bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-molecule FRET dynamics of molecular motors in an ABEL Trap
Authors: Dienerowitz Maria , Howard Jamieson A. L. , Quinn Steven D. , Dienerowitz Frank , Leake Mark C.
Published: September 2020

Single-molecule Förster resonance energy transfer (smFRET) of molecular motors provides transformative insights into their dynamics and conformational changes both at high temporal and spatial resolution simultaneously. However, a key challenge of such FRET investigations is to observe a molecule in action for long enough without restricting its natural function. The Anti-Brownian ELectrokinetic Trap (ABEL trap) sets out to combine smFRET with molecular confinement to enable observation times of up to several seconds while removing any requirement of tethered surface attachment of the molecule in question. In addition, the ABEL trap’s inherent ability to selectively capture FRET active molecules accelerates the data acquisition process. In this work we exemplify the capabilities of the ABEL trap in performing extended timescale smFRET measurements on the molecular motor Rep, which is crucial for removing protein blocks ahead of the advancing DNA replication machinery and for restarting stalled DNA replication. We are able to monitor single Rep molecules up to 6 s with sub-millisecond time resolution capturing multiple conformational switching events during the observation time. Here we provide a step-by-step guide for the rational design, construction and implementation of the ABEL trap for smFRET detection of Repin vitro. We include details of how to model the electric potential at the trap site and use Hidden Markov analysis of the smFRET trajectories.
Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma
Authors: Jermakowicz Anna , Kurimchak Alison M. , Sarkaria Jann , Komotar Ricardo , Ivan Michael E. , Schürer Stephan , Duncan James S. , Ayad Nagi G.
Published: September 2020

Glioblastoma (GBM) is the most common and aggressive adult brain tumor. Despite years of research, clinical trials have not improved the outcome for GBM. Standard of care for newly diagnosed GBM includes surgical resection, followed by radiation and chemotherapy. Tumor recurrence is inevitable and since most patients are not candidates for a second surgical resection, there is an urgent need to identify resistance mechanisms that arise in recurrent GBM. We postulated that examining the differences of activated kinases between newly diagnosed and recurrent GBM may provide insight to resistance mechanisms.

To map the kinome landscape of newly diagnosed (nGBM) and recurrent GBM (rGBM) patient derived xenograft tumors, we used Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). We performed pathway analysis of kinases that differed in MIB-binding between nGBM and rGBM to identify kinase-driven signaling pathways. We also analyzed transcriptional profiles to determine the overlap in signaling pathways seen using proteomics or transcriptomics.

Using MIB-MS kinome profiling, we found key differences in kinase-driven signaling pathways that may account for the increase in aggressive behavior seen in recurrent GBM. This included a shift in pathways driving cell invasion and proliferation, as well as upregulation of signaling pathways that drive GBM stem-cell like cell differentiation. Analysis of RNA-sequencing showed no statistically significant differences between enriched gene ontologies in nGBM and rGBM, demonstrating the importance of MIB-MS kinome profiling. Collectively, these studies suggest that kinome profiling may inform future clinical trials for kinase inhibitors in GBM.
Para-cellular and transcellular diapedesis are divergent but inter-connected evolutionary events
Authors: Kubick Norwin , Klimovich Pavel , Henckel Patrick , Mickael Michel-Edwar
Published: September 2020

Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a para-cellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used phylogenetic analysis, HH search, ancestor sequence reconstruction together with functional specificity and positive selection analysis to investigate this intriguing question further. We found that the two systems share several ancient components, such as RhoA protein that plays an important role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens and it was only reported in trans-cellular process. Para-cellular process core proteins had at least two distinct starting points. First, during drosophila emergence, Tre1 which is homologous to melatonin GPCR receptor diverged. Secondly, PECAM1 emerged from FASL5/3 during elephant shark divergence. Lastly, both systems employ late divergent genes such as ICAM1 and PECAM1. Taken together our results suggest that these two systems constitute different yet interconnected mechanisms of immune cells infiltrations of the brain. Our analysis indicates that this system coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the adaptive immune system.
Epigenetic clock and methylation studies in the rhesus macaque
Authors: Horvath Steve , Zoller Joseph A. , Haghani Amin , Jasinska Anna J. , Raj Ken , Breeze Charles E. , Ernst Jason , Mattison Julie A.
Published: September 2020

Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n=281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regards to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R=0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within theKLF14promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). It is expected that the macaque clocks will reveal an epigenetic aging rate associated with a host of health conditions and thus lend themselves for identifying and validating anti-aging interventions.
Dorsal raphe nucleus to anterior cingulate cortex 5-HTergic neural circuit modulates consolation and sociability
Authors: Li Lai-Fu , Zhang Li-Zi , He Zhi-Xiong , Zhang Yu-Ting , Ma Huan , Xun Yu-Feng , Yuan Wei , Hou Wen-Juan , Li Yi-Tong , Lv Zi-Jian , Jia Rui , Tai Fa-Dao
Published: September 2020

Consolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of 5-HT terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.
An in-silico study to determine whether changes to mitochondria organization through engineered mitochondrial dynamics can enhance bioenergetics in cardiomyocytes
Authors: Kumbhari Adarsh , Ghosh Shouryadipta , Kim Peter S. , Rajagopal Vijay
Published: September 2020

Mitochondria are the powerhouse of the cell and owing to their unique energetic demands, heart muscles contain a high density of mitochondria. In conditions such as heart failure and diabetes-induced heart disease, changes in the organization of cardiac mitochondria are common. While recent studies have also shown that cardiac mitochondria split and fuse throughout the cell, a mechanistic understanding of how mitochondrial dynamics may affect energy output is lacking. Using a mathematical model that has been fitted to experimental data, we test if briefly altering fission or fusion rates improves ATP production and supply in cardiomyocytes. Unexpectedly, we found that cardiac bioenergetics, e.g., the ADP/ATP ratio, were robust to changes in fusion and fission rates and consequently mitochondria organization. Our study highlights complex nonlinear feedback loops that are at play in the cross-talk between mitochondrial dynamics and bioenergetics. The study motivate further in-silico and experimental investigations to determine the mechanistic basis for new therapies that target mitochondrial dynamics.
Transcriptome analysis of potato leaves in response to infection with the necrotrophic pathogenAlternaria solani
Authors: Tian Mengjun , Wang Jinhui , Li Zheng , Wang Chen , Zhang Dai , Yang Yiqing , Pan Yang , Zhao Dongmei , Yang Zhihui , Zhu Jiehua
Published: September 2020

The potato early blight was caused byAlternaria solani(Aso). At present, potato early blight resistant varieties are lacking. The experiment of Aso inoculation on a.k.a. Favorita showed that the content of chlorophyll decreased continuously within 2 days after inoculation. In addition, the contents of JA-Ile, SA, ABA and IAA were determined by LC-MS.The results of two defense-related hormones showed that jasmonic acid content decreased significantly, while jasmonic acid content did not change significantly. In order to understand the difference in gene expression of potatoes infected by Aso, the 24 hpi, 36 hpi and 48 hpi transcriptome were determined. The results showed that the gene annotation and cluster analysis of DEGs revealed a variety of defense responses to Aso infection, especially the plant hormone signal transduction pathway. The differential expression of 10 DEGs was confirmed by qPCR analysis. Finally, through weighted gene co-expression network analysis (WGCNA), “samonl” was determined as a key hormone-related network in the process of Aso infection in potatoes. This study provides an important clue for understanding the interaction between potato and Aso and for disease resistance breeding.
Rapid changes in chromatin structure during dedifferentiation of primary hepatocytes in vitro
Authors: Seirup Morten , Sengupta Srikumar , Swanson Scott , McIntosh Brian E. , Colins Mike , Chu Li-Fang , Cheng Zhang , Gorkin David U. , Duffin Bret , Bolin Jennifer M. , Argus Cara , Stewart Ron , Thomson James A.
Published: September 2020

Primary hepatocytes are widely used in the pharmaceutical industry to screen drug candidates for hepatotoxicity, but isolated hepatocytes quickly dedifferentiate and lose their mature metabolic function in culture. Attempts have been made to better recapitulate thein vivoliver environment in culture, but the full spectrum of signals required to maintain hepatocyte functionin vitroremains elusive. Here we studied the dedifferentiation process in detail through RNA-sequencing of hepatocytes cultured over eight days. We identified three distinct phases of dedifferentiation. An early phase, where mature hepatocyte genes are rapidly downregulated in a matter of hours. A middle phase, where fetal genes are activated, leading to hepatocytes with a fetal phenotype. A late phase, where initially rare contaminating non-parenchymal cells over-grow the culture as the hepatocytes gradually die. Using genetically tagged hepatocytes, we demonstrate that the cells reactivating fetal marker alpha-fetoprotein arise from cells previously expressing the mature hepatocyte marker albumin, and not from albumin negative precursor cells, proving that hepatocytes undergo true dedifferentiation. To better understand the signaling events that result in the rapid down-regulation of mature hepatocyte genes, we examined changes in chromatin accessibility of hepatocytes during the first 24h of culture using ATAC-seq. We find that drastic and rapid changes in chromatin accessibility occurs immediately upon start of culture. Using binding motif analysis of the areas of open chromatin sharing similar temporal profiles, we identify several candidate transcription factors potentially involved in the dedifferentiation of primary hepatocytes in culture.
Deep neural net tracking of human pluripotent stem cells reveals intrinsic behaviors directing morphogenesis
Authors: Joy David A. , Libby Ashley R. G. , McDevitt Todd C.
Published: September 2020

Lineage tracing is a powerful tool traditionally used in developmental biology to interrogate the evolutionary time course of tissue formation, but the dense, three-dimensional nature of tissue limits the ability to assemble individual traces into complete reconstructions of development. Human induced pluripotent stem cells (hiPSCs) enable recapitulation of various aspects of developmental processes, thereby providing anin vitroplatform to assess the dynamic collective behaviors directing tissue morphogenesis. Here, we trained an ensemble of independent convolutional neural networks to identify individual hiPSCs imaged via time lapse microscopy in order to generate longitudinal measures of individual cell and dense cellular neighborhood properties simultaneously on timescales ranging from minutes to days. Our analysis reveals that while individual cell parameters are not strongly affected by extracellular microenvironmental conditions such as pluripotency maintenance regime or soluble morphogenic cues, regionally specific cell behaviors change in a manner predictive of organization dynamics. By generating complete multicellular reconstructions of hiPSC behavior, our cell tracking pipeline enables fine-grained understanding of developmental organization by elucidating the role of regional behavior stratification in early tissue formation.
Subclinical ocular inflammation in persons recovered from ambulatory COVID-19
Authors: Bakhoum Mathieu F. , Ritter Michele , Garg Anupam K. , Chan Alison X , Bakhoum Christine Y. , Smith Davey M.
Published: September 2020

Coronavirus disease 2019 (COVID-19) is characterized by striking variability in clinical severity, and a hyperinflammatory response in the lung is associated with high mortality. Little is known about the extent and duration of inflammation in persons recovering from COVID-19. Here, we used spectral domain optical coherence tomography (SD-OCT) to detect the presence of inflammatory cells in the vitreous cavity, an immune-privileged microenvironment, in persons recovered from COVID-19. Our results provide quasi-histologic evidence that neuroinflammation is present in persons who recovered from COVID-19, only one of whom required hospitalization. Our results also suggest that persons who feel that their recovery is incomplete have evidence of subclinical eye inflammation, which may be a marker of residual inflammation elsewhere as well.
Performance of a universally offered prenatal screening program incorporating cfDNA in Ontario, Canada: a descriptive population-based cohort study of 280,000 pregnancies
Authors: Dougan Shelley D , Okun Nan , Bellai-Dussault Kara , Meng Lynn , Howley Heather E , Huang Tianhua , Reszel Jessica , Lanes Andrea , Walker Mark C , Armour Christine M
Published: September 2020

Abstract

Objectives

To measure the population-based performance and impact of Ontario, Canada’s modified-contingent prenatal screening system for the detection of trisomies 21 (T21) and 18 (T18).

Design

A retrospective, descriptive cohort study examining routinely collected data from BORN Ontario, which captures linkable population data for prenatal and neonatal health encounters across a variety of settings (e.g., laboratories, birthing hospitals and midwifery practice groups).

Setting

A province-wide and publicly funded prenatal screening program in Ontario, Canada offering cfDNA screening for those at increased risk of having a pregnancy with T21 or T18.

Participants

373,682 singleton pregnancies with an estimated due date between September 1 2016 and March 31, 2019 who were offered publicly funded prenatal screening.

Main outcome measures

Prenatal detection of T21 or T18, ascertained by cytogenetic results. Performance was assessed by calculating sensitivity, specificity, positive predictive value and negative predictive value against confirmatory diagnostic cytogenetic results and birth outcomes. The secondary objective was to determine the impact of contingent cfDNA screening by measuring uptake and the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing (PND).

Results

69% of pregnancies in Ontario underwent prenatal screening for T21/T18. The modified-contingent screen sensitivity was 89.9% for T21 and 80.5% for T18. The modified-contingent screen-positive rate was 1.6% for T21 and 0.2% for T18. The cfDNA screening test failure rate was 2.2% (final result including multiple attempts). The PND rate among pregnancies screened was 2.4%.

Conclusions

This study is the largest evaluation of population-based performance of a publicly funded cfDNA prenatal screening system. We demonstrated a robust screening system with high sensitivity and low PND consistent with smaller validation studies
Epidemiology and precision of SARS-CoV-2 detection following lockdown and relaxation measures
Authors: Leuzinger Karoline , Gosert Rainer , Søgaard Kirstine K. , Naegele Klaudia , Bielicki Julia , Roloff Tim , Bingisser Roland , Nickel Christian H. , Khanna Nina , Sutter Sarah Tschudin , Widmer Andreas F. , Rentsch Katharina , Pargger Hans , Siegemund Martin , Stolz Daiana , Tamm Michael , Bassetti Stefano , Osthoff Michael , Battegay Manuel , Egli Adrian , Hirsch Hans H.
Published: September 2020

Introduction

SARS-CoV-2-detection is critical for clinical and epidemiological assessment of the ongoing CoVID-19 pandemic.

Aim

To cross-validate manual and automated high-throughput (Roche-cobas®6800-Target1/Target2) testing for SARS-CoV-2-RNA, to describe detection rates following lockdown and relaxation, and to evaluate SARS-CoV-2-loads in different specimens.

Method

The validation cohort prospectively compared Basel-S-gene, Roche-E-gene, and Roche-cobas®6800-Target1/Target2 in 1344 naso-oropharyngeal swabs (NOPS) taken in calendar week 13 using Basel-ORF8-gene-assay for confirmation. Follow-up-cohort-1 and -2 comprised 12363 and 10207 NOPS taken over 10 weeks until calendar week 24 and 34, respectively. SARS-CoV-2-loads were compared in follow-up NOPS, lower respiratory fluids, and plasma.

Results

Concordant results were obtained in 1308 cases (97%) including 97 (9%) SARS-CoV-2-positives showing high quantitative correlations (Spearman r>0.95; p<0.001) for all assays. Discordant samples (N=36) had significantly lower SARS-CoV-2-loads (p<0.001). Following lockdown, weekly detection rates declined to <1% reducing single-test positive predictive values from 99.3% to 85.1%. Following relaxation, rates flared up to 4% with similarly high SARS-CoV-2-loads, but patients were significantly younger than during lockdown (34 vs 52 years, p<0.001). SARS-CoV-2-loads in follow-up NOPS declined by 3log10 copies/mL within 10 days post-diagnosis (p<0.001). SARS-CoV-2-loads in NOPS correlated weakly with those in time-matched lower respiratory fluids and plasma, but remained detectable in 14 and 7 cases of NOPS with undetectable SARS-CoV-2, respectively.

Conclusion

Evaluated manual and automated assays are highly concordant and correlate quantitatively. Following successful lockdown, declining positive predictive values require dual-target-assays for clinical and epidemiologic assessment. Confirmatory and quantitative follow-up testing should be considered within <5 days, using lower respiratory fluids in symptomatic patients with SARS-CoV-2-negative NOPS.
Optimal Dynamic Prioritization of Scarce COVID-19 Vaccines
Authors: Buckner Jack H. , Chowell Gerardo , Springborn Michael R.
Published: September 2020

Multiple promising COVID-19 vaccines are under rapid development, with deployment of the initial supply expected by 2021. Careful design of a vaccine prioritization strategy across socio-demographic groups is an imminent and crucial public policy challenge given that (1) the eventual vaccine supply will be highly constrained for at least the first several months of the vaccination campaign, and (2) there are stark differences in transmission and severity of impacts from SARS-CoV-2 across groups. Previous experience with vaccine development mid-pandemic offers limited insights for SARS-CoV-2 prioritization: SARS and Zika vaccine development was incomplete when those outbreaks ended and the epidemiology of endemic human influenza viruses differ substantially from that of SARS-CoV-2. We assess the optimal allocation of a limited and dynamic COVID-19 vaccine supply in the U.S. across socio-demographic groups differentiated by age and essential worker status. The transmission dynamics are modeled using a compartmental (SEIR) model parameterized to capture our current understanding of the transmission and epidemiological characteristics of COVID-19, including key sources of group heterogeneity (susceptibility, severity, and contact rates). We investigate tradeoffs between three alternative policy objectives: minimizing infections, years of life lost, or deaths. Moreover, we model dynamic vaccine prioritization policies that respond to changes in the epidemiological status of the population as SARS-CoV-2 continues its march. Because contacts tend to be concentrated within age groups, there is diminishing marginal returns as vaccination coverage increases in a given group, increasing the group’s protective immunity against infection and mortality. We find that optimal prioritization consistently targets older essential workers. However, depending on the policy objective, younger essential workers are prioritized to minimize infections or seniors in order to minimize mortality. Optimal prioritization outperforms non-targeted vaccination strategies by up to 18% depending on the outcome optimized. For example, in our baseline model, cumulative mortality decreased on average by 17% (25,000 deaths in the U.S. population) over the course of the outbreak.
A Cost Analysis of Childbirth for Pregnant Women with COVID-19 in Nigeria’s Epicentre
Authors: Banke-Thomas Aduragbemi , Makwe Christian Chigozie , Balogun Mobolanle , Afolabi Bosede Bukola , Alex-Nwangwu Theresa Amaogechukwu , Ameh Charles Anawo
Published: September 2020

The Coronavirus disease 2019 (COVID-19) has been a major disruptor of health systems globally. Its emergence has warranted the need to reorganize maternity services for childbirth. However, it is not known if this comes at an additional cost to women. We conducted a hospital-based cost analysis to estimate the out-of-pocket cost of spontaneous vaginal delivery (SVD) and caesarean delivery (CD). Specifically, we collected facility-based and household costs of all nine pregnant women with COVID-19 who were managed between 1st April and 30th August 2020 at the largest teaching hospital in Lagos, the epicentre of COVID-19 in Nigeria. We compared the mean facility-based costs for the cohort with costs paid by pregnant women pre-COVID-19, identifying major cost drivers. We also estimated what would have been paid without subsidies, testing assumptions with a sensitivity analysis. Findings showed that total utilization cost ranged from US$494 (N190,150) for SVD with mild COVID-19 to US$4,553 (N1,751,165) for emergency CD with severe COVID-19. Though 32-66% of facility-based cost has been subsidized, cost of SVD and CD have doubled and tripled respectively during the pandemic compared to those paid pre-COVID. Out of the facility-based costs paid, cost of personal protective equipment (PPE) was the major cost driver (50%) for SVD and CD. Supplemental oxygen was a major cost driver when women had severe COVID-19 symptoms and required long admission (48%). Excluding treatment costs specifically for COVID-19, mean facility-based costs for SVD and CD are US$228 (N87,750) and US$948 (N364,551) respectively. Our study demonstrates that despite cost exemptions and donations, utilization costs remain prohibitive. Regulation of the PPE and medical oxygen supply chain can help drive down utilization cost and reduce mark-ups being passed to users. The pandemic offers an opportunity to expand advocacy for subscription to health insurance schemes in order to avoid any catastrophic health expenditure.

KEY MESSAGES

Total utilization cost ranged from US$494 (N190,150) for spontaneous vaginal delivery with mild COVID-19 to US$4,553 (N1,751,165) for emergency caesarean delivery with severe COVID-19.

Cost of personal protective equipment was the major cost driver (50%) for vaginal and elective caesarean deliveries. Medical oxygen was a major cost driver when women had severe COVID-19 symptoms (48%) and required long admission.

Though 32-66% of total cost have been subsidized, facility-based cost of vaginal and caesarean deliveries has doubled and tripled respectively during the pandemic compared to those paid pre-COVID.

The study findings highlight the urgent need to implement strategies that can help to minimize the rising costs that pregnant women with COVID-19 face in accessing and utilizing critical intra-partum care.
Delayed viral clearance and exacerbated airway hyperinflammation in hypertensive COVID-19 patients
Authors: Trump Saskia , Lukassen Soeren , Anker Markus S. , Chua Robert Lorenz , Liebig Johannes , Thürmann Loreen , Corman Victor , Binder Marco , Loske Jennifer , Klasa Christina , Krieger Teresa , Hennig Bianca P. , Messingschlager Marey , Pott Fabian , Kazmierski Julia , Twardziok Sven , Albrecht Jan Philipp , Eils Jürgen , Hadzibegovic Sara , Lena Alessia , Heidecker Bettina , Goffinet Christine , Kurth Florian , Witzenrath Martin , Völker Maria Theresa , Müller Sarah Dorothea , Liebert Uwe Gerd , Ishaque Naveed , Kaderali Lars , Sander Leif-Erik , Laudi Sven , Drosten Christian , Eils Roland , Conrad Christian , Landmesser Ulf , Lehmann Irina
Published: September 2020

In COVID-19, hypertension and cardiovascular diseases have emerged as major risk factors for critical disease progression. Concurrently, the impact of the main anti-hypertensive therapies, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), on COVID-19 severity is controversially discussed. By combining clinical data, single-cell sequencing data of airway samples andin vitroexperiments, we assessed the cellular and pathophysiological changes in COVID-19 driven by cardiovascular disease and its treatment options. Anti-hypertensive ACEi or ARB therapy, was not associated with an altered expression of SARS-CoV-2 entry receptorACE2in nasopharyngeal epithelial cells and thus presumably does not change susceptibility for SARS-CoV-2 infection. However, we observed a more critical progress in COVID-19 patients with hypertension associated with a distinct inflammatory predisposition of immune cells. While ACEi treatment was associated with dampened COVID-19-related hyperinflammation and intrinsic anti-viral responses, under ARB treatment enhanced epithelial-immune cell interactions were observed. Macrophages and neutrophils of COVID-19 patients with hypertension and cardiovascular comorbidities, in particular under ARB treatment, exhibited higher expression ofCCL3, CCL4, and its receptorCCR1, which associated with critical COVID-19 progression. Overall, these results provide a potential explanation for the adverse COVID-19 course in patients with cardiovascular disease, i.e. an augmented immune response in critical cells for the disease course, and might suggest a beneficial effect of clinical ACEi treatment in hypertensive COVID-19 patients.
An analysis of clinical and geographical metadata of over 75,000 records in the GISAID COVID-19 database
Authors: Velazquez Anjelina , Bustria Mhealyssah , Ouyang Youwen , Moshiri Niema
Published: September 2020

During the SARS-CoV-2 outbreak that caused the coronavirus pandemic it is important now more than ever that scientists and public health officials work side-by-side and use their available resources to track patient information from those that have been affected by the novel coronavirus. The ability to track the disease helps identify possible trends and patterns that can be used by public health officials to make more informed decisions. Tracking data like this may be the key to helping states and countries safely re-open. However, when analyzing large collections of data there is the occurrence of confounding factors such as biases in patient sampling. In this project, a massive collection of COVID-19 data was analyzed, and explored potential biases in patient sampling were explored.
APPLAUSE: Automatic Prediction of PLAcental health via U-net Segmentation and statistical Evaluation
Authors: Pietsch Maximilian , Ho Alison , Bardanzellu Alessia , Zeidan Aya Mutaz Ahmad , Chappell Lucy C. , Hajnal Joseph V. , Rutherford Mary , Hutter Jana
Published: September 2020

Purpose

Artificial-intelligence population-based automated quantification of placental maturation and health from a rapid functional Magnetic Resonance scan. The placenta plays a crucial role for any successful human pregnancy. Deviations from the normal dynamic maturation throughout gestation are closely linked to major pregnancy complications. Antenatal assessment in-vivo using T2* relaxometry has shown great promise to inform management and possible interventions but clinical translation is hampered by time consuming manual segmentation and analysis techniques based on comparison against normative curves over gestation.

Methods

This study proposes a fully automatic pipeline to predict the biological age and health of the placenta based on a rapid (sub-30 second) T2* scan in two steps: Automatic segmentation using a U-Net and a Gaussian Process regression model to characterize placental maturation and health. These are trained and evaluated on 110 3T MRI placental data sets including 20 high-risk pregnancies diagnosed with pre-eclampsia and/or fetal growth restriction.

Results

Automatic segmentation achieves comparable performance to human experts (mean DICE coefficients automatic-manual 0.76, Pearson Correlation Coefficient 0.986 for mean T2* within the masks). The placental health prediction achieves an excellent ability to differentiate early cases of placental in-sufficiency before 32 weeks. High abnormality scores correlate with low birth weight, premature birth and histopathological findings. Retrospective application on a different cohort imaged at 1.5T illustrates the ability for direct clinical translation.

Conclusion

The presented automatic pipeline facilitates a fast, robust and reliable prediction of placental maturation. It yields human-interpretable and verifiable intermediate results and quantifies uncertainties on the cohort-level and for individual predictions. The proposed machine-learning pipeline runs in close to real-time and, deployed in clinical settings, has the potential to become a cornerstone of diagnosis and intervention of placental insufficiency.
Empirical transmission advantage of the D614G mutant strain of SARS-CoV-2
Authors: Leung Kathy , Pei Yao , Leung Gabriel M , Lam Tommy TY , Wu Joseph T
Published: September 2020

The SARS-CoV-2 lineage carrying the amino acid change D614G has become the dominant variant in the global COVID-19 pandemic. The rapid spread of the G614 mutant suggests that it may have a transmission advantage over the D614 wildtype. Using our previous epidemiological framework to analyze COVID-19 surveillance and sequence data, we estimated that the G614 mutant is 31% (28-34%) more transmissible than the D614 wildtype. As such, interventions that were previously effective in containing or mitigating the D614 wildtype (e.g. in China, Vietnam, Thailand, etc.) might be less effective against the G614 mutant. Our framework can be readily integrated into current COVID-19 surveillance to monitor the emergence and fitness of mutant strains, such that pandemic surveillance, disease control and development of treatment and vaccines can be adjusted dynamically.
Quantification of abdominal fat from computed tomography using deep learning and its association with electronic health records in an academic biobank
Authors: MacLean Matthew T. , Jehangir Qasim , Vujkovic Marijana , Ko Yi-An , Litt Harold , Borthakur Arijitt , Sagraiya Hersh , Rosen Mark , Mankoff David A. , Schnall Mitchell D. , Shou Haochang , Chirinos Julio , Damrauer Scott M. , Torigian Drew A. , Carr Rotonya , Rader Daniel J. , Witschey Walter R.
Published: September 2020

Objective

The objective was to develop a fully automated algorithm for abdominal fat segmentation and deploy this method at scale and associated with diagnoses in an academic biobank.

Materials and Methods

We built a fully automated image curation and labeling technique using deep learning and distributive computing to identify subcutaneous and visceral abdominal fat compartments from 47,587 CT scans in 13,422 patients in the Penn Medicine Biobank (PMBB). A classification network identified the inferior and superior borders of the abdomen, and a segmentation network differentiated visceral and subcutaneous fat. Following technical evaluation of our method, we conducted studies to validate known relationships with adiposity.

Results

When compared with 100 manually annotated cases, the classification network was on average within one 5 mm slice for both the superior (0.3±0.6 slices) and inferior (0.7±0.6 slices) borders. The segmentation network also demonstrated excellent performance with interclass correlation coefficients of 0.99 (p<2e-16) for subcutaneous and 0.99 (p<2e-16) for visceral fat on 100 testing cases. We performed integrative analyses of abdominal fat with the phenome extracted from the electronic health record and found highly significant associations with diabetes mellitus, hypertension, renal failure, among other phenotypes.

Conclusion

This work presents a fully automated and highly accurate method for the quantification of abdominal fat that can be applied to routine clinical imaging studies to fuel translation scientific discovery.
Exploratory and confirmatory factor analysis of the Cognitive Social Capital Scale in a Colombian sample
Authors: Campo-Arias Adalberto , Caballero-Domínguez Carmen Cecilia , Pedrozo-Pupo John Carlos
Published: September 2020

During the last two decades, the concept of social capital has been used with increasing frequency in health sciences due to the direct and indirect relationships between social capital and populations’ physical and mental health. Therefore, it is necessary to build an instrument to quantify this concept confidently and reliably. The study aimed to perform exploratory and confirmatory factor analyses on a seven-item scale to measure social capital in adults of Colombia’s general population. An online validation study was done, including a sample of 700 adults aged between 18 and 76 years; 68% were females. Participants completed a seven-item scale called the Cognitive Social Capital Scale (CSCS). Cronbach’s alpha and McDonald’s omega were computed to test internal consistency. Exploratory and confirmatory factor analyses were conducted to explore the dimensionality of the CSCS. The CSCS presented a low internal consistency (Cronbach’s alpha of 0.56 and McDonald’s omega of 0.59) and poor dimensionality. Then, a five-item version (CSCS-5) was tested. The CSCS-5 showed high internal consistency (Cronbach’s alpha of 0.79 and McDonald’s omega of 0.80) and a one-dimension structure with acceptable goodness-of-fit indicators. In conclusion, the CSCS-5 presents high internal consistency and a one-dimension structure to measure cognitive capital social in Colombian sample. It can be recommended for the measuring of social capital in the general Colombian population. Further research should corroborate these findings on pencil and paper applications and explore other reliability and validity indicators.
Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis
Authors: Illouz Tomer , Nicola Raneen , Ben-Shuhan Linoy , Madar Ravit , Biragyn Arya , Okun Eitan
Published: September 2020

Down Syndrome (DS) features a life-long overexpression of theAPPandDYRK1Agenes, leading to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation. As DS can be diagnosed in utero, maternally transferred anti-Aβ antibodies might promote removal of early accumulation of Aβ from the CNS. A DNA-vaccine expressing Aβ1-11was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation, similar to individuals with DS. Maternal Aβ-specific antibodies provided transgenic offspring with passive immunization against Aβ via the placental and subsequently lactation. Maternal antibodies reduced cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits and activation of the FcγR1/Syk/Cofilin pathway in microglia. Sera from immunized dams facilitated Aβ clearance by microglia in a Syk-dependent manner. These data suggest that maternal anti-Aβ immunization is a potential strategy to alleviate cognitive decline in individuals with DS.
RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis
Authors: Soni Sourabh , Anand Prince , Swarnkar Mohit Kumar , Patial Vikram , Tirpude Narendra V. , Padwad Yogendra S.
Published: September 2020

Background

Transcriptome profiling has been pivotal in better comprehending the convoluted biology of tumors including head and neck squamous cell carcinoma (HNSCC). Recently, growing evidence has implicated the role of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in many human diseases including tumors. MK2 has been recently reported as a critical regulator of HNSCC that functionsviamodulating the transcript turnover of crucial genes involved in its pathogenesis. Comprehensive MK2-centric transcriptomic analyses could help the scientific community to delve deeper into MK2-pathway driven mechanisms of tumor progression, but such studies have not yet been reported. Consequently, to delineate the biological relevance of MK2 and its intricate crosstalk in the tumor milieu, an extensive transcriptome analysis of HNSCC was conceptualized and effectuated with MK2 at the nexus.

Methods

In the current study, comprehensive next-generation sequencing-based transcriptome profiling was accomplished to ascertain global patterns of mRNA expression profiles in bothin vitroandin vivomodels of the HNSCC microenvironment. The findings of the RNA-sequencing analysis were cross-validatedviarobust validation using nCounter gene expression assays, immunohistochemistry, and real-time quantitative polymerase chain reaction (RT–qPCR).

Results

Transcriptomic characterization followed by annotation and differential gene expression analyses identified certain MK2-regulated candidate genes constitutively involved in regulating HNSCC pathogenesis, and the biological significance of these genes was established by pathway enrichment analysis. Additionally, advanced gene expression assays through the nCounter system in conjunction with immunohistochemical analysis validated the transcriptome profiling outcomes quite robustly. Furthermore, the results obtained from immunohistochemistry and transcript stability analysis indicated the crucial role of MK2 in the modulation of the expression pattern of these genes in HNSCC tumors and cells.

Conclusions

Conclusively, the findings have paved the way toward the identification of new effective tumor markers and potential molecular targets for HNSCC management. The results have accentuated the importance of certain differentially expressed MK2-regulated genes that are constitutively involved in HNSCC pathogenesis to potentially serve as putative candidates for future endeavors pertaining to diagnosis and therapeutic interventions for HNSCC.
Genes on Different Strands Mark Boundaries Associated with Co-regulation Domains
Authors: Baguette Audrey , Bilodeau Steve , Bourque Guillaume
Published: September 2020

Gene regulation is influenced by chromatin conformation. Current models suggest that topologically associating domains (TADs) act as regulatory units, which could also include distinct co-expression domains (CODs) favouring correlated gene expression. We integrated publicly available RNA-seq, ChIP-seq and Hi-C data from A549 cells stimulated with the glucocorticoid dexamethasone to explore how differentially expressed genes are co-regulated among TADs and CODs. Interestingly, we found that gene position and orientation also impact co-regulation. Indeed, divergent and convergent pairs of genes we enriched at sub-TAD boundaries, forming distinct CODs. We also found that genes at COD boundaries were less likely to be separated by structural proteins such as Cohesin and CTCF. A complementary analysis of lung expression quantitative trait loci (eQTL) demonstrated that genes affected by the same variant were more likely to be found on the same strand while lacking a TAD boundary. Taken together, these results suggest a model where gene orientation can provide a boundary between CODs, at the sub-TAD level, thus affecting their likelihood of co-regulation.
A causal study of bumetanide on a marker of excitatory-inhibitory balance in the human brain
Authors: Botch Thomas L. , Spiegel Alina , Ricciardi Catherine , Robertson Caroline E.
Published: September 2020

Bumetanide has received much interest as a potential pharmacological modulator of the putative imbalance in excitatory/inhibitory (E/I) signaling that is thought to characterize autism spectrum conditions. Yet, currently, no studies of bumetanide efficacy have used an outcome measure that is modeled to depend on E/I balance in the brain. In this manuscript, we present the first causal study of the effect of bumetanide on an objective marker of E/I balance in the brain, binocular rivalry, which we have previously shown to be sensitive to pharmacological manipulation of GABA. Using a within-subjects placebo-control crossover design study, we show that, contrary to expectation, acute administration of bumetanide does not alter binocular rivalry dynamics in neurotypical adult individuals. Neither changes in response times nor response criteria can account for these results. These results raise important questions about the efficacy of acute bumetanide administration for altering E/I balance in the human brain, and highlight the importance of studies using objective markers of the underlying neural processes that drugs hope to target.
EEG Cross-Frequency Phase Synchronization as an Index of Memory Matching in Visual Search
Authors: Biel Anna Lena , Minarik Tamas , Sauseng Paul
Published: September 2020

Visual perception is influenced by our expectancies about incoming sensory information. It is assumed that mental templates of expected sensory input are created and compared to actual input, which can be matching or not. When such mental templates are held in working memory, cross-frequency phase synchronization (CFS) between theta and gamma band activity has been proposed to serve matching processes between prediction and sensation. We investigated how this is affected by the number of activated templates that could be matched by comparing conditions where participants had to keep either one or multiple templates in mind for successful visual search. We found a transient CFS between EEG theta and gamma activity in an early time window around 150ms after search display presentation, in right hemispheric parietal cortex. Our results suggest that for single template conditions, stronger transient theta-gamma CFS at posterior sites contralateral to target presentation can be observed than for multiple templates. This can be interpreted as evidence to the idea of sequential attentional templates. But mainly, it is understood in line with previous theoretical accounts strongly arguing for transient synchronization between posterior theta and gamma phase as a neural correlate of matching incoming sensory information with contents from working memory and as evidence for limitations in memory matching during multiple template search.
Structural basis for conformational equilibrium of the catalytic spliceosome
Authors: Wilkinson Max E. , Fica Sebastian M. , Galej Wojciech P. , Nagai Kiyoshi
Published: September 2020

The catalytic spliceosome exists in equilibrium between the branching (B*/ C) and exon ligation (C*/ P) conformations. Here we present the electron cryo-microscopy reconstruction of theSaccharomyces cerevisiaeC complex at 2.8 Å resolution and identify a novel C-complex intermediate (Ci) that elucidates the molecular basis for this equilibrium. In the Ciconformation, the exon-ligation factors Prp18 and Slu7 are already bound before ATP hydrolysis by Prp16, which destabilises the branching conformation. Biochemical assays suggest these pre-bound factors prime C complex for conversion to C* by Prp16. A complete model of the Prp19-complex (NTC) shows how the NTC pre-recruits the branching factors Yju2 and Isy1 before branching. Prp16 remodels Yju2 binding after branching, allowing Yju2 to remain associated with the C* and P spliceosomes and promote exon ligation. Our results explain how Prp16 action modulates dynamic binding of step-specific factors to alternatively stabilise the C or C* conformation and establish equilibrium of the catalytic spliceosome.