bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice
Authors: Ghebremedhin Anghesom , Salam Ahmad Bin , Adu-Addai Benjamin , Noonan Steve , Stratton Richard , Ahmed Md. Shakir Uddin , Khantwal Chandra , Martin George R , Lin Huixian , Andrews Chris , Karanam Balasubramanyam , Rudloff Udo , Lopez Henry , Jaynes Jesse , Yates Clayton
Published: July 2020

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM)in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNFα, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-β1 and α-SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNFα, IL-6, IL-10, INF-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.
Bayesian model selection favors parametric over categorical fMRI subsequent memory models in young and older adults
Authors: Soch Joram , Richter Anni , Schütze Hartmut , Kizilirmak Jasmin M. , Assmann Anne , Knopf Lea , Raschick Matthias , Schult Annika , Maass Anne , Ziegler Gabriel , Richardson-Klavehn Alan , Düzel Emrah , Schott Björn H.
Published: July 2020

Subsequent memory paradigms allow to identify neural correlates of successful encoding by separating brain responses as a function of memory performance during later retrieval. In functional magnetic resonance imaging (fMRI), the paradigm typically elicits activations of medial temporal lobe, prefrontal and parietal cortical structures in young, healthy participants. This categorical approach is, however, limited by insufficient memory performance in older and particularly memory-impaired individuals. A parametric modulation of encoding-related activations with memory confidence could overcome this limitation. Here, we applied cross-validated Bayesian model selection (cvBMS) for first-level fMRI models to a visual subsequent memory paradigm in young (18-35 years) and older (51-80 years) adults. Nested cvBMS revealed that parametric models, especially with non-linear transformations of memory confidence ratings, outperformed categorical models in explaining the fMRI signal variance during encoding. We thereby provide a framework for improving the modeling of encoding-related activations and for applying subsequent memory paradigms to memory-impaired individuals.
Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution
Authors: Higgs M. J. , Hill M. J. , John R. M. , Isles A. R.
Published: July 2020

Background

Although a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels.

Results

We established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examined brain-wide datasets to test enrichment within distinct brain regions and neuron subpopulations and demonstrated over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we identified hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression.

Conclusions

These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted gene expression converges. Our findings indicate the neuronal regulation of motivated behaviours such as feeding and sleep, alongside the regulation of pituitary function as functional hotspots for imprinting, thus adding statistical rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.
ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma
Authors: Sheybani Natasha D. , Paul Soumen , McCauley Katelyenn S. , Breza Victoria R. , Berr Stuart S. , Miller G. Wilson , Neumann Kiel D. , Price Richard J.
Published: July 2020

Phagocytic immunotherapies such as CD47 blockade have emerged as promising strategies for glioblastoma (GB) therapy, but the blood brain/tumor barriers (BBB/BTB) pose a persistent challenge for mCD47 delivery that can be overcome by focused ultrasound (FUS)-mediated BBB/BTB disruption. We here leverage immuno-PET imaging to determine how timing of [89Zr]-mCD47 injection relative to FUS impacts antibody penetrance into orthotopic murine gliomas. We then design and implement a rational paradigm for combining FUS and mCD47 for glioma therapy. We demonstrate that timing of antibody injection relative to FUS BBB/BTB disruption is a critical determinant of mCD47 access, with post-FUS injection conferring superlative antibody delivery to gliomas. We also show that mCD47 delivery across the BBB/BTB with repeat sessions of FUS can significantly constrain tumor outgrowth and extend survival in glioma-bearing mice. This study generates provocative insights for ongoing pre-clinical and clinical evaluations of FUS-mediated antibody delivery to brain tumors. Moreover, our results confirm that mCD47 delivery with FUS is a promising therapeutic strategy for GB therapy.
Hello darkness, my old friend: 3-Ketoacyl-Coenzyme A Synthase4 is a branch point in the regulation of triacylglycerol synthesis inArabidopsis thaliana
Authors: Luzarowska Urszula , Ruß Anne-Kathrin , Joubès Jérôme , Batsale Marguerite , Szymański Jędrzej , Thirumalaikumar Venkatesh Periyakavanam , Luzarowski Marcin , Wu Si , Zhu Feng , Endres Niklas , Khedhayir Sarah , Schumacher Julia , Jasinska Weronika , Xu Ke , Correa Cordoba Sandra Marcela , Weil Simy , Skirycz Aleksandra , Fernie Alisdair Robert , Li-Beisson Yonghua , Fusari Corina Mariana , Brotman Yariv
Published: July 2020

Due to their sessile lifestyle, plants have evolved unique mechanisms to deal with environmental challenges. Under stress, plant lipids are important as alternative sources of carbon and energy when sugars or starch are limited. Here, we applied combined heat and darkness and extended darkness to a panel of ∼ 300 Arabidopsis accessions to study lipid remodeling under carbon starvation. Natural allelic variation at3-KETOACYL-COENZYME A SYNTHASE4(KCS4), a gene encoding for an enzyme involved in very long chain fatty-acid (VLCFA) synthesis, underlies a differential accumulation of polyunsaturated triacylglycerols (puTAGs) under stress. Ectopic expression in yeast and plants proved that KCS4 is a functional enzyme localized in the ER with specificity for C22 and C24 saturated acyl-CoA. Allelic mutants and transient overexpressionin plantarevealed the differential role ofKCS4alleles in VLCFA synthesis and wax coverage, puTAG accumulation and biomass. Moreover, the region harboringKCS4is under high selective pressure and allelic variation atKCS4correlated with environmental parameters from the locales of Arabidopsis accessions. Our results provide evidence that KCS4 plays a decisive role in the subsequent fate of fatty acids released from chloroplast-membrane lipids under carbon starvation. This work sheds light on both plant response mechanisms and the evolutionary events shaping the lipidome under carbon starvation.

One sentence summary

Natural variation atKCS4underlies a differential accumulation of polyunsaturated triacylglycerols under carbon starvation, by acting as a regulatory branch point in the fate of fatty acids.
Larger organ size caused by obesity is a mechanism for higher cancer risk
Authors: Grant Haley , Zhang Yifan , Li Lu , Wang Yan , Kawamoto Satomi , Pénisson Sophie , Fouladi Daniel F. , Shayesteh Shahab , Blanco Alejandra , Ghandili Saeed , Zinreich Eva , Graves Jefferson S. , Park Seyoun , Kern Scott , Hooper Jody , Yuille Alan L. , Fishman Elliot K , Chu Linda , Tomasetti Cristian
Published: July 2020

Obesity increases significantly cancer risk in various organs. Although this has been recognized for decades, the mechanism through which this happens has never been explained. Here, we show that obese people (BMI ≥30) have on average 55% (95%CI: 46%-66%), 68% (95%CI: 59%-76%), and 39% (95%CI: 29%-49%) larger kidneys, liver, and pancreas, respectively. We also find a significant linear relationship between the increase in organ volume and the increase in cancer risk (P-value<10−12). These results provide a mechanism explaining why obese individuals have higher cancer risk in several organs: the larger the organ volume the more cells at risk of becoming cancerous. These findings are important for a better understanding of the effects that obesity has on cancer risk and, more generally, for the development of better preventive strategies to limit the mortality caused by obesity.
Mutagenicity of folic acid deficiency and supplementation is tissue-specific and results in distinct mutation profiles
Authors: Diaz G. Stephanie , LeBlanc Danielle P. , Gagné Remi , Behan Nathalie A. , Wong Alex , Marchetti Francesco , MacFarlane Amanda J.
Published: July 2020

Cancer incidence varies by tissue due to differences in environmental risk factor exposure, gene variant inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia. Conversely, high folic acid (FA) intake has been associated with higher CRC risk. However, the mutagenic potential of FA intake in different tissues has not been characterized. Here we quantified mutations in folate-susceptible somatic tissues, namely bone marrow and colon, from the same MutaMouse mice and determined the FA-induced mutation profiles of both tissues using next generation sequencing. FA-induced mutagenesis was tissue- and dose-specific: FA deficiency increased mutant frequency (MF) in bone marrow while FA supplementation increased MF in colon. Analyses of mutation profiles suggested that FA interacted with mutagenic mechanisms that are unique to each tissue. These data illuminate potential mechanisms underpinning differences in susceptibility to FA-related cancers.
DehydratedCaenorhabditis elegansstocks are resistant to multiple freeze-thaw cycles
Authors: McClanahan Patrick D. , McCloskey Richard J. , Hing Melanie Ng Tung , Raizen David M. , Fang-Yen Christopher
Published: July 2020

Ultracold preservation is widely used for storage of genetic stocks ofCaenorhabditis elegans. Current cryopreservation protocols are vulnerable to refrigeration failures, which can result in the loss of stock viability due to damage during re-freezing. Here we present a method for preserving worms in a dehydrated and frozen form that retains viability after multiple freeze/thaw cycles. After dehydration in the presence of trehalose or glycerol,C. elegansstocks can be frozen and thawed multiple times while maintaining viability. While both dauer and non-dauer larvae survive desiccation and freezing, the dauer defective mutantdaf-16does not survive desiccation. Our technique is useful for storing stocks in a manner robust to freezer failures, and potentially for shipping strains between laboratories.
High resolution mouse subventricular zone stem cell niche transcriptome reveals features of lineage, anatomy, and aging
Authors: Xie Xuanhua P. , Laks Dan R. , Sun Daochun , Poran Asaf , Laughney Ashley M. , Wang Zilai , Sam Jessica , Belenguer German , Fariñas Isabel , Elemento Olivier , Zhou Xiuping , Parada Luis F.
Published: July 2020

Adult neural stem cells (NSC) serve as a reservoir for brain plasticity and origin for certain gliomas. Lineage tracing and genomic approaches have portrayed complex underlying heterogeneity within the major anatomical location for NSC, the subventricular zone (SVZ). To gain a comprehensive profile of NSC heterogeneity, we utilized a well validated stem/progenitor specific reporter transgene in concert with single cell RNA sequencing to achieve unbiased analysis of SVZ cells from infancy to advanced age. The magnitude and high specificity of the resulting transcriptional data sets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia), and non-central nervous system cells (endothelial, immune). Initial mining of the data delineates four quiescent NSC and three progenitor cell subpopulations formed in a linear progression. Further evidence indicates that distinct stem and progenitor populations reside in different regions of the SVZ. As stem/progenitor populations progress from neonatal to advanced age, they acquire a deficiency in transition from quiescence to proliferation. Further data mining identifies stage specific biological processes, transcription factor networks, and cell surface markers for investigation of cellular identities, lineage relationships, and key regulatory pathways in adult NSC maintenance and neurogenesis.

Significance Statement

Adult neural stem cells (NSC) are closely related to multiple neurological disorders and brain tumors. Comprehensive investigation of their composition, lineage, and aging will provide new insights that may lead to enhanced patient treatment. This study applies a novel transgene to label and manipulate neural stem/progenitor cells, and monitor their evolution during aging. Together with high-throughput single cell RNA sequencing, we are able to analyze the subventricular zone (SVZ) cells from infancy to advanced age with unprecedented granularity. Diverse new cell states are identified in the stem cell niche, and an aging related NSC deficiency in transition from quiescence to proliferation is identified. The related biological features provide rich resources to inspect adult NSC maintenance and neurogenesis.
CelLEVITAS: Label-free rapid sorting and enrichment of live cells via magnetic levitation
Authors: Chin Elliot K. , Grant Colin A. , Ogut Mehmet Giray , Cai Bocheng , Durmus Naside Gozde
Published: July 2020

Sorting methods that remove non-viable cells and debris, while retaining a high yield of viable cells, are crucial for many applications in biotechnology, genomics, tissue engineering and medicine. However, a significant challenge is gentle sorting of these different cell states based on very minute differences in density and magnetic signatures, without relying on any labels, tags or markers. Here, a new magnetic levitation-based technology, CelLEVITAS, is developed for the label-free sorting and enrichment of live cells. This work reports the first use of magnetic levitation for sorting of viable and non-viable cells within a microfluidic device and demonstrates extremely effective removal of dead cells and debris from heterogeneous samples. First, the levitation conditions for separating viable and non-viable cells under a magnetic field were fine-tuned. Levitation trajectories of live and dead cell states were then monitored in real-time, as cells magnetically focused to their corresponding levitation bands. CelLEVITAS successfully sorted and enriched live cells from a variety of input cell concentrations (100-200,000 cells/mL) and a variety of input purities (10-50%) into consistently high output purities (>80%). This method is sensitive, does not impair cell viability during sorting, and significantly increases the input sample viability up to 7-fold. Overall, this new magnetic levitation-based sorting strategy drastically reduces the processing time to a single-step, 30-minute sorting protocol and eliminates the manual pre-processing and labeling steps that are required for traditional flow cytometry techniques.
Insights into the catalytic properties of the mitochondrial rhomboid protease PARL
Authors: Lysyk Laine , Brassard Raelynn , Arutyunova Elena , Siebert Verena , Jiang Zhenze , Takyi Emmanuella , Morrison Melissa , Young Howard S. , Lemberg Marius K. , O’Donoghue Anthony J. , Lemieux M. Joanne
Published: July 2020

The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac, which have crucial roles in mitochondrial quality control and apoptosis. To gain insight into the catalytic properties of the PARL protease, we expressed human PARL in yeast and used FRET-based kinetic assays to measure proteolytic activityin vitro. We show PARL activity in detergent is enhanced by cardiolipin. Significantly higher turnover rates are observed for PARL reconstituted in proteoliposomes, with Smac being cleaved most rapidly at a rate of 1 min−1. PGAM5 is cleaved with the highest efficiency compared to PINK1 and Smac. In proteoliposomes, a truncated β-cleavage form of PARL is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5 and Smac. Multiplex substrate profiling reveals a substrate preference for PARL with a bulky side chain Phe in P1, which is distinct from small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences.
Low Dose Lead Exposure Induces Alterations on Heterochromatin Hallmarks Persisting Through SH-SY5Y Cell Differentiation
Authors: Lin Li , Xie Junkai , Sanchez Oscar F. , Bryan Chris , Freeman Jennifer , Yuan Chongli
Published: July 2020

Lead (Pb) is a commonly found heavy metal due to its historical applications. Recent studies have associated the early-life Pb exposure with the onset of various neurodegenerative disease. The molecular mechanisms of Pb conferring long-term neurotoxicity, however, is yet to be elucidated. In this study, we explored the persistency of alteration in epigenetic marks that arise from exposure to low dose of Pb using a combination of image-based and gene expression analysis. Using SH-SY5Y as a model cell line, we observed significant alterations in global 5-methycytosine (5mC) and histone 3 lysine 27 tri-methylation (H3K27me3) and histone 3 lysine 9 tri-methylation (H3K9me3) levels in a dose-dependent manner immediately after Pb exposure. The changes are partially associated with alterations in epigenetic enzyme expression levels. Long term culturing (14 days) after cease of exposure revealed persistent changes in 5mC, partial recovery in H3K9me3 and overcompensation in H3K27me3 levels. The observed alterations in H3K9me3 and H3K27me3 are reversed after neuronal differentiation, while reduction in 5mC levels are amplified with significant changes in patterns as identified via texture clustering analysis. Moreover, correlation analysis demonstrates a strong positive correlation between trends of 5mC alteration after differentiation and neuronal morphology. Collectively, our results suggest that exposure to low dose of Pb prior to differentiation can result in persistent epigenome alterations that can potentially be responsible for observed phenotypic changes.
The Development of a Pipeline for the Identification and Validation of Small-Molecule RelA Inhibitors for Use as Anti-biofilm Drugs
Authors: Hall Donald C. , Król Jarosław E. , Cahill John P. , Ji Hai-Feng , Ehrlich Garth D.
Published: July 2020

Biofilm infections have no effective medical treatments and can only be disrupted via physical means. This means that any biofilm infection that is not addressable surgically can never be eliminated and can only be managed as a chronic disease. Therefore, there is an urgent need for the development of new classes of drugs that can target the metabolic mechanisms within biofilms which render them recalcitrant to traditional antibiotics. This antibiotic recalcitrance of bacterial biofilms can be attributed largely to the formation of persister cells within the biofilm structure. These biofilm persister cells can be resistant to up to 1000 times the minimal inhibitory concentrations of many antibiotics as compared to their planktonic envirovars; they are thought to be the prokaryotic equivalent of metazoan stem cells. Their metabolic resistance has been demonstrated to be an active process induced by the stringent response that is triggered by the ribosomally-associated enzyme RelA in response to amino acid starvation. This 84-kD pyrophosphokinase produces the “magic spot” alarmones, collectively called (p)ppGpp. These alarmones act by directly regulating transcription by binding to RNA polymerase. These transcriptional changes lead to a major shift in cellular function to both upregulate oxidative stress-combating enzymes and down regulate major cellular functions associated with growth and replication. These changes in gene expression produce the quiescent persister cells. In this work, we describe a hybridin silico-laboratory pipeline for identifying and validating small-molecule inhibitors of RelA for use in the combinatorial treatment of bacterial biofilms as re-potentiators of classical antibiotics.
Mechanistic modelling of coronavirus infections and the impact of confined neighbourhoods on a short time scale
Authors: Ahmed Danish A , Ansari Ali R , Imran Mudassar , Dingle Kamaludin , Ahmed Naveed , Bonsall Michael B
Published: July 2020

Background

To mitigate the spread of the COVID-19 coronavirus, some countries have adopted more stringent non-pharmaceutical interventions in contrast to those widely used (for e.g. the state of Kuwait). In addition to standard practices such as enforcing curfews, social distancing, and closure of non-essential service industries, other non-conventional policies such as the total confinement of highly populated areas has also been implemented.

Methods

In this paper, we model the movement of a host population using a mechanistic approach based on random walks, which are either diffusive or super-diffusive. Infections are realised through a contact process, whereby a susceptible host may be infected if in close spatial proximity of the infectious host. Our focus is only on the short-time scale prior to the infectious period, so that no further transmission is assumed.

Results

We find that the level of infection depends heavily on the population dynamics, and increases in the case of slow population diffusion, but remains stable for a high or super-diffusive population. Also, we find that the confinement of homogeneous or overcrowded sub-populations has minimal impact in the short term.

Conclusions

Our results indicate that on a short time scale, confinement restrictions or complete lock down of whole residential areas may not be effective. Finally, we discuss the possible implications of our findings for total confinement in the context of the current situation in Kuwait.
Multimorbidity patterns among COVID-19 deaths: considerations for a better medical practice
Authors: Fernández-Niño Julián A. , Guerra-Gómez John A. , Idrovo Alvaro J.
Published: July 2020

Medical care of individuals diagnosed with severe COVID-19 is complex, especially when patients are older adults with multimorbidity. The objective of this study was to describe patterns of multimorbidity among fatal cases of COVID-19. Data of Colombian confirmed deaths of COVID-19 until June 11, 2020, were included in this analysis (1488 deaths). Relationships between COVID-19, combinations of health conditions and age were explored using locally weighted polynomial regressions. Some multimorbidity patterns increase probability of death among older individuals, whereas other patterns are not age-related, or decreases the probability of death among older people. Consider multimorbidity in the medical management of COVID-19 patients is important to determine the more adequate medical interventions. In addition to the co-occurrence of COVID-19 with diseases of high prevalence in the world, in Colombia there are cases more complex with COVID-19 co-occur with endemic and orphan tropical diseases. In these cases, although its occurrence may be low, clinical management requires adjusting to its complex clinical condition.
Assessing the (Un)Trustworthiness of Saliency Maps for Localizing Abnormalities in Medical Imaging
Authors: Arun Nishanth , Gaw Nathan , Singh Praveer , Chang Ken , Aggarwal Mehak , Chen Bryan , Hoebel Katharina , Gupta Sharut , Patel Jay , Gidwani Mishka , Adebayo Julius , Li Matthew D. , Kalpathy-Cramer Jayashree
Published: July 2020

Saliency maps have become a widely used method to make deep learning models more interpretable by providing post-hoc explanations of classifiers through identification of the most pertinent areas of the input medical image. They are increasingly being used in medical imaging to provide clinically plausible explanations for the decisions the neural network makes. However, the utility and robustness of these visualization maps has not yet been rigorously examined in the context of medical imaging. We posit that trustworthiness in this context requires 1) localization utility, 2) sensitivity to model weight randomization, 3) repeatability, and 4) reproducibility. Using the localization information available in two large public radiology datasets, we quantify the performance of eight commonly used saliency map approaches for the above criteria using area under the precision-recall curves (AUPRC) and structural similarity index (SSIM), comparing their performance to various baseline measures. Using our framework to quantify the trustworthiness of saliency maps, we show that all eight saliency map techniques fail at least one of the criteria and are, in most cases, less trustworthy when compared to the baselines. We suggest that their usage in the high-risk domain of medical imaging warrants additional scrutiny and recommend that detection or segmentation models be used if localization is the desired output of the network.
Disparities in Case Frequency and Mortality of Coronavirus Disease 2019 (COVID-19) Among Various States in the United States
Authors: Loomba Rohit S. , Aggarwal Gaurav , Aggarwal Saurabh , Flores Saul , Villarreal Enrique G. , Farias Juan S. , Lavie Carl J.
Published: July 2020

Objective

To utilize publicly reported, state-level data to identify factors associated with the frequency of cases, tests, and mortality in the US.

Materials & Methods

Retrospective study using publicly reported data collected included the number of COVID-19 cases, tests, and mortality from March 14ththrough April 30th, 2020. Publicly available state-level data was collected which included: demographics comorbidities, state characteristics and environmental factors. Univariate and multivariate regression analyses were performed to identify the significantly associated factors with percent mortality, case and testing frequency. All analyses were state-level analyses and not patient-level analyses.

Results

A total of 1,090,500 COVID-19 cases were reported during the study period. The calculated case and testing frequency were 3,332 and 19,193 per 1,000,000 patients. There were 63,642 deaths during this period which resulted in a mortality of 5.8%. Factors including to but not limited to population density (beta coefficient 7.5, p< 0.01), transportation volume (beta coefficient 0.1, p< 0.01), tourism index (beta coefficient -0.1, p=0.02) and older age (beta coefficient 0.2, p=0.01) are associated with case frequency and percent mortality.

Conclusions

There were wide variations in testing and case frequencies of COVID-19 among different states in the US. States with higher population density had a higher case and testing rate. States with larger population of elderly and higher tourism had a higher mortality.

Key Messages

There were wide variations in testing and case frequencies of COVID-19 among different states in the US.

States with higher population density had a higher case and testing rate.

States with larger population of elderly and higher tourism had a higher mortality.
SARS-CoV-2 detection with de novo designed synthetic riboregulators
Authors: Köksaldi İlkay Çisil , Ahan Recep Erdem , Köse Sila , Haciosmanoğlu Nedim , Şahin Kehribar Ebru , Güngen Murat Alp , Özkul Aykut , Özgür Şafak Şeker Urartu
Published: July 2020

Sars-CoV-2 is a human pathogen and is the main cause of COVID-19 disease. COVID-19 is announced as a global pandemic by World Health Organization. COVID-19 is characterized by severe conditions and early diagnosis can make dramatic changes both for personal and public health. In order to increase the reach for low cost equipment which requires a very limited technical knowledge can be beneficial to diagnose the viral infection. Such diagnostic capabilities can have a very critical role to control the transmission of the disease. Here we are reporting a state-of-the-art diagnostic tool developed by using an in vitro synthetic biology approach by employing engineered de novo riboregulators. Our design coupled with a home-made point-of-care device setting can detect and report presence of Sars-CoV-2 specific genes. The presence of Sars-CoV-2 related genes triggers translation of sfGFP mRNAs, resulting in green fluorescence output. The approach proposed here has the potential of being a game changer in Sars-COV-2 diagnostics by providing an easy-to-run, low-cost-demanding diagnostic capability.
Models of SIV rebound after treatment interruption that involve multiple reactivation events
Authors: van Dorp Christiaan H. , Conway Jessica M. , Whitney James B. , Barouch Dan H. , Perelson Alan S.
Published: July 2020

In order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevychet al.and Hillet al.of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate, and a 11% decrease of the viral growth rate. We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.

Author Summary

HIV-1 persists during suppressive antiretroviral therapy (ART) due to a reservoir of latently infected cells. When ART is stopped, HIV generally rebounds within a few weeks. However, there is a small fraction of patients that do not rebound over a period of months or years. A variety of treatments are being tested for their ability to reduce the size of the latent reservoir, to induce effective immune responses against the virus, or to prevent or prolong the time to viral rebound after ART interruption. These novel treatments are typically first tested in SIV infected macaques, and the efficacy of the treatment assessed by interrupting ART and measuring the time to viral rebound. Here, we develop and test a mathematical and statistical model that describes the process of viral rebound. The model can be used for statistical inference of the efficacy of newly developed treatments. Importantly, the model takes into account that multiple recrudescence events can precede rebound. We test the model using data from early treated SIV infected macaques.
Patient-tailored design of AML cell subpopulation-selective drug combinations
Authors: Ianevski Aleksandr , Lahtela Jenni , Javarappa Komal K. , Sergeev Philipp , Ghimire Bishwa R. , Gautam Prson , Vähä-Koskela Markus , Turunen Laura , Linnavirta Nora , Kuusanmäki Heikki , Kontro Mika , Porkka Kimmo , Heckman Caroline A. , Mattila Pirkko , Wennerberg Krister , Giri Anil K. , Aittokallio Tero
Published: July 2020

The extensive primary and secondary drug resistance in acute myeloid leukemia (AML) requires rational approaches to design personalized combinatorial treatments that exploit patient-specific therapeutic vulnerabilities to optimally target disease-driving AML cell subpopulations. However, the large number of AML-relevant drug combinations makes the testing impossible in scarce primary patient cells. This combinatorial problem is further exacerbated by the translational challenge of how to design such personalized and selective drug combinations that do not only show synergistic effect in overall AML cell killing but also result in minimal toxic side effects on non-malignant cells. To solve these challenges, we implemented a systematic computational-experimental approach for identifying potential drug combinations that have a desired synergy-efficacy-toxicity balance. Our mechanism-agnostic approach combines single-cell RNA-sequencing (scRNA-seq) withex vivosingle-agent viability testing in primary patient cells. The data integration and predictive modelling are carried out at a single-cell resolution by means of a machine learning model that makes use of compound-target interaction networks to narrow down the massive search space of potentially effective drug combinations. When applied to two diagnostic and two refractory AML patient cases, each having a different genetic background, our integrated approach predicted a number of patient-specific combinations that were shown to result not only in synergistic cancer cell inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Overall, 53% of the 59 predicted combinations were experimentally confirmed to show synergy, and 83% were non-antagonistic, as validated with viability assays, which is a significant improvement over the success rate of randomly guessing a synergistic drug combination (5%). Importantly, 67% of the predicted combinations showed low toxicity to non-malignant cells, as validated with flow-based population assays, suggesting their selective killing of AML cell populations. Our data-driven approach provides an unbiased means for systematic prioritization of patient-specific drug combinations that selectively inhibit AML cells and avoid co-inhibition of non-malignant cells, thereby increasing their likelihood for clinical translation. The approach uses only a limited number of patient primary cells, and it is widely applicable to hematological cancers that are accessible for scRNA-seq profiling andex vivocompound testing.
Stem girth changes in response to soil water potential in lowland dipterocarp forest in Borneo: a phenomenological and individualistic time-series analysis
Authors: Newbery D. M. , Lingenfelder M.
Published: July 2020

Time series data offer a way of investigating the causes driving ecological processes as phenomena. To test for possible differences in water relations between species of different forest structural guilds at Danum (Sabah, NE Borneo), daily stem girth increments (gthi), of 18 trees across six species were regressed individually on soil moisture potential (SMP) and temperature (TEMP), accounting for temporal autocorrelation (in GLS-arima models), and compared between a wet and a dry period. The best-fitting significant variables were SMP the day before and TEMP the same day. The first resulted in a mix of positive and negative coefficients, the second largely positive ones. An adjustment for dry-period showers was applied. Interactions were stronger in dry than wet period. Negative relationships for overstorey trees can be interpreted in a reversed causal sense: fast transporting stems depleted soil water and lowered SMP. Positive relationships for understorey trees meant they took up most water at high SMP. The unexpected negative relationships for these small trees may have been due to their roots accessing deeper water supplies (if SMP was inversely related to that of the surface layer), and this was influenced by competition with larger neighbour trees. A tree-soil flux dynamics manifold may have been operating. Patterns of mean diurnal girth variation were more consistent among species, and time-series coefficients were negatively related to their maxima. Expected differences in response to SMP in the wet and dry periods did not clearly support a previous hypothesis differentiating drought and non-drought tolerant understorey guilds. Trees within species showed highly individual responses when tree size was standardized. Data on individual root systems and SMP at several depths are needed to get closer to the mechanisms that underlie the tree-soil water phenomena in these tropical forests. Neighborhood stochasticity importantly creates varying local environments experienced by individual trees.
CHK2 inhibition provides a strategy to suppress hematological toxicity from PARP inhibitors
Authors: Xu Zhen , Vandenberg Cassandra J , Lieschke Elizabeth , Scott Clare L , Majewski Ian J
Published: July 2020

Cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) experience various side effects, with hematological toxicity being most common. Short term treatment of mice with olaparib resulted in depletion of reticulocytes, B cell progenitors and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen targeting DNA repair genes to identify strategies to suppress hematological toxicity. The screen revealed that sgRNAs targeting the serine/threonine kinase CHK2 were enriched following olaparib treatment. Genetic or pharmacological inhibition of CHK2 blunted PARPi response in lymphoid and myeloid cell lines, and in primary pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short-circuit this response. Cotreatment with a CHK2 inhibitor did not antagonise olaparib response in ovarian cancer cells. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs.
Citizen science, cells and CNNs – deep learning for automatic segmentation of the nuclear envelope in electron microscopy data, trained with volunteer segmentations
Authors: Spiers Helen , Songhurst Harry , Nightingale Luke , de Folter Joost , Hutchings Roger , Peddie Christopher J , Weston Anne , Strange Amy , Hindmarsh Steve , Lintott Chris , Collinson Lucy M , Jones Martin L
Published: July 2020

Advancements in volume electron microscopy mean it is now possible to generate thousands of serial images at nanometre resolution overnight, yet the gold standard approach for data analysis remains manual segmentation by an expert microscopist, resulting in a critical research bottleneck. Although some machine learning approaches exist in this domain, we remain far from realising the aspiration of a highly accurate, yet generic, automated analysis approach, with a major obstacle being lack of sufficient high-quality ground-truth data. To address this, we developed a novel citizen science project, Etch a Cell, to enable volunteers to manually segment the nuclear envelope of HeLa cells imaged with Serial Blockface SEM. We present our approach for aggregating multiple volunteer annotations to generate a high quality consensus segmentation, and demonstrate that data produced exclusively by volunteers can be used to train a highly accurate machine learning algorithm for automatic segmentation of the nuclear envelope, which we share here, in addition to our archived benchmark data.
A Portable Impedance Microflow Cytometer for Measuring Cellular Response to Hypoxia
Authors: Dieujuste Darryl , Qiang Yuhao , Du E
Published: July 2020

This paper presents the development and testing of a low-cost, portable microflow cytometer based on electrical impedance sensing, for single cell analysis under controlled oxygen microenvironment. The cytometer system is based on an AD5933 impedance analyzer chip, a microfluidic chip, and an Arduino microcontroller operated by a custom Android application. A representative case study on human red blood cells (RBCs) affected by sickle cell disease is conducted to demonstrate the capability of the cytometry system. Equivalent circuit model of a suspending biological cell is used to interpret the electrical impedance of single flowing RBCs. In normal blood, cytoplasmic resistance and membrane capacitance do not change significantly with the change in oxygen tension. In contrast, RBCs affected by sickle cell disease show that upon hypoxia treatment, the cytoplasmic resistance decrease from 11.6 MΩ to 23.4 MΩ, and membrane capacitance decrease from 1.1 pF to 0.8 pF. Strong correlations are identified between the changes in these subcellular electrical components of single cells and the cell sickling process induced by hypoxia treatment. The representative results reported in this paper suggest that single cell electrical impedance can be used as a sensitive biophysical marker for quantifying cellular response to change in oxygen concentration. The developed flow cytometry system and the methodology can also be extended to analysis of cellular response to hypoxia in other cell types.
Lipidome profiles of plasma microvesicles differ in experimental cerebral malaria, compared to malaria without neurological complications
Authors: Batarseh Amani M , Vafaee Fatemeh , Hosseini-Beheshti Elham , Chen Alex , Cohen Amy , Juillard Annette , Hunt Nicholas Henry , Mariani Michael , Mitchell Todd , Raymond Grau Georges Emile
Published: July 2020

Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms, which include an excessive release of microvesicles (MV). Plasma MV levels have been found elevated in CM patients and in the experimental mouse model.

We compared lipid profiles in circulating MV purified from CBA mice infected withP. bergheiANKA (PbA), which causes CM, to those fromP. yoelii(Py), which does not. Here we show that plasma MV produced at the time of CM differed dramatically from those from non-CM mice, in spite of identical levels of parasitaemia. Using high-resolution LCMS, we identified over 300 lipid species within 12 lipid classes. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to uninfected mice, while they were unchanged in Py MV, and lysophosphatidylcholine (LPC) was more significantly reduced in PbA mice compared to the other two groups. These results suggest, for the time, that experimental CM is characterised by specific changes in lipid composition of circulating MV, pointing towards triglycerides (TG) especially docosahexaenoic acid (DHA 22:6) containing species, phosphatidylethanolamine (PE), LPC, LPE, and diacylglycerol (DG) as potential important players in CM pathogenesis.
Deep Texture Representations as a Universal Encoder for Pan-cancer Histology
Authors: Komura Daisuke , Kawabe Akihiro , Fukuta Keisuke , Sano Kyohei , Umezaki Toshikazu , Koda Hirotomo , Suzuki Ryohei , Tominaga Ken , Konishi Hiroki , Nishida Shu , Furuya Genta , Katoh Hiroto , Ushiku Tetsuo , Fukayama Masahi , Ishikawa Shumpei
Published: July 2020

Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented direct comparison and accumulation of large-scale datasets. Here we show that deep texture representations (DTRs) produced by a bilinear Convolutional Neural Network, express cancer morphology well in an unsupervised manner, and work as a universal encoder for cancer histology. DTRs are useful for content-based image retrieval, enabling quick retrieval of histologically similar images from optimally area selected datasets of 7,175 cases from The Cancer Genome Atlas. Via comprehensive comparison with driver and clinically actionable gene mutations, we have successfully predicted 309 combinations of genomic features and cancer types from hematoxylin and eosin-stained images at high accuracy (AUC > 0.70 and q < 0.02). With its mounting capabilities on accessible devices such as smartphones, DTR-based encoding for cancer histology has a potentially strong impact on global equalization for cancer diagnosis and targeted therapies.