bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial scales in human movement between reservoirs of infection
Authors: Hardwick Robert J. , Vegvari Carolin , Collyer Benjamin , Truscott James E. , Anderson Roy M.
Published: April 2020

The life cycle of parasitic organisms that are the cause of much morbidity in humans often depend on reservoirs of infection for transmission into their hosts. Understanding the daily, monthly and yearly movement patterns of individuals between reservoirs is therefore of great importance to implementers of control policies seeking to eliminate various parasitic diseases as a public health problem. This is due to the fact that the underlying spatial extent of the reservoir of infection, which drives transmission, can be strongly affected by inputs from external sources, i.e., individuals who are not spatially attributed to the region defined by the reservoir itself can still migrate and contribute to it. In order to study the importance of these effects, we build and examine a novel theoretical model of human movement between spatially-distributed focal points for infection clustered into regions defined as ‘reservoirs of infection’. Using our model, we vary the spatial scale of human moment defined around focal points and explicitly calculate how varying this definition can influence the temporal stability of the effective transmission dynamics — an effect which should strongly influence how control measures, e.g., mass drug administration (MDA), define evaluation units (EUs). Considering the helminth parasites as our main example, by varying the spatial scale of human movement, we demonstrate that a critical scale exists around infectious focal points at which the migration rate into their associated reservoir can be neglected for practical purposes. This scale varies by species and geographic region, but is generalisable as a concept to infectious reservoirs of varying spatial extents and shapes. Our model is designed to be applicable to a very general pattern of infectious disease transmission modified by the migration of infected individuals between clustered communities. In particular, it may be readily used to study the spatial structure of hosts for macroparasites with temporally stationary distributions of infectious focal point locations over the timescales of interest, which is viable for the soil-transmitted helminths and schistosomes. Additional developments will be necessary to consider diseases with moving reservoirs, such as vector-born filarial worm diseases.
Large-scale implementation of pooled RNA-extraction and RT-PCR for SARS-CoV-2 detection
Authors: Ben-Ami Roni , Klochendler Agnes , Seidel Matan , Sido Tal , Gurel-Gurevich Ori , Yassour Moran , Meshorer Eran , Benedek Gil , Fogel Irit , Oiknine-Djian Esther , Gertler Asaf , Rotstein Zeev , Lavi Bruno , Dor Yuval , Wolf Dana G. , Salton Maayan , Drier Yotam ,   The Hebrew University-Hadassah COVID-19 diagnosis team
Published: April 2020

Testing for active SARS-CoV-2 infection is a fundamental tool in the public health measures taken to control the COVID-19 pandemic. Due to the overwhelming use of SARS-CoV-2 RT-PCR tests worldwide, availability of test kits has become a major bottleneck. Here we demonstrate pooling strategies to perform RNA extraction and RT-PCR in pools, significantly increasing throughput while maintaining clinical sensitivity. We implemented the method in a routine clinical diagnosis setting of asymptomatic populations, and already tested 5,464 individuals for SARS-CoV-2 using 731 RNA extraction and RT-PCR kits. We identified six SARS-CoV-2 positive patients corresponding to 0.11% of the tested population.
Untargeted metabolomic study of autism in newborn screening samples: a pilot study
Authors: Courraud Julie , Ernst Madeleine , Laursen Susan Svane , Hougaard David M. , Cohen Arieh S.
Published: April 2020

Background

The etiopathology of autism spectrum disorder (ASD) is unclear. Main risk factors include both genetic and non-genetic factors, especially prenatal and perinatal events. The Danish Neonatal Screening Biobank in connection with registry data provides unique opportunities to study early signs of disease. Therefore, we aimed to study the metabolomic profiles of dried blood spot (DBS) of newborns later diagnosed with ASD.

Methods

From the iPsych cohort, we randomly selected 37 subjects born in 2005 and diagnosed with ASD in 2012 (cases) together with 37 matched controls and submitted their biobanked DBS to an LC-MS/MS-based untargeted metabolomics protocol. Raw data were preprocessed using MZmine 2.41.2 and metabolites were subsequently putatively annotated using mzCloud, GNPS feature-based molecular networking and other metabolome mining tools (MolNetEnhancer). Statistical analyses and data visualization included principal coordinates analyses, PERMANOVAs, t-tests, and fold-change analyses.

Results

4360 mass spectral features were detected, of which 150 could be putatively annotated at a high confidence level. Chemical structure information at a broad level could be retrieved for a total of 1009 metabolites, covering 31 chemical classes including bile acids, various lipids, nucleotides, amino acids, acylcarnitines and steroids. Although the untargeted analysis revealed no clear distinction between cases and controls, 18 compounds repeatedly reported in the ASD literature could be detected in our study and three mass spectral features were found differentially abundant in cases and controls before FDR correction. In addition, our results pinpointed important other factors influencing chemical profiles of newborn DBS samples such as gestational age, age at sampling and month of birth.

Limitations

Inherent to pilot studies, our sample size was insufficient to reveal metabolic markers of ASD. Nevertheless, we were able to establish an efficient metabolomic data acquisition and analysis pipeline and flag main confounders to be considered in future studies.

Conclusions

In this first untargeted DBS metabolomic study, newborns later diagnosed with ASD did not show a significantly different metabolic profile when compared to controls. Nevertheless, our method covered many metabolites associated with ASD in previous studies, suggesting that biochemical markers of ASD are present at birth and may be monitored during newborn screening.
Holistic AI-Driven Quantification, Staging and Prognosis of COVID-19 Pneumonia
Authors: Chassagnon Guillaume , Paragios Nikos
Published: April 2020

Improving screening, discovering therapies, developing a vaccine and performing staging and prognosis are decisive steps in addressing the COVID-19 pandemic. Staging and prognosis are especially crucial for organizational anticipation (intensive-care bed availability, patient management planning) and accelerating drug development; through rapid, reproducible and quantified response-to-treatment assessment. In this letter, we report on an artificial intelligence solution for performing automatic staging and prognosis based on imaging, clinical, comorbidities and biological data. This approach relies on automatic computed tomography (CT)-based disease quantification using deep learning, robust data-driven identification of physiologically-inspired COVID-19 holistic patient profiling, and strong, reproducible staging/outcome prediction with good generalization properties using an ensemble of consensus methods. Highly promising results on multiple independent external evaluation cohorts along with comparisons with expert human readers demonstrate the potentials of our approach. The developed solution offers perspectives for optimal patient management, given the shortage of intensive care beds and ventilators1, 2, along with means to assess patient response to treatment.
Polygenic risk, susceptibility genes, and breast cancer over the life course
Authors: Mars Nina , Widén Elisabeth , Kerminen Sini , Meretoja Tuomo , Pirinen Matti , Palta Priit ,   FinnGen, Palotie Aarno , Kaprio Jaakko , Joensuu Heikki , Daly Mark , Ripatti Samuli
Published: April 2020

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their clinical applicability. We set out to study how PRS could help in clinical decision making. Among 99,969 women in the FinnGen study with 6,879 breast cancer cases, the PRS was associated not only with breast cancer incidence but also with a range of breast cancer-related endpoints. Women with a breast cancer PRS above the 90th percentile had both higher breast cancer mortality (HR 2.40, 95%CI 1.82-3.17) and higher risk for non-localized disease at diagnosis (HR 2.94, 95%CI 2.63-3.28), compared to those with PRS <80th percentile. The PRS modified the breast cancer risk of two high-impact frameshift risk variants. Women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 263 carriers) and an average PRS (20-80th percentile) had a lifetime risk of breast cancer at 58% (95%CI 50-66%), which increased to 85% (70-100%) with a high PRS (>90th percentile), and decreased to 27% (15-39%) with a low PRS (<20th percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1,543 carriers), the respective lifetime risks were 27% (95%CI 25-30%), 59% (52-67%), and 18% (13-22%). Among breast cancer cases, a PRS >90th percentile was associated with risk of contralateral breast cancer with HR 1.66 (95%CI 1.24-2.22). Finally, the PRS significantly refined the risk assessment of women with first-degree relatives diagnosed with breast cancer, i.e. the combination of high PRS (>90th percentile) and a positive family-history was associated with a 2.33-fold elevated risk (95%CI 1.57-3.46) compared to a positive family history alone. These findings demonstrate opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.
Forecasting of COVID-19 Cases and Deaths Using ARIMA Models
Authors: Bayyurt Lutfi , Bayyurt Burcu
Published: April 2020

After the outbreak of severe acute respiratory syndrome (SARS-2002/2003) and middle east respiratory syndrome (MERS-2012/2014) in the world, new public health crisis, called new coronavirus disease (COVID-19), started in China in December 2019 and has spread all over countries. COVID-19 coronavirus has been global threat of the disease and infected humans rapidly. Control of the pandemi is urgently essential, and science community have continued to research treatment agents. Support therapy and intensive care units in hospitals are also efective to overcome of COVID-19. Statistic forecasting models could aid to healthcare system in preventation of COVID-19. This study aimed to compose of forecasting model that could be practical to predict the spread of COVID-19 in Italy, Spain and Turkey. For this purpose, we performed Auto Regressive Integrated Moving Average (ARIMA) model on the European Centre for Disease Prevention and Control COVID-19 data to predict the number of cases and deaths in COVID-19. According to the our results, while number of cases in Italy and Spain is expected to decrease as of July, in Turkey is expected to decline as of September. The number of deaths in Italy and Spain is expected to be the lowest in July. In Turkey, this number is expected to reach the highest in July. In addition, it is thought that if studies in which the sensitivity and validity of this method are tested with more cases, they will contribute to researchers working in this field.
Sustaining Social Distancing Policies to Prevent a Dangerous Second Peak of COVID-19 Outbreak
Authors: Feng Zhilan , Damon-Feng Haiyun , Zhao Henry
Published: April 2020

Governments around the world have enacted strict social distancing policies in order to slow the spread of COVID-19. The next step is figuring out when to relax these restrictions and to what degree. Our results predict potentially disastrous implications of ending these policies too soon, based on projections made from a Susceptible-Exposed-Infectious-Removed (SEIR) epidemic model. Even when infection rates appear to be slowing down or decreasing, prematurely returning to “business as usual” produces a severe second peak far worse than the first. Furthermore, such a second peak is made more likely when very severe restrictions are initially enacted. Only an appropriately measured and committed set of restrictions can appropriately control COVID-19 outbreak levels.
Quantitative Method for Comparative Assessment of Particle Filtration Efficiency of Fabric Masks as Alternatives to Standard Surgical Masks for PPE
Authors: Mueller Amy V. , Eden Matthew J. , Oakes Jessica M. , Bellini Chiara , Fernandez Loretta A.
Published: April 2020

In response to the COVID-19 pandemic, cloth masks are being used to control the spread of virus, but the efficacy of these loose-fitting masks is not well known. Here, tools and methods typically used to assess tight-fitting respirators were modified to quantify the efficacy of community- and commercially-produced fabric masks as PPE. Two particle counters concurrently sample ambient air and air inside the masks; mask performance is evaluated by mean particle removal efficiency and statistical variability when worn as designed and with a nylon overlayer, to independently assess fit and material. Worn as designed both commercial surgical masks and cloth masks had widely varying effectiveness (53-75% and 28-90% filtration efficiency, respectively). Most surgical-style masks improved with the nylon overlayer, indicating poor fit. This rapid testing method uses widely available hardware, requires only a few calculations from collected data, and provides both a holistic and aspect-wise evaluation of mask performance.
A low-cost multi-patient pressure-controlled ventilation system with individualized parameter settings
Authors: Jardim-Neto Alcendino Cândido , Perlman Carrie E.
Published: April 2020

In a major health crisis, demand for mechanical ventilators may exceed supply. This scenario has led to the idea of connecting ventilation circuits in parallel to ventilate multiple patients simultaneously with the same machine. However, simple parallel connection may be harmful when the patients’ respiratory system mechanics differ. The aim of this work was to develop and test a low-cost, multi-patient, pressure-controlled ventilation system in which parameter settings could be individualized. Two types of circuits were built from polyvinyl chloride plumbing tubes and connectors, with ball valves and water columns used to control pressures. The circuits were connected to test lungs of differing compliances, ventilated in parallel at 20 cycles per minute and assessed for control error, variability and interdependency during peak inspiratory (20 to 35 cmH2O, in 5 cmH2O steps) and positive end-expiratory (5 to 20 to 5 cmH2O, in 5 cmH2O steps) pressure changes in one of the circuits. Results showed control errors lower than 1 cmH2O, a maximum standard deviation in pressure of 1.4 cmH2O and no dependency between the parallel circuits during the pressure maneuvers or a controlled disconnection/reconnection. This pressure-control system might be used to expand a commercial ventilator or, with constant gas inflow and an automated outlet valve, as a stand-alone ventilator with individually-controlled settings for multiple patients. In conclusion, the proposed solution is presented as a potentially reliable strategy for safely individualizing pressure-control parameters in a multi-patient ventilation system during a major health crisis.
Comparison of Four Molecular In Vitro Diagnostic Assays for the Detection of SARS-CoV-2 in Nasopharyngeal Specimens
Authors: Zhen Wei , Manji Ryhana , Smith Elizabeth , Berry Gregory J.
Published: April 2020

The novel human coronavirus SARS-CoV-2 was first discovered in the city of Wuhan, Hubei province, China, causing an outbreak of pneumonia in January 2020. As of April 10, 2020, the virus has rapidly disseminated to over 200 countries and territories, causing more than 1.6 million confirmed cases of COVID-19 and 97,000 deaths worldwide. The clinical presentation of COVID-19 is fairly non-specific, and symptoms overlap with other seasonal respiratory infections concurrently circulating in the population. Further, it is estimated that up to 80% of infected individuals experience mild symptoms or are asymptomatic, confounding efforts to reliably diagnose COVID-19 empirically. To support infection control measures, there is an urgent need for rapid and accurate molecular diagnostics to identify COVID-19 positive patients. In the present study, we have evaluated the analytical sensitivity and clinical performance of four SARS-CoV-2 molecular diagnostic assays granted Emergency Use Authorization by the FDA using nasopharyngeal swabs from symptomatic patients. This information is crucial for both laboratories and clinical teams, as decisions on which testing platform to implement are made.
Surveying Tenants of Permanent Supportive Housing in Skid Row about COVID-19
Authors: Henwood Benjamin F. , Redline Brian , Lahey Jack
Published: April 2020

Permanent supportive housing (PSH) enrolls highly vulnerable homeless adults who experience early onset of geriatric conditions and require in-home support. Thus, there is potentially a high risk for COVID-19 within PSH, which may necessitate tenants to take protective measures. This study reports on survey results collected from 532 PSH tenants in Los Angeles, California during the 4th week of March in 2020. Results show that nearly all tenants were aware of COVID-19, and 65% considered it to be a very serious health threat. The latter characteristic was a strong predictor of taking protective measures (i.e., handwashing and social distancing). Tenants in units with shared bathroom facilities had lower odds of social distancing than those in studio apartments. Tenants with mental health diagnoses had lower odds of consistent handwashing. Lack of access to food, hygiene items, and medication delivery were commonly reported barriers to sheltering in place.
Effects of medical resource capacities and intensities of public mitigation measures on outcomes of COVID-19 outbreaks
Authors: Wang Xia , Li Qian , Sun Xiaodan , He Sha , Xia Fan , Song Pengfei , Shao Yiming , Wu Jianhong , Cheke Robert A. , Tang Sanyi , Xiao Yanni
Published: April 2020

The COVID-19 pandemic is complex and is developing in different ways according to the country involved. To identify the key parameters or processes that have the greatest effects on the pandemic and reveal the different progressions of epidemics in different countries, we quantified enhanced control measures and the dynamics of the production and provision of medical resources. We then nested these within a COVID-19 epidemic transmission model, which is parameterized by multi-source data. We obtained rate functions related to the intensity of mitigation measures, the effective reproduction numbers and the timings and durations of runs on medical resources, given differing control measures implemented in various countries. Increased detection rates may induce runs on medical resources and prolong their durations, depending on resource availability. Nevertheless, improving the detection rate can effectively and rapidly reduce the mortality rate, even after runs on medical resources. Combinations of multiple prevention and control strategies and timely improvement of abilities to supplement medical resources are key to effective control of the COVID-19 epidemic. A 50% reduction in comprehensive control measures would have led to the cumulative numbers of confirmed cases and deaths exceeding 590000 and 60000, respectively, by 27 March 2020 in mainland China. The proposed model can assist health authorities to predict when they will be most in need of hospital beds and equipment such as ventilators, personal protection equipment, drugs and staff.

One sentence summary

Multiple data sources and cross validation of a COVID-19 epidemic model, coupled with a medical resource logistic model, reveal that the key factors that affect epidemic progressions and their outbreak patterns in different countries are the type of emergency medical response to avoid runs on medical resources, especially improved detection rates, the ability to promote public health measures, and the synergistic effects of combinations of multiple prevention and control strategies.
Is iron deficiency a major cause of anaemia in Sri Lankan children aged 5-10 years?
Authors: Jayatissa Renuka , Fernando DN , Ranbanda JM , De Silva KH
Published: April 2020

Background

To assess the iron status among children aged 5–10 years

Methods

A cross sectional study in Gampaha district. A sample of 704 children aged 5-10 years resident in a sample of households selected using a two-stage sampling method. A pre tested interviewer administered questionnaire was used to collect information on socio demographic characteristics, housing and sanitation facilities and other relevant variables from the households. Anthropometry was performed on all children aged 5–10 years using standard procedures. Venous blood samples were taken to assess the haemoglobin (Hb) level, levels of Serum Ferritin and C-Reactive Protein.

Results

Overall prevalence rate of anaemia, iron deficiency and iron deficiency anaemia in children aged 5-10 years in Gampaha district was 22.7%, 22.1% and 13.5% respectively. The prevalence of iron deficiency among the urban children was significantly higher than that among rural children. The source of water to the households in the households with piped water had a higher prevalence of iron deficiency which was different from the others. The prevalence of iron deficiency among stunted and wasted children was higher though not at a significant level. A substantial proportion of children who were not anaemic were iron deficient.

Conclusions

Iron deficiency is an important health problem in this population. Only half of iron deficient children were anaemic and anaemia cannot be solely explained by iron deficiency.
Utah-Stanford Ventilator (Vent4US): Developing a rapidly scalable ventilator for COVID-19 patients with ARDS
Authors: Li Hongquan , Li Ethan , Krishnamurthy Deepak , Kolbay Patrick , Chacin Beca , Hoehne Soeren , Cybulski Jim , Brewer Lara , Petelenz Tomasz , Orr Joseph , Sakata Derek , Clardy Thomas , Kuck Kai , Prakash Manu
Published: April 2020

We describe a minimum, rapidly scalable ventilator designed for COVID-19 patients with ARDS. Our design philosophy is not only to try to address potential ventilator shortages, but also to account for uncertainties in the supply chains of parts commonly used in traditional ventilators. To do so we employ a modular design approach and broadly explore taking advantage of parts from non-traditional supply chains. In our current prototype, we demonstrate volume control with assist control on a test lung and present a linear actuator-driven pinch valve-based implementation for both pressure control and volume control with decelerating inspiratory flow. We estimate the component cost of the system to be around $500. We publish our draft design documents and current implementation which is open and accessible in the hope that broadening the community globally will accelerate arriving at a solution and that peer review will improve the final design.
Diagnostics and prognostic potential of current biomarkers in heart failure with preserved ejection fraction: a systematic review and meta-analysis
Authors: Chen Hao , Chhor Michael , Rayner Benjamin , McGrath Kristine , McClements Lana
Published: April 2020

Aims

Circulating biomarkers are commonly used in diagnosis and prognosis of heart failure with preserved ejection fraction (HFpEF) in clinical practice. However, the diagnostic and prognostic potential of current biomarkers in HFpEF remain unclear.

Methods and results

We conducted a search of the PubMed, Web of Science, MEDLINE and SCOPUS (1900 to January 2020) databases of all diagnostic (n=1,104) and prognostic (n=53,497) biomarkers investigated in people with HFpEF. B-type natriuretic peptide (BNP) displayed satisfactory sensitivity (0.81, 95% CI: 0.76 to 0.85; I2=0) and specificity (0.86, 95% CI: 0.82 to 0.89; I2=16.9%) for the diagnosis of HFpEF. Natriuretic peptides (NPs), including N-terminal pro BNP (NT-proBNP) and BNP, were associated with over two-fold increased risk of mortality (NT-proBNP: HR=2.27, 95% CI: 1.69 to 3.06, I2=87.6%; BNP: HR=3.01, 95% CI: 1.27 to 7.21, I2=97.2%), hospitalisation (NT-proBNP: HR=3.54, 95% CI: 2.83 to 4.43, I2=83.4%), and a composite event of both (NT-proBNP: HR=2.55, 95% CI: 2.13 to 3.05, I2=78.1%; BNP: HR=2.28, 95% CI: 1.42 to 3.69, I2=75.8%) in people with HFpEF. Interestingly, Galectin-3 (Gal-3) (sensitivity: 0.70, 95% CI: 0.63 to 0.75, I2=86.7%; specificity: 0.78, 95% CI: 0.69 to 0.85, I2=68.6%) and soluble suppression of tumorigenicity 2 (sST2) (sensitivity: 0.58, 95% CI: 0.52 to 0.64, I2=88.1%; specificity: 0.59, 95% CI: 0.49 to 0.68, I2=69.5%) showed limited diagnostic potential of HFpEF.

Conclusion

Amongst currently available biomarkers, BNP remains the most reliable diagnostic marker of HFpEF. Although there was high heterogeneity between the studies included, BNP or NT-proBNP could also have promising prognostic potential in HFpEF.
A Chronological and Geographical Analysis of Personal Reports of COVID-19 on Twitter
Authors: Klein Ari Z. , Magge Arjun , O’Connor Karen , Cai Haitao , Weissenbacher Davy , Gonzalez-Hernandez Graciela
Published: April 2020

The rapidly evolving outbreak of COVID-19 presents challenges for actively monitoring its spread. In this study, we assessed a social media mining approach for automatically analyzing the chronological and geographical distribution of users in the United States reporting personal information related to COVID-19 on Twitter. The results suggest that our natural language processing and machine learning framework could help provide an early indication of the spread of COVID-19.
GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background
Authors: Sinnott-Armstrong Nasa , Naqvi Sahin , Rivas Manuel , Pritchard Jonathan K
Published: April 2020

Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—with better-understood biology than most other complex traits. We find that many of the most significant hits are readily and surprisingly interpretable. We observe huge enrichment of associations near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of each trait, including differences in testosterone regulation between females and males. At the same time, even these molecular traits are highly polygenic, with many thousands of variants spread across the genome contributing to trait variance. In summary, for these three molecular traits we identify strong enrichment of signal in putative core gene sets, even while most of the SNP-based heritability is driven by a massively polygenic background.
ILC1-derived TGFβ1 drives intestinal remodelling
Authors: Jowett Geraldine M. , Norman Michael D. A. , Yu Tracy T. L. , Arévalo Patricia Rosell , Hoogland Dominique , Lust Suzette , Read Emily , Hamrud Eva , Walters Nick J. , Niazi Umar , Chung Matthew Wai Heng , Marciano Daniele , Omer Omer Serhan , Zabinski Tomasz , Danovi Davide , Lord Graham M. , Hilborn Jöns , Evans Nicholas D. , Dreiss Cécile A. , Bozec Laurent , Oommen Oommen P. , Lorenz Christian D. , da Silva Ricardo M.P. , Neves Joana F. , Gentleman Eileen
Published: April 2020

Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we developed gut organoid co-cultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate for the first time that murine and human ILC1 secrete TGFβ1, driving expansion of CD44v6+epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial-mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues.
Role of c-Met/β1 integrin complex in the metastatic cascade
Authors: Lau Darryl , Wadhwa Harsh , Sudhir Sweta , Jain Saket , Chandra Ankush , Nguyen Alan , Spatz Jordan , Shah Sumedh S. , Cheng Justin , Safaee Michael , Yagnik Garima , Jahangiri Arman , Aghi Manish K.
Published: April 2020

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. While individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a structural complex between receptor tyrosine kinase c-Met and β1 integrin in metastases. Using novel cell culture andin vivoassays, we found that c-Met/β1 complex induction promotes breast cancer intravasation and adhesion to the vessel wall, but does not increase extravasation. These effects may be driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction. A β1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/β1 binding, decreased invasion and mesenchymal gene expression and morphology of breast cancer cells. Bone-seeking breast cancer cells exhibited higher c-Met/β1 complex levels than parental controls and preferentially adhere to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 levels than brain metastases. Thus, the c-Met/β1 complex drives breast cancer cell intravasation and preferential affinity for bone tissue-specific matrix. Pharmacological targeting of the complex may prevent metastases, particularly osseous metastases.
Synonymous mutations and the molecular evolution of SARS-Cov-2 origins
Authors: Wang Hongru , Pipes Lenore , Nielsen Rasmus
Published: April 2020

Human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely related, by average genetic distance, to two coronaviruses isolated from bats, RaTG13 and RmYN02. However, there is a segment of high amino acid similarity between human SARS-CoV-2 and a pangolin isolated strain, GD410721, in the receptor binding domain (RBD) of the spike protein, a pattern that can be caused by either recombination or by convergent amino acid evolution driven by natural selection. We perform a detailed analysis of the synonymous divergence, which is less likely to be affected by selection than amino acid divergence, between human SARS-CoV-2 and related strains. We show that the synonymous divergence between the bat derived viruses and SARS-CoV-2 is larger than between GD410721 and SARS-CoV-2 in the RBD, providing strong additional support for the recombination hypothesis. However, the synonymous divergence between pangolin strain and SARS-CoV-2 is also relatively high, which is not consistent with a recent recombination between them, instead it suggests a recombination into RaTG13. We also find a 14-fold increase in thedN/dSratio from the lineage leading to SARS-CoV-2 to the strains of the current pandemic, suggesting that the vast majority of non-synonymous mutations currently segregating within the human strains have a negative impact on viral fitness. Finally, we estimate that the time to the most recent common ancestor of SARS-CoV-2 and RaTG13 or RmYN02 based on synonymous divergence, is 51.71 years (95% C.I., 28.11-75.31) and 37.02 years (95% C.I., 18.19-55.85), respectively.
Dynamical asymmetry exposes 2019-nCoV prefusion spike
Authors: Roy Susmita
Published: April 2020

The novel coronavirus (2019-nCoV) spike protein is a smart molecular machine that instigates the entry of coronavirus to the host cell causing the COVID-19 pandemic. In this study, a structural-topology based model Hamiltonian of C3 symmetric trimeric spike is developed to explore its complete conformational energy landscape using molecular dynamic simulations. The study finds 2019-nCoV to adopt a unique strategy by undertaking a dynamic conformational asymmetry induced by a few unique inter-chain interactions. This results in two prevalent asymmetric structures of spike where one or two spike heads lifted up undergoing a dynamic transition likely to enhance rapid recognition of the host-cell receptor turning on its high-infectivity. The crucial interactions identified in this study are anticipated to potentially affect the efficacy of therapeutic targets.

One Sentence Summary

Inter-chain-interaction driven rapid symmetry breaking strategy adopted by the prefusion trimeric spike protein likely to make 2019-nCoV highly infective.
Erythropoietin regulates transcription and YY1 dynamics in a pre-established chromatin architecture
Authors: Perreault Andrea A. , Brown Jonathan D. , Venters Bryan J.
Published: April 2020

The three dimensional architecture of the genome plays an essential role in establishing and maintaining cell identity. By contrast, the magnitude and temporal kinetics of changes in chromatin structure that arise during cell differentiation remain poorly understood. Here, we leverage a murine model of erythropoiesis to study the relationship between chromatin conformation, the epigenome, and transcription in erythroid cells. We discover that acute transcriptional responses induced by erythropoietin (EPO), the hormone necessary for erythroid differentiation, occur within an invariant chromatin topology. Within this pre-established landscape, Yin Yang 1 (YY1) occupancy dynamically redistributes to sites in proximity to EPO-regulated genes. Using HiChIP, we identify chromatin contacts mediated by H3K27ac and YY1 that are enriched for enhancer-promoter interactions of EPO-responsive genes. Taken together, these data are consistent with an emerging model that rapid, signal-dependent transcription occurs in the context of a pre-established chromatin architecture.
Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens
Authors: Liu Jun , Babka April M. , Kearney Brian J. , Radoshitzky Sheli R. , Kuhn Jens H. , Zeng Xiankun
Published: April 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than one million cases and tens of thousands of deaths. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscopein situhybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.
Rab14/MACF2/CAMSAP3 Complex Regulates Endosomal Targeting to the Abscission Site During Cytokinesis
Authors: Gibieža Paulius , Peterman Eric , Hoffman Huxley K. , Van Engeleburg Schuyler , Arvydas Skeberdis Vytenis , Prekeris Rytis
Published: April 2020

Abscission is complex cellular process that is required for mitotic division. It is well-established that coordinated and localized changes in actin and microtubule dynamics are vital for cytokinetic ring formation, as well as establishment of the abscission site. Actin cytoskeleton reorganization during abscission would not be possible without the interplay between Rab11- and Rab35-containing endosomes and their effector proteins, whose roles in regulating endocytic pathways at the cleavage furrow have now been studied extensively. Here, we identified Rab14 as novel regulator of abscission. We demonstrate that depletion of Rab14 causes either cytokinesis failure or significantly prolongs division time. We show that Rab14 regulates the efficiency of recruiting Rab11-endosomes to the central spindle microtubules and that Rab14 knockout leads to inhibition of actin clearance at the abscission site. Finally, we demonstrate that Rab14 binds to microtubule minus-end interacting MACF2/CAMSAP3 complex and that this binding is required for targeting of early endosomes to the central spindle. Collectively, our data identified Rab14/MACF2/CAMSAP3 as a protein complex that regulates Rab11-endosome targeting and the establishment of the abscission site.
Two-Step Mixed Model Approach to Analyzing Differential Alternative RNA Splicing
Authors: Luo Li , Kang Huining , Li Xichen , Ness Scott A. , Stidley Christine A.
Published: April 2020

Changes in gene expression can correlate with poor disease outcomes in two ways: through changes in relative transcript levels or through alternative RNA splicing leading to changes in relative abundance of individual transcript isoforms. The objective of this research is to develop new statistical methods in detecting and analyzing both differentially expressed and spliced isoforms, which appropriately account for the dependence between isoforms and multiple testing corrections for the multi-dimensional structure of at both the gene- and isoform-level. We developed a linear mixed effects model-based approach for analyzing the complex alternative RNA splicing regulation patterns detected by whole-transcriptome RNA-sequencing technologies. This approach thoroughly characterizes and differentiates three types of genes related to alternative RNA splicing events with distinct differential expression/splicing patterns. We applied the concept of appropriately controlling for the gene-level overall false discovery rate (OFDR) in this multi-dimensional alternative RNA splicing analysis utilizing a two-step hierarchical hypothesis testing framework. In the initial screening test we identify genes that have differentially expressed or spliced isoforms; in the subsequent confirmatory testing stage we examine only the isoforms for genes that have passed the screening tests. Comparisons with other methods through application to a whole transcriptome RNA-Seq study of adenoid cystic carcinoma and extensive simulation studies have demonstrated the advantages and improved performances of our method. Our proposed method appropriately controls the gene-level OFDR, maintains statistical power, and is flexible to incorporate advanced experimental designs.
Climatic drivers ofVerticillium dahliaeoccurrence in Mediterranean olive-growing areas of southern Spain
Authors: Requena-Mullor Juan Miguel , García-Garrido Jose Manuel , García Pedro Antonio , Rodríguez Estefanía
Published: April 2020

Verticillium wilt, caused by the soil-borne fungusVerticillium dahliae,is one of the most harmful diseases in Mediterranean olive-growing areas. Although, the effects of both soil temperature and moisture onV. dahliaeare well known, there is scant knowledge about what climatic drivers affect the occurrence of the pathogen on a landscape scale. Here, we investigate what climatic drivers determineV. dahliaeoccurrence in olive-growing areas in southern Spain. In order to bridge this gap in knowledge, a landscape-scale field survey was carried out to collect data on the occurrence ofV. dahliaein 779 olive groves in Granada province. Forty models based on competing combinations of climatic variables were fitted and evaluated using information-theoretic methods. A model that included a multiplicative combination of seasonal and extreme climatic variables was found to be the most viable one. Isothermality and the seasonal distribution of precipitation were the most important variables influencing the occurrence of the pathogen. The isothermal effect was in turn modulated by the seasonality of rainfall, and this became less negative as seasonality increases. Thus,V. dahliaeoccurs more frequently in olive-growing areas where the day-night temperature oscillation is lower than the summer-winter one. We also found that irrigation reduced the influence of isothermality on occurrence. Our results demonstrate that long-term “sophisticated” climatic factors rather than “primary” variables, such as annual trends, can better explain the spatial patterns ofV. dahliaeoccurrence in Mediterranean, southern Spain. One important implication of our study is that appropriate irrigation management, when temperature oscillation approaches optimal conditions forV. dahliaeto thrive, may reduce the appearance of symptoms in olive trees.
Patterns of acquired HIV-1 drug resistance mutations and predictors of virological failure in Moshi, northern Tanzania
Authors: Mziray Shabani Ramadhani , Kumburu Happiness H , Assey Hellen B , Sonda Tolbert B , Mahande Michael J , Msuya Sia E , Kiwelu Ireen E
Published: April 2020

Drug resistance is a public health concern. Profiles of HIV drug resistance mutations (HIVDRM) and virological failure (VF) are not extensively studied in Tanzania. This study aimed to determine HIVDRM and predictors of VF in HIV-infected individuals failing first-line HIV drugs in Moshi, northern Tanzania. A case-control study was conducted at KCMC, Mawenzi, Pasua and Majengo health facilities with HIV-care and treatment clinics in Moshi from October, 2017 to August, 2018. Cases and controls were HIV-infected individuals with VF and viral suppression (VS) respectively. HIV-1 reverse transcriptase and protease genes were amplified and sequenced. Stanford University’s HIV drug resistance database and REGA HIV-1 Subtyping tool 3.0 determined HIVDRM and HIV-1 subtypes respectively. Odds ratios with 95% confidence intervals investigated predictors of VF. P-value <5% was considered statistically significant. A total of 124 participants were recruited, of whom 63 (50.8%) had VF and 61 (49.2%) had VS. Majority (66.1%) were females. Median [IQR] age and duration on ART were 45 [35-52] years and 72 [48-104] months respectively. Twenty five out of 26 selected HIV-1 RNA samples from cases were successively sequenced. Twenty four samples (96%) had at least one major mutation conferring resistance to HIV drugs, with non-nucleoside reverse transcriptase inhibitor (NNRTI) associated mutations as the majority (92%). Frequent NNRTI resistance mutations were K103N (n=11), V106M (n=5) and G190A (n=5). Prevalent nucleoside reverse transcriptase inhibitors mutations were M184V (n=17), K70R (n=7) and D67N (n=6). Dual-class resistance was observed in 16 (64%) samples. Thirteen samples (52%) had at least one thymidine analogue-associated resistance mutation (TAM). Three samples (12%) had T69D mutation with at least 1 TAM. Age was independently associated with VF [aOR 0.94 (0.90-0.97) p<0.001]. In conclusion, HIV drug resistance is common among people failing antiretroviral therapy and resistance testing will help to guide switching of HIV drugs.
Elucidating the differences in the molecular mechanism of receptor binding between 2019-nCoV and the SARS-CoV viruses using computational tools
Authors: Lai Hien T. T. , Nguyen Ly H. , Kranjc Agata , Nguyen Toan T. , Nguyen-Manh Duc
Published: April 2020

The outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex. These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV. Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.
Distributed implementation of Boolean functions by transcriptional synthetic circuits
Authors: Al-Radhawi M. Ali , Tran Anh Phong , Ernst Elizabeth A. , Chen Tianchi , Voigt Christopher A. , Sontag Eduardo D.
Published: April 2020

Starting in the early 2000s, a sophisticated technology has been developed for the rational construction of synthetic genetic networks that implement specified logical functionalities. Despite impressive progress, however, the scaling necessary in order to achieve greater computational power has been hampered by many constraints, including repressor toxicity and the lack of large sets of mutually-orthogonal repressors. As a consequence, a typical circuit contains no more than roughly seven repressor-based gates per cell. A possible way around this scalability problem is to distribute the computation among multiple cell types, which communicate among themselves using diffusible small molecules (DSMs) and each of which implements a small sub-circuit. Examples of DSMs are those employed by quorum sensing systems in bacteria. This paper focuses on systematic ways to implement this distributed approach, in the context of the evaluation of arbitrary Boolean functions.

The unique characteristics of genetic circuits and the properties of DSMs require the development of new Boolean synthesis methods, distinct from those classically used in electronic circuit design. In this work, we propose a fast algorithm to synthesize distributed realizations for any Boolean function, under constraints on the number of gates per cell and the number of orthogonal DSMs. The method is based on an exact synthesis algorithm to find the minimal circuit per cell, which in turn allows us to build an extensive database of Boolean functions up to a given number of inputs.

For concreteness, we will specifically focus on circuits of up to 4 inputs, which might represent, for example, two chemical inducers and two light inputs at different frequencies. Our method shows that, with a constraint of no more than seven gates per cell, the use of a single DSM increases the total number of realizable circuits by at least 7.58-fold compared to centralized computation. Moreover, when allowing two DSM’s, one can realize 99.995% of all possible 4-input Boolean functions, still with at most 7 gates per cell. The methodology introduced here can be readily adapted to complement recent genetic circuit design automation software.