ hybridization co-localized viral RNA with cellular damage. Whole genome sequence and haplotype network analyses showed tigers and lions were infected with two different SARS-CoV-2 strains, suggesting independent viral introductions. The source of SARS-CoV-2 infection in the lions is unknown. Epidemiological data and genetic similarities between keeper and tiger viruses indicate human to animal transmission.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.212803v1?rss=1

Authors: Minamikawa, T., Ichimura-Shimizu, M., Takanari, H., Morimoto, Y., Shiomi, R., Tanioka, H., Hase, E., Yasui, T., Tsuneyama, K.

Abstract:

Predominant evidence of non-alcoholic fatty liver disease (NAFLD) is the accumulation of excess lipids in the liver. A small group with NAFLD may have a more serious condition named non-alcoholic steatohepatitis (NASH). However, there is a lack of investigation of the accumulated lipids with spatial and molecular information. Raman microscopy has the potential to characterize molecular species and structures of lipids based on molecular vibration and can achieve high spatial resolution at the organelle level. We aim to demonstrate the feasibility of Raman microscopy for the investigation of NAFLD based on the molecular features of accumulated lipids. By applying the Raman microscopy to the liver of the NASH model mice, we succeeded in visualizing the distribution of lipid droplets (LDs) in hepatocytes. The detailed analysis of Raman spectra revealed the difference of molecular structural features of the LDs, such as the degree of saturation of lipids in the LDs. We also found that the inhomogeneous distribution of cholesterol in the LDs depending on the histology of lipid accumulation. We visualized and characterized the lipids of NASH model mice by Raman microscopy at organelle level. Our findings demonstrated that the Raman imaging analysis was feasible to characterize the NAFLD in terms of the molecular species and structures of lipids.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.20.211714v1?rss=1

Authors: Longbottom, J., Wamboga, C., Bessell, P. R., Torr, S. J., Stanton, M.

Abstract:

BackgroundSurveillance is an essential component of global programs to eliminate infectious diseases, with surveillance systems often being considered the first line in averting epidemics for (re-)emerging diseases. As the numbers of cases decline, costs of treatment and control diminish, but those for surveillance remain high even after the last case. Economies made by reducing surveillance risk missing persistent or (re-)emerging foci of disease, therefore it is vital that surveillance networks are adequately designed; however, guidance on how best to optimise disease surveillance in an elimination setting is lacking. Here, we use a simulation-based approach to determine the minimal number of passive surveillance sites required to ensure maximum coverage of the population at-risk (PAR) of an infectious disease.

Methodology and Principal FindingsFor this study, we use Gambian human African trypanosomiasis (g-HAT) in north-western Uganda, a neglected tropical disease (NTD) which has been reduced to historically low levels (<1000 cases/year), as an example application. To quantify travel time to diagnostic facilities, a proxy for surveillance coverage, we produced a high spatial-resolution friction surface and performed cost-distance analyses. We simulated travel time for the PAR with different numbers (n = 1...170) and locations (170,000 total placement combinations) of diagnostic facilities, quantifying the percentage of the PAR within 1h and 5h travel of the facilities, as per in-country targets. Our simulations indicate that a minimum of 54 diagnostic centres are required to meet provisional targets, and we determine where best to place these facilities, enabling a minimal impact scale back from 170 facilities operational in 2017. Scaling back operational facilities ensures that costs can be reduced without impairing surveillance of the core areas with remaining cases.

ConclusionsOur results highlight that surveillance of g-HAT in north-western Uganda can be scaled back without reducing coverage of the PAR. The methodology described can contribute to cost-effective strategies for the surveillance of NTDs and other infectious diseases approaching elimination or applied to (re-)emerging diseases for which the design of a novel surveillance network is required.

Author SummaryDisease surveillance systems are an essential component of public health practice and are often considered the first line in averting epidemics for (re-)emerging diseases. Regular evaluation of surveillance systems ensures that they remain operating at maximum efficiency; systems that survey diseases of low incidence, such as those within elimination settings, should be simplified to reduce the reporting burden. A lack of guidance on how best to optimise disease surveillance in an elimination setting may result in added expense, and/or the underreporting of disease. Here, we propose a framework methodology to determine systematically the optimal number and placement of surveillance sites for the surveillance of infectious diseases approaching elimination. By utilising estimates of geographic accessibility, through the construction of a friction surface and a simulation approach, we identify that the number of operational diagnostic facilities for Gambian human African trypanosomiasis in north-western Uganda can be reduced without affecting coverage targets. Our analysis can be used to inform the number and positioning of surveillance sites for diseases within an elimination setting. Passive surveillance becomes increasingly important as cases decline and active surveillance becomes less cost-effective; methods to evaluate how best to engage this passive surveillance capacity given facility capacity and geographic distribution are pertinent for several NTDs where diagnosis is complex. Not only is this a complicated research area for diseases approaching elimination, a well-designed surveillance system is essential for the detection of emerging diseases, with this work being topical in a climate where emerging pathogens are becoming more commonplace.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.17.208348v1?rss=1

Authors: Rudresha, G. V., Urs, A. P., Manjuprasanna, V. N., Gowda, M. D. M., Jayachandra, K., Rajaiah, R., Vishwanath, B.

Abstract:

Echis carinatus (EC) is known as saw-scaled viper and it is endemic to the Indian subcontinent. Envenoming by EC represents a major cause of snakebite mortality and morbidity in the Indian subcontinent. Zinc (Zn++)-dependent snake venom metalloproteases (SVMPs) present in Echis carinatus venom is well known to cause systemic hemorrhage and coagulopathy in experimental animals. An earlier report has shown that ECV activates neutrophils and releases neutrophil extracellular traps (NETs) that blocks blood vessels leading to severe tissue necrosis. However, the direct involvement of SVMPs in the release of NETs is not clear. Here, we investigated the direct involvement of EC SVMPs in observed pathological symptoms in a preclinical setup using zinc (Zn++) metal chelator, Tetraethylthiuram disulfide (TTD)/disulfiram. TTD potently antagonizes the activity of SVMPs-mediated ECM protein degradation in vitro and skin hemorrhage in mice. In addition, TTD protected mice from ECV-induced footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in footpad tissue. TTD also neutralized ECV-induced systemic hemorrhage and conferred protection against lethality in mice. Moreover, TTD inhibited ECV-induced NETosis in human neutrophils and decreased the expression of peptidylarginine deiminase (PAD) 4, citH3, MPO and pERK. Further, we demonstrated that ECV-induced NETosis and tissue necrosis is mediated via PAR-1-ERK axis. Overall, our results provide an insight into SVMPs-induced toxicities and the promising protective efficacy of TTD can be extrapolated to treat severe tissue necrosis complementing ASV.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.15.203885v1?rss=1

Authors: Alsina-Sachis, E., Muelfarth, R., Moll, I., Mogler, C., Rodriguez-Vita, J., Fischer, A.

Abstract:

Oil is frequently used as a solvent to inject lipophilic substances into the peritoneum of laboratory animals. Although mineral oil causes chronic peritoneal inflammation, little is known whether other oils are better suited. Here we show that olive, peanut, corn or mineral oil causes xanthogranulomatous inflammation with depletion of resident peritoneal macrophages. However, there were striking differences in the severity of the inflammatory response. Peanut and mineral oil caused severe chronic inflammation with persistent neutrophil and monocyte recruitment, expansion of the vasculature and fibrosis. Corn and olive oil provoked no or only mild signs of chronic inflammation. Mechanistically, the vegetal oils were taken up by macrophages leading to foam cell formation and induction of cell death. Olive oil triggered caspase-3 cleavage and apoptosis, which facilitates the resolution of inflammation. Peanut oil and, to a lesser degree, corn oil triggered caspase-1 activation and macrophage pyroptosis, which impairs the resolution of inflammation. As such, intraperitoneal oil administration can interfere with the outcome of subsequent experiments. As a proof-of-principle, intraperitoneal peanut oil injection was compared to its oral delivery in a thioglycolate-induced peritonitis model. The chronic peritoneal inflammation due to peanut oil injection impeded the proper recruitment of macrophages and the resolution of inflammation in this peritonitis model. In summary, the data indicate that it is advisable to deliver lipophilic substances like tamoxifen by oral gavage instead of intraperitoneal injection.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.15.201327v1?rss=1

Authors: Abyzov, A., Van Beers, B. E., Garteiser, P.

Abstract:

Abdominal quantitative susceptibility mapping (QSM), especially in small animals, is challenging because of respiratory motion and blood flow that, in addition to noise, deteriorate the quality of the input data. Efficient artefact suppression in QSM reconstruction is crucial in these conditions. Single-step QSM algorithms combine background field removal and magnetic field-to-susceptibility inverse problem regularization in a single optimization equation. Here, we propose a single-step QSM algorithm that uses spherical mean value kernels of different radii for background field removal and structure prior (consistency with magnitude image) with L1 norm for regularization. The optimization problem is solved using the split-Bregman method on the graphic processor unit. The method was compared with previously reported singlestep methods: a method using discrete Laplacian instead of spherical mean value kernels, a method using total variational penalty instead of structure prior, and a method using L2 norm for structure prior. With the proposed method relative to the previous ones, a numerical susceptibility phantom was reconstructed more precisely. In living mice, susceptibility maps with more homogeneous liver, higher contrast between liver and blood vessels, and well-preserved structural details were obtained. In patients, susceptibility maps with more homogeneous subcutaneous fat and higher contrast between subcutaneous fat and liver were obtained. These results show the potential of the proposed single-step method for abdominal QSM in small animals and humans.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.15.205633v1?rss=1

Authors: Hugonnet, H., Kim, Y. W., Lee, M., Shin, S., Hruban, R. H., Hong, S.-M., Park, Y.

Abstract:

Histopathology relies upon the staining and sectioning of biological tissues, which can be laborious and may cause artefacts and distort tissues. Here, we demonstrate label-free volumetric imaging of thick-tissue slides, exploiting refractive index distributions as intrinsic imaging contrast. The present method systematically exploits label-free quantitative phase imaging techniques, volumetric reconstruction of intrinsic refractive index distributions in tissues, and numerical algorithms for the seamless stitching of multiple 3D tomograms and for reducing scattering-induced image distortion. We demonstrate demonstrated label-free volumetric imaging of thick tissues with the field of view of 2 mm x 1.75 mm x 0.2 mm with a spatial resolution of 170 nm x 170 nm x 1200 nm. The number of optical modes, calculated as the reconstructed volume divided by the size of the point spread function, was approximately 20 Giga voxels. We have also demonstrated that different tumour types, and a variety of precursor lesions and pathologies can be visualized with the present method.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.14.202721v1?rss=1

Authors: Ye, T., Bartlett, M. J., Sherman, S. J., Falk, T., Cowen, S. L.

Abstract:

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinsons disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured locomotor and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, high-dose priming triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed under the low-dose procedure despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. Instead, the low-dose procedure resulted in the weeks-long gradual emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID, but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamines therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures associated with the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD, and as we identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.07.15.205427v1?rss=1

Authors: Andueza, A., Kumar, S., Kim, J., Kang, D. W., Mumme, H. L., Perez, J. I., Jo, H.

Abstract:

Disturbed flow (d-flow) induces atherosclerosis by regulating gene expression in endothelial cells (ECs). For further mechanistic understanding, we carried out a single-cell RNA sequencing (scRNAseq) and scATACseq study using endothelial-enriched single-cells from the left- and right carotid artery exposed to d-flow (LCA) and stable-flow (s-flow in RCA) using the mouse partial carotid ligation (PCL) model. We found 8 EC clusters along with immune cells, fibroblasts, and smooth muscle cells. Analyses of marker genes, pathways, and pseudo-time revealed that ECs are highly heterogeneous and plastic. D-flow induced a dramatic transition of ECs from atheroprotective phenotypes to pro-inflammatory, mesenchymal (EndMT), hematopoietic stem cells, endothelial stem/progenitor cells, and an unexpected immune cell-like (EndICLT) phenotypes. While confirming KLF4/KLF2 as s-flow-sensitive transcription factor binding site, we also found those sensitive to d-flow (RELA, AP1, STAT1, and TEAD1). D-flow reprograms ECs from atheroprotective to pro-atherogenic phenotypes including EndMT and potentially EndICLT.

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