bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-dependence of healthcare interventions for SARS-CoV-2 infection in Ontario, Canada
Authors: Papst Irena , Li Michael , Champredon David , Bolker Benjamin M. , Dushoff Jonathan , Earn David J.D.
Published: September 2020

Background

Patient age is the most salient clinical indicator of risk from COVID-19. Age-specific distributions of known SARS-CoV-2 infections and COVID-19-related deaths are available for most countries. However, relatively little attention has been given to the age distributions of hospitalizations and serious healthcare interventions administered to COVID-19 patients. We examined these distributions in Ontario, Canada, in order to quantify the age-related impacts of COVID-19, and to identify potential risks should the healthcare system become overwhelmed with COVID-19 patients in the future.

Methods

We analysed known SARS-CoV-2 infection records from the integrated Public Health Information System (iPHIS) and the Toronto Public Health Coronavirus Rapid Entry System (CORES) between 23 January 2020 and 17 June 2020 (N = 30,546), and estimated the age distributions of hospitalizations, ICU admissions, intubations, and ventilations. We quantified the probability of hospitalization given known SARS-CoV-2 infection, and of survival given COVID-19-related hospitalization.

Results

The distribution of COVID-19-related hospitalizations peaks with a wide plateau covering ages 54-90, whereas deaths are sharply concentrated in very old ages, with a maximum at age 90. The estimated probability of hospitalization given known SARS-CoV-2 infection reaches a maximum of 32.0% at age 75 (95% CI 27.5%-36.7%). The probability of survival given COVID-19-related hospitalization is uncertain for children (due to small sample size), and near 100% for adults younger than 40. After age 40, survival of hospitalized COVID-19 patients declines substantially; for example, a hospitalized 50-year-old patient has a 90.4% chance of surviving COVID-19 (95% CI 81.9%-95.7%).

Interpretation

Concerted efforts to control the spread of SARS-CoV-2 have kept prevalence of the virus low in the population of Ontario. The healthcare system has not been overstretched, yet the probability of survival given hospitalization for COVID-19 has been lower than is generally recognized for patients over 40. If prevalence of the virus were to increase and healthcare capacities were to be exceeded, survival of individuals in the broad age range requiring acute care would be expected to decrease, potentially expanding the distribution of COVID-19-related deaths toward younger ages.
Investigating post-breeding moult locations and diets of Common Guillemots (Uria aalge) in the North Sea using stable isotope analyses
Authors: Christie Alec P.
Published: September 2020

Seabird movements and diet during the non-breeding season are poorly studied, yet understanding these aspects of seabird ecology is extremely important to effectively conserve these protected species. Stable isotope analyses (SIA) provide a cost-effective solution to filling these knowledge gaps, yielding information on diet and foraging locations of animals. This study aimed to use SIA to investigate whether Common Guillemots (Uria aalge) from different age classes and locations in the UK had contrasting diets and foraging areas during the post-breeding moult (July-September). SIA of secondary feathers and a newly-developed North Sea isoscape were used to identify the likeliest foraging areas and diets of deceased guillemots recovered from beaches in eastern Scotland and mixed fisheries in Cornwall and the Celtic Sea. Overall, guillemots foraged widely in the western, eastern and southern North Sea, consuming a variety of clupeid, gadoid and invertebrate prey. There were negligible dietary differences between age classes and birds from different recovery locations. Juveniles showed a wider range in foraging areas, but both age classes foraged in similar parts of the North Sea. Guillemots recovered from Scotland may have foraged further north, only overlapping with guillemots recovered from the southwestern UK in the southern and eastern North Sea. Their winter recovery locations also implied that they exhibited different movement strategies during the non-breeding season, meriting further investigation. Conservation efforts should target foraging areas in the southern and eastern North Sea which are highly threatened by gillnet fishing, shipping traffic and oil infrastructure.
Experimentally disambiguating models of sensory cue integration
Authors: Scarfe Peter
Published: September 2020

Sensory cue integration is one of the primary areas in which a normative mathematical framework has been used to define the “optimal” way in which to make decisions based upon ambiguous sensory information and compare these predictions to behaviour. The conclusion from such studies is that sensory cues are integrated in a statistically optimal fashion. However, numerous alternative computational frameworks exist by which sensory cues could be integrated, many of which could be described as “optimal” based on different criteria. Existing studies rarely assess the evidence relative to different candidate models, resulting in an inability to conclude that sensory cues are integrated according to the experimenter’s preferred framework. The aims of the present paper are to summarise and highlight the implicit assumptions rarely acknowledged in testing models of sensory cue integration, as well as to introduce an unbiased and principled method by which to determine, for a given experimental design, the probability with which a population of observers behaving in accordance with one model of sensory integration can be distinguished from the predictions of a set of alternative models.
The Epidermal Barrier is Indispensable for Systemic Energy Homeostasis
Authors: Kruse Vibeke , Neess Ditte , Marcher Ann-Britt , Wæde Mie Rye , Vistisen Julie , Møller Pauline M. , Petersen Rikke , Brewer Jonathan R. , Ma Tao , Colleluori Georgia , Severi Ilenia , Cinti Saverio , Gerhart-Hines Zach , Mandrup Susanne , Færgeman Nils J.
Published: September 2020

Objectives

Homeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures.

Methods

To unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/-and skin-specific ACBP-/-knockout mice) or defects in skin structural proteins (ma/ma Flgft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT).

Results

We show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30°C) or by pharmacological β-adrenergic blocking. These findings show that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature.

Conclusion

Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis.

Highlights

Energy expenditure is significantly augmented in mice with impaired epidermal barrier.

Mice with compromised barrier display increased food intake while maintaining normal bodyweight.

Mice with an impaired epidermal barrier are resistant to diet-induced obesity and insulin resistance.

Compromised barrier function induces expression of brown-selective gene programs in iWAT.

Thermoneutral housing or blocking β-adrenergic signaling prevents induction of brite-selective genes in iWAT and reverses food intake.
ASO-basedPKMSplice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth
Authors: Ma Wai Kit , Voss Dillon M. , Scharner Juergen , Costa Ana S. H. , Lin Kuan-Ting , Jeon Hyun Yong , Wilkinson John E. , Jackson Michaela , Rigo Frank , Bennett C. Frank , Krainer Adrian R.
Published: September 2020

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in the Warburg effect, which is characterized by the preference for aerobic glycolysis for energy metabolism. PKM2 is an alternative-splice isoform of thePKMgene and is a potential therapeutic target. Previously, we developed antisense oligonucleotides (ASOs) that switchPKMsplicing from the cancer-associatedPKM2to thePKM1isoform and induce apoptosis in cultured glioblastoma cells. Here, we explore the potential of ASO-basedPKMsplice-switching as a targeted therapy for liver cancer. We utilize a more potent lead cEt/DNA ASO and demonstrate that it inducesPKMsplice-switching and inhibits the growth of cultured hepatocellular-carcinoma (HCC) cells. ThisPKMisoform switch increases pyruvate-kinase activity and alters glucose metabolism. The lead ASO and a second ASO targeting a non-overlapping site inhibit tumorigenesis in an orthotopic-xenograft HCC mouse model. Finally, a surrogate mouse-specific ASO inducesPkmsplice-switching and inhibits HCC growth, without observable toxicity, in a genetic HCC mouse model. These results lay the groundwork for a potential ASO therapy for HCC.

Statement of significance

Antisense oligonucleotides are used to force a change inPKMisoform usage in HCC, reversing the Warburg effect and inhibiting tumorigenesis.
The Effect of Population Structure on Murine Genome-Wide Association Studies
Authors: Wang Meiyue , Fang Zhuoqing , Yoo Boyoung , Bejerano Gill , Peltz Gary
Published: September 2020

Population structure (PS) has been shown to cause false positive signals in genome-wide association studies (GWAS). Since PS correction is routinely used in human GWAS, it was assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been thoroughly investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Surprisingly, we found that the PS had a minimal impact on datasets characterizing responses in ≤20 strains; and relatively little impact on the majority of datasets characterizing >20 strains. Moreover, there were examples where association signals within known causative genes could be rejected if PS correction methods were utilized. PS assessment should be carefully used and should be considered in conjunction with other criteria when assessing the candidate genes identified in GWAS using inbred mouse strains.
Manipulation of IRE1-dependent MAPK signaling by a Vibrio agonist-antagonist effector pair
Authors: De Nisco Nicole J. , Casey Amanda K. , Kanchwala Mohammed , Lafrance Alexander E. , Coskun Fatma S. , Kinch Lisa N. , Grishin Nick V. , Xing Chao , Orth Kim
Published: September 2020

Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (1). The type III secretion system 1 of the marine pathogen,Vibrio parahaemolyticus, utilizes the sequential action of four effectors to induce a rapid, pro-inflammatory cell death uniquely characterized by a pro-survival host transcriptional response (2, 3). Herein, we show that this pro-survival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ causing a disruption in membrane integrity. Additionally, we observe that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR) resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveal new connections between V-ATPase function, UPR and MAPK signaling.

Importance

Vibrio parahaemolyticus (V. para)is a seafood-borne pathogen that encodes two Type 3 Secretion Systems (T3SS). The first system T3SS1 is thought to be maintained in all strains ofV. parato to maintain survival in the environment, whereas the second sytem T3SS2 is linked to clinical isolates and disease in humans. Herein, we find that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within three hours. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host surval signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector VopS reverses activation and inhibition of these signaling systems ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.
Digital droplet PCR accurately quantifies SARS-CoV-2 viral load from crude lysate without nucleic acid purification
Authors: Vasudevan Harish N. , Xu Peng , Servellita Venice , Miller Steve , Liu Leqian , Gopez Allan , Chiu Charles Y. , Abate Adam R.
Published: September 2020

The COVID-19 pandemic caused by the SARS-CoV-2 virus motivates diverse diagnostic approaches due to the novel causative pathogen, incompletely understood clinical sequelae, and limited availability of testing resources. Given the variability in viral load across and within patients, absolute viral load quantification directly from crude lysate is important for diagnosis and surveillance. Here, we investigate the use of digital droplet PCR (ddPCR) for SARS-CoV-2 viral load measurement directly from crude lysate without nucleic acid purification. We demonstrate ddPCR accurately quantifies SARS-CoV-2 standards from purified RNA and multiple sample matrices, including commonly utilized universal transport medium (UTM). In addition, we find ddPCR functions robustly at low input viral copy numbers on nasopharyngeal swab specimens stored in UTM without upfront RNA extraction. We also show ddPCR, but not qPCR, from crude lysate shows high concordance with viral load measurements from purified RNA. Our data suggest ddPCR offers advantages to qPCR for SARS-CoV-2 detection with higher sensitivity and robustness when using crude lysate rather than purified RNA as input. More broadly, digital droplet assays provide a potential method for nucleic acid measurement and infectious disease diagnosis with limited sample processing, underscoring the utility of such techniques in laboratory medicine.
Real-time monitoring of COVID-19 dynamics using automated trend fitting and anomaly detection
Authors: Jombart Thibaut , Ghozzi Stéphane , Schumacher Dirk , Leclerc Quentin J , Jit Mark , Flasche Stefan , Greaves Felix , Ward Tom , Eggo Rosalind M , Nightingale Emily , Meakin Sophie , Brady Oliver J ,   Centre for Mathematical Modelling of Infectious Diseases COVID-19 Working Group, Medley Graham F , Höhle Michael , Edmunds W John
Published: September 2020

As several countries gradually release social distancing measures, rapid detection of new localised COVID-19 hotspots and subsequent intervention will be key to avoiding large-scale resurgence of transmission. We introduce ASMODEE (Automatic Selection of Models and Outlier Detection for Epidemics), a new tool for detecting sudden changes in COVID-19 incidence. Our approach relies on automatically selecting the best (fitting or predicting) model from a range of user-defined time series models, excluding the most recent data points, to characterise the main trend in an incidence. We then derive prediction intervals and classify data points outside this interval as outliers, which provides an objective criterion for identifying departures from previous trends. We also provide a method for selecting the optimal breakpoints, used to define how many recent data points are to be excluded from the trend fitting procedure. The analysis of simulated COVID-19 outbreaks suggest ASMODEE compares favourably with a state-of-art outbreak-detection algorithm while being simpler and more flexible. We illustrate our method using publicly available data of NHS Pathways reporting potential COVID-19 cases in England at a fine spatial scale, for which we provide a template automated analysis pipeline. ASMODEE is implemented in the free R package trendbreaker.
The lower-airway microbiome and metabolome in preterm infants: Identifying potential predictive biomarkers of bronchopulmonary dysplasia
Authors: Xu Qi , Yu Jialin , He Junli , Tan Qi , He Yu
Published: September 2020

The lower-airway microbiome may influence the pathogenesis of lung disease. Bronchopulmonary dysplasia (BPD) is a serious morbidity associated with preterm birth that may be influenced by lower-airway microbial or metabolic alterations. This study used16S rRNA gene sequencing, metabolomic analyses, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to investigate the lower-airway microbiome and metabolome in a cohort of preterm infants with mild, moderate, or severe BPD or no BPD. Differences in the diversity and composition of the infants’ lower airway microbiota, as well as metabolic status, were initially observed, but became less pronounced at 7 days of life. Decreased diversity of the lower-airway microbiome, increased abundance ofStenotrophomonas, and increased level of sn-glycerol 3-phosphoethanolamine were associated with increased BPD severity, and have potential as predictive biomarkers for BPD.Stenotrophomonasmay contribute to the development of BPD and influence the composition of the lower-airway microbiome through its metabolite, sn-glycerol 3-phosphoethanolamine. These findings provide novel insights into the lower-airway microbiome and its role in BPD.
A UK national survey of prophylactic platelet transfusion thresholds in non-bleeding, critically ill adults
Authors: Shah Akshay , Gould Doug W , Doidge James , Mouncey Paul R , Harrison David A , Young J Duncan , Stanworth Simon J , Watkinson Peter J
Published: September 2020

Thrombocytopaenia is common in critically ill patients and associated with poor clinical outcomes. Current guideline recommendations for prophylactic platelet transfusions, to prevent bleeding in critically ill patients with thrombocytopaenia, are based on observational data. Recent studies conducted in non-critically ill patients have demonstrated harm associated with platelet transfusions and have also called into question the efficacy of platelet transfusion. To date, there are no well-conducted randomised controlled trials (RCTs) evaluating platelet transfusion in critically ill patients. To inform the design of such an RCT, we sought to characterise current clinical practice across four commonly encountered scenarios in non-bleeding critically ill adult patients with thrombocytopaenia. An online survey link was sent to Clinical Directors and contacts of all adult general ICUs participating in the Intensive Care National Audit and Research Centre Case Mix Programme national clinical audit (n=200). The survey collected data regarding the respondents place of work, training grade and their current individual practice and possible limits of equipoise for prescribing prophylactic platelet transfusions across four scenarios: prophylaxis but with no procedure planned (NPP); ultrasound guided insertion of a right internal jugular central venous catheter (JVI); percutaneous tracheostomy (PT); and surgery with a low bleeding risk (SLBR). After excluding nine responses with missing data on all four of the main questions, responses were received from 99 staff, covering 78 ICUs (39.0% of 200 ICUs invited to participate). While nearly all respondents (98.0%) indicated a platelet transfusion threshold of 30 x 10^9/L or less for patients with no planned procedure, thresholds for planned procedures varied widely and centred at medians of 40 x 10^9/L for JVI (range: 10 to 70), 50 x 10^9/L for SLBR (range: 10 to 100) and 70 x 10^9/L for PT (range: 20 to greater than 100). Current platelet transfusion practice in UK ICUs prior to invasive procedures with relatively low bleeding risks is highly variable. Well-designed studies are needed to determine the optimal platelet transfusion thresholds in critical care.
Temporal stability of the ventral attention network and general cognition along the Alzheimer’s disease spectrum
Authors: Chumin Evgeny J. , Risacher Shannon L. , West John D. , Apostolova Liana G. , Farlow Martin R. , McDonald Brenna C. , Wu Yu-Chien , Saykin Andrew J. , Sporns Olaf
Published: September 2020

Understanding the interrelationships of clinical manifestations of Alzheimer’s disease (AD) and functional connectivity (FC) as the disease progresses is necessary for use of FC as a potential neuroimaging biomarker. Degradation of resting-state networks in AD has been observed when FC is estimated over the entire scan, however, the temporal dynamics of these networks are less studied. We implemented a novel approach to investigate the modular structure of static (sFC) and time-varying (tvFC) connectivity along the AD spectrum in a two-sample Discovery/Validation design (n=80 and 81, respectively). Cortical FC networks were estimated across 4 diagnostic groups (cognitively normal, subjective cognitive decline, mild cognitive impairment, and AD) for whole scan (sFC) and with sliding window correlation (tvFC). Modularity quality (across a range of spatial scales) did not differ in either sFC or tvFC. For tvFC, group differences in temporal stability within and between multiple resting state networks were observed; however, these differences were not consistent between samples. Correlation analyses identified a relationship between global cognition and temporal stability of the ventral attention network, which was reproduced in both samples. While the ventral attention system has been predominantly studied in task-evoked designs, the relationship between its intrinsic dynamics at-rest and general cognition along the AD spectrum highlights its relevance regarding clinical manifestation of the disease.
Computed Tomography Features of COVID-19 in Children: A Systematic Review and Meta-analysis
Authors: Wang Ji-gan , Mo Yu-fang , Su Yu-heng , Wang Li-chuang , Liu Guang-bing , Meng-Li  , Qin Qian-qiu
Published: September 2020

Objectives

To systematically analyze the chest CT imaging features of children with COVID-19 and provide references for clinical practice.

Methods

We searched PubMed, Web of Science, and Embase; data published by Johns Hopkins University; and Chinese databases CNKI, Wanfang, and Chongqing Weipu. Reports on chest CT imaging features of children with COVID-19 from January 1, 2020, to August 10, 2020, were analyzed retrospectively and a meta-analysis carried out using Stata12.0 software.

Results

Thirty-seven articles (1747 children) were included in this study. The overall rate of abnormal lung CT findings was 63.2% (95% confidence interval [CI]: 55.8–70.6%), with a rate of 61.0% (95% CI: 50.8–71.2%) in China and 67.8% (95% CI: 57.1–78.4%) in the rest of the world in the subgroup analysis. The incidence of ground-glass opacities was 39.5% (95% CI: 30.7–48.3%), multiple lung lobe lesions 65.1% (95% CI: 55.1–67.9%), and bilateral lung lesions 61.5% (95% CI: 58.8–72.2%). Other imaging features included nodules (25.7%), patchy shadows (36.8%), halo sign(24.8%), consolidation (24.1%), air bronchogram signs (11.2%), cord-like shadows (9.7%), crazy-paving pattern (6.1%), and pleural effusion (9.1%). Two articles reported three cases of white lung, another reported two cases of pneumothorax, and another one case of bullae.

CONCLUSION

The lung CT results of children with COVID-19 are usually normal or slightly atypica, with a low sensitivity and specificity compared with that in adults. The lung lesions of COVID-19 pediatric patients mostly involve both lungs or multiple lobes, and the common manifestations are patchy shadows, ground-glass opacities, consolidation, partial air bronchogram signs, nodules, and halo signs; white lung, pleural effusion, and paving stone signs are rare.

CLINICAL IMPACT

Therefore, chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool.

Registration

This systematic review and meta-analysis was registered in the Prospero International Prospective Register of Systemic Reviews (CRD42020196602).

Strengths and limitations of this study

The lung CT findings of children with COVID-19 are usually normal or slightly atypical, with a low sensitivity and specificity compared with that in adults. From a systematic review of current literature, the overall rate of abnormal lung CT findings in children was revealed to be 63.2%.

Chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool.

The sample size of some included studies is small, which may affect the results.
Isolation of potential plant growth-promoting bacteria from nodules of legumes grown in arid Botswana soil
Authors: Kosty Melissa , Pule-Meulenberg Flora , Humm Ethan A. , Martínez-Hidalgo Pilar , Maymon Maskit , Mohammadi Sophia , Cary Josh , Yang Paul , Reddi Krisanavane , Huntemann Marcel , Clum Alicia , Foster Brian , Foster Bryce , Roux Simon , Palaniappan Krishnaveni , Varghese Neha , Mukherjee Supratim , Reddy T.B.K. , Daum Chris , Copeland Alex , Ivanova Natalia N. , Kyrpides Nikos C. , del Rio Tajana Glavina , Eloe-Fadrosh Emiley A. , Hirsch Ann M.
Published: September 2020

As the world population increases, improvements in crop growth and yield will be needed to meet rising food demands, especially in countries that have not developed agricultural practices optimized for their own soils and crops. In many African countries, farmers improve agricultural productivity by applying synthetic fertilizers and pesticides to crops, but their continued use over the years has had serious environmental consequences including air and water pollution as well as loss of soil fertility. To reduce the overuse of synthetic amendments, we are developing inocula for crops that are based on indigenous soil microbes, especially those that enhance plant growth and improve agricultural productivity in a sustainable manner. We first isolated environmental DNA from soil samples collected from an agricultural region to study the composition of the soil microbiomes and then used Vigna unguiculata (cowpea), an important legume crop in Botswana and other legumes as “trap” plants using the collected soil to induce nitrogen-fixing nodule formation. We have identified drought-tolerant bacteria from Botswana soils that stimulate plant growth; many are species of Bacillus and Paenibacillus. In contrast, the cowpea nodule microbiomes from plants grown in these soils house mainly rhizobia particularly Bradyrhizobium, but also Methylobacterium spp. Hence, the nodule microbiome is much more limited in non-rhizobial diversity compared to the soil microbiome, but also contains a number of potential pathogenic bacteria.
miR-200deficiency promotes lung cancer metastasis by activating cancer-associated fibroblasts
Authors: Xue Bin , Chuang Chen-Hua , Prosser Haydn M. , Fuziwara Cesar Seigi , Chan Claudia , Sahasrabudhe Neil , Kühn Maximilian , Wu Yalei , Chen Jingqi , Biton Anne , Chen Caifu , Wilkinson John Erby , McManus Michael T. , Bradley Allan , Winslow Monte M , Su Bo , He Lin
Published: September 2020

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identifiedmiR-200miRNAs as potent suppressors for lung adenocarcinoma metastasis.miR-200expression is specifically repressed in mouse metastatic lung adenocarcinomas, andmiR-200decrease strongly correlates with poor patient survival. Consistently, deletion ofmir-200c/141in theKrasLSL-G12D/+; Trp53flox/floxlung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer.miR-200deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells.miR-200regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.
Graph Convolutional Network-based Method for Clustering Single-cell RNA-seq Data
Authors: Zeng Yuansong , Lin Jinxing , Zhou Xiang , Lu Yutong , Yang Yuedong
Published: September 2020

Single-cell RNA sequencing (scRNA-seq) technologies promise to characterize the transcriptome of genes at cellular resolution, which shed light on unfolding cell heterogeneity and diversity. Fast-growing scRNA-seq profiles require efficient clustering algorithms to identify the same type of cells. Although many methods have been developed for cell clustering, existing clustering methods are limited to extract the representations from expression data of individual cells, while ignoring the high-order structural relations between cells. Here, we proposed GraphSCC, a robust graph artificial intelligence model to cluster single cells by accounting for structural relations between cells. The representation learned from the graph convolutional network, together with another representation output from a denoising autoencoder network, are optimized by a dual self-supervised module for better cell clustering. The experimental results indicate that GraphSCC model outperforms state-of-the-art methods in terms of various evaluation metrics on both simulated and real datasets. Further visualizations show that GraphSCC provides representations for better intra-cluster compactness and inter-cluster separability.
C/EBPβ regulates hypertrophic versus hyperplastic fat tissue growth
Authors: Müller Christine , Zidek Laura M. , Eichwald Sabrina , Calkhoven Cornelis F.
Published: September 2020

Chronic obesity is correlated with severe metabolic and cardiovascular diseases as well as with an increased risk for developing cancers. Obesity is usually characterized by fat accumulation in enlarged - hypertrophic – adipocytes that are a source of inflammatory mediators, which is seen as causal for developing metabolic disorders. Yet, in certain healthy obese individuals fat is stored in metabolically more favorablehyperplasticfat tissue that contains an increased number of smaller adipocytes that are less inflamed. In a previous study we demonstrated that C/EBPβ-LIP deficient, yet C/EBPβ-LAP proficient mice show an expanded health and lifespan. Here we show that in mice on a high-fat diet LIP-deficiency results in adipocyte hyperplasia as well as efficient fat storage in subcutaneous depots associated with metabolic and inflammatory improvements. Our data identify C/EBPβ as a regulator of adipocyte fate in response to increased fat intake, which has major implications for metabolic health and aging.
comboFM: leveraging multi-way interactions for systematic prediction of drug combination effects
Authors: Julkunen Heli , Cichonska Anna , Gautam Prson , Szedmak Sandor , Douat Jane , Pahikkala Tapio , Aittokallio Tero , Rousu Juho
Published: September 2020

We presentcomboFM, a machine learning framework for predicting the responses of drug combinations in preclinical studies, such as those based on cell lines or patient-derived cells.comboFMmodels the cell context-specific drug interactions through higher-order tensors, and efficiently learns latent factors of the tensor using powerful factorization machines. The approach enablescomboFMto leverage information from previous experiments performed on similar drugs and cells when predicting responses of new combinations in so far untested cells; thereby, it achieves highly accurate predictions despite sparsely populated data tensors. We demonstrated high predictive performance ofcomboFMin various prediction scenarios using data from cancer cell line drug screening. Subsequent experimental validation of a set of previously untested drug combinations further supported the practical and robust applicability ofcomboFM. For instance, we confirmed a novel synergy between anaplastic lymphoma kinase (ALK) inhibitor crizotinib and proteasome inhibitor bortezomib in lymphoma cells. Overall, our results demonstrate thatcomboFMprovides an effective means for systematic pre-screening of drug combinations to support precision oncology applications.
ETV7 regulates breast cancer stem-like cell plasticity by repressing IFN-response genes
Authors: Pezzè Laura , Forcato Mattia , Pontalti Stefano , Badowska Kalina Aleksandra , Rizzotto Dario , Skvortsova Ira-Ida , Bicciato Silvio , Ciribilli Yari
Published: September 2020

Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-Flouororuacil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24lowcell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-β. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-β treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-β, with the aim of avoiding resistance development and relapse in breast cancer.
CRISPR-nRAGE, a Cas9 nickase-reverse transcriptase assisted versatile genetic engineering toolkit forE. coli
Authors: Tong Yaojun , Jørgensen Tue S. , Whitford Christopher M. , Weber Tilmann , Lee Sang Yup
Published: September 2020

In most prokaryotes, missing and poorly active non-homologous end joining (NHEJ) DNA repair pathways heavily restrict the direct application of CRISPR-Cas for DNA double-strand break (DSB)-based genome engineering without providing editing templates. CRISPR base editors, on the other hand, can be directly used for genome engineering in a number of bacteria, includingE. coli, showing advantages over CRISPR-Cas9, since they do not require DSBs. However, as the current CRISPR base editors can only engineer DNA by A to G or C to T/G/A substitutions, they are incapable of mediating deletions, insertions, and combinations of deletions, insertions and substitutions. To address these challenges, we developed a Cas9 nickase (Cas9n)-reverse transcriptase (Moloney Murine Leukemia Virus, M-MLV) mediated, DSB-free, versatile, and single-nucleotide resolution genetic manipulation toolkit for prokaryotes, termed CRISPR-nRAGE (CRISPR-Cas9n Reverse transcriptase Assisted Genome Engineering) system. CRISPR-nRAGE can be used to introduce substitutions, deletions, insertions, and the combination thereof, both in plasmids and the chromosome ofE. coli. Notably, small sized-deletion shows better editing efficiency compared to other kinds of DNA engineering. CRISPR-nRAGE has been used to delete and insert DNA fragments up to 97 bp and 33 bp, respectively. Efficiencies, however, drop sharply with the increase of the fragment size. It is not only a useful addition to the genome engineering arsenal forE. coli, but also may be the basis for the development of similar toolkits for other organisms.
Peroxisomes contribute to intracellular calcium dynamics
Authors: Sargsyan Yelena , Bickmeyer Uta , Streckfuss-Bömeke Katrin , Bogeski Ivan , Thoms Sven
Published: September 2020

Peroxisomes communicate with other cellular compartments by transfer of various metabolites. However, whether peroxisomes are sites for calcium handling and exchange has remained contentious. Here we generated sensors for assessment of peroxisomal calcium and applied them for single cell-based calcium imaging in HeLa cells and cardiomyocytes. We found that peroxisomes in HeLa cells take up calcium upon depletion of intracellular calcium stores and upon calcium influx across the plasma membrane. Further, we show that peroxisomes of neonatal rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes can take up calcium in a controlled manner. Our results indicate that peroxisomal and cytosolic calcium signals are tightly interconnected. Hence, peroxisomes may play an important role in shaping cellular calcium dynamics by serving as buffers or sources of intracellular calcium.
Human-associated microbiota suppress invading bacteria even under disruption by antibiotics
Authors: Letten Andrew D. , Baumgartner Michael , Pfrunder-Cardozo Katia R. , Levine Jonathan , Hall Alex R.
Published: September 2020

In light of their adverse impacts on resident microbial communities, it is widely predicted that broad-spectrum antibiotics can promote the spread of resistance by releasing resistant strains from competition with other strains and species. We investigated the invasion success of a resistant strain ofEscherichia coliinoculated into human-associated communities in the presence and absence of the broad and narrow spectrum antibiotics rifampicin and polymyxin B, respectively. We found strong evidence of community-level suppression of the resistant strain in the absence of antibiotics and, despite large changes in community composition and abundance following rifampicin exposure, suppression of the invading resistant strain was maintained in both antibiotic treatments. Instead, the strength of competitive suppression was more strongly associated with the individual donor from which the community was sampled. This suggests microbiome composition strongly influences susceptibility to invasion by antibiotic-resistant strains, but at least some antibiotic-associated disruption can be tolerated before invasion susceptibility increases. A deeper understanding of this association will aid the development of ecologically-aware strategies for managing antibiotic resistance.
Phenotypic and transcriptomic responses to stress differ according to population geography in an invasive species
Authors: Marin Pierre , Jaquet Angelo , Picarle Justine , Fablet Marie , Merel Vincent , Delignette-Muller Marie-Laure , Ferrarini Mariana Galvão , Gibert Patricia , Vieira Cristina
Published: September 2020

Background

Adaptation to rapid environmental changes must occur within a short time scale. In this context, studies of invasive species may provide insights into the underlying mechanisms of rapid adaptation as these species have repeatedly encountered and successfully adapted to novel environmental conditions. Here we investigated how invasive and non-invasive populations ofD. suzukiideal with an oxidative stress at both the phenotypic and molecular level. We also investigated the impact of transposable element insertions on the differential gene expression between genotypes in response to oxidative stress.

Results

Invasive populations lived longer in the untreated condition than non-invasive Japanese populations. As expected, lifespan was greatly reduced following exposure to paraquat, but this reduction varied among genotypes (a genotype by environment interaction, GEI) with invasive genotypes appearing more affected by exposure than non-invasive genotypes. We also performed transcriptomic sequencing of selected genotypes upon and without paraquat and detected a large number of genes differentially expressed, distinguishing the genotypes in the untreated environment. While a small core set of genes were differentially expressed by all genotypes following paraquat exposure, much of the response of each population was unique. Interestingly, we identified a set of genes presenting genotype by environment interaction (GEI). Many of these differences may reflect signatures of history of past adaptation. Transposable elements (TEs) were not activated after oxidative stress and differentially expressed (DE) genes were significantly depleted of TEs.

Conclusion

In the decade since the invasion from the south of Asia, invasive populations ofD. suzukiihave diverged from populations in the native area regarding their genetic response to oxidative stress. This suggests that such transcriptomic changes could be involved in the rapid adaptation to local environments.
Graphia: A platform for the graph-based visualisation and analysis of complex data
Authors: Freeman Tom C. , Horsewell Sebastian , Patir Anirudh , Harling-Lee Josh , Regan Tim , Shih Barbara B. , Prendergast James , Hume David A. , Angus Tim
Published: September 2020

Quantitative and qualitative data derived from the analysis of genomes, genes, proteins or metabolites from tissue or cells are currently generated in huge volumes during biomedical research. Graphia is an open-source platform created for the graph-based analysis of such complex data, e.g. transcriptomics, proteomics, genomics data. The software imports data already defined as a network or a similarity matrix and is designed to rapidly visualise very large graphs in 2D or 3D space, providing a wide range of functionality for graph exploration. An extensive range of analysis algorithms, routines for graph transformation, and options for the visualisation of node and edge attributes are also available. Graphia’s core is extensible through the deployment of plugins, supporting rapid development of additional computational analyses and features necessary for a given analysis task or data source. A plugin for correlation network analysis is distributed with the core application, to support the generation of correlation graphs from any tabular matrix of continuous or discrete values. This provides a powerful analysis solution for the interpretation of high-dimensional data from many sources. Several use cases of Graphia are described, to showcase its wide range of applications. Graphia runs on all major desktop operating systems and is freely available to download fromhttps://graphia.app/.
Deleterious impacts of inactivity and beneficial impacts of neuromuscular electrical stimulation on muscle structure and function in the zebrafish model of Duchenne Muscular Dystrophy
Authors: Kilroy Elisabeth A. , Brann Kaylee L. , Schaffer Claire E. , Varney Devon , Silknitter Kodey J. , Miner Jordan N. , Almaghasilah Ahmed , Spellen Tashawna L. , Lewis Alexandra D. , Tilbury Karissa , King Benjamin L. , Kelley Joshua B. , Henry Clarissa A.
Published: September 2020

Although it is known that inactivity is deleterious for healthy individuals, less is known about the consequences of inactivity on muscle disease. Reduced activity is frequently encouraged for individuals with congenital muscular dystrophies such as Duchenne Muscular Dystrophy (DMD). We used the zebrafishdmdmutant and a longitudinal design to elucidate the consequences of inactivity versus activity on muscle health. Inactivity worsened muscle structure and survival. We designed four neuromuscular stimulation paradigms loosely based on weight lifting regimens. Each paradigm differentially affected muscle structure, function, and survival. Only endurance neuromuscular stimulation (eNMES) improved all outcome measures. We found that eNMES (1) returns gene expression to wild-type levels, (2) increases muscle adhesion to the extracellular matrix (ECM), and (3) remodels the ECM and supports regeneration. Our data indicate that inactivity is deleterious but neuromuscular stimulation can be beneficial, suggesting that the right type of activity may benefit patients with muscle disease.