bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the SARS-CoV-2 infected population fraction and the infection-to-fatality ratio: A data-driven case study based on Swedish time series data
Authors: Wacker Andreas , Jöud Anna , Bernhardsson Bo , Gerlee Philip , Gustafsson Fredrik , Soltesz Kristian
Published: May 2021

Aim

To estimate the COVID-19 infection-to-fatality ratio (IFR), infection-to-case ratio (ICR), and infection-to-ICU admission ratio (IIAR) in Sweden; to suggest methods for time series reconstruction and prediction.

Methods

We optimize a set of simple finite impulse response (FIR) models comprising of a scaling factor and time-delay between officially reported cases, ICU admissions and deaths time series using the least squares method. Combined with randomized PCR study results, we utilize this simple model to estimate the total number of infections in Sweden, and the corresponding IFR.

Results

The model class provides a good fit between ICU admissions and deaths throughout 2020. Cases fit consistently from July 2020, by when PCR tests had become broadly available. We observe a diminished IFR in late summer as well as a strong decline during 2021, following the launch of a nation-wide vaccination program. The total number of infections during 2020 is estimated to 1.3 million.

Conclusions

A FIR model with a delta filter function describes the evolution of epidemiological data in Sweden well. The fact that we found IFR, ICR and IIAR constant over large parts of 2020 is in contrast with claims of healthcare adaptation or mutated virus variants importantly affecting these ratios. The model allows us to retrospectively estimate the COVID-19 epidemiological trajectory, and conclude that Sweden was far from herd immunity by the end of 2020.
COVID-19 vaccine uptake in United States counties: geospatial vaccination patterns and trajectories towards herd immunity
Authors: Chernyavskiy Pavel , Richardson Jeanita W. , Ratcliffe Sarah J.
Published: May 2021

Following the COVID-19 pandemic, safe and effective vaccines were developed and authorized for use in the general population. Studying factors that encourage community acceptance of these vaccines is needed to prevent proliferation of SARS-CoV-2 variants, to safely relax local restrictions, and to return to pre-pandemic living conditions. To our knowledge, United States (US) county-level disparities in vaccination are yet to be investigated. Our data span February - May 2021 across 3138 US counties. We consider percentage of residents with at least one dose of an authorized COVID vaccine as the outcome. Spatio-temporal models were used to determine associations of vaccination rates with time-fixed and time-varying covariates. Spatial variability was modelled via Conditional Auto-regressive models; county trajectories over time were specified using random slopes. Greater vaccination rates occur in counties with older residents, high educational attainment, and high proportion of minority residents. Vaccination rates change with COVID risk metrics, suggesting continued slowing of vaccine uptake due to decreasing incidence and infection rates. County effects reveal strong regional patterns in average vaccination rates and trajectories. Although local herd immunity can be expected in August 2021 for counties with typical uptake rates, these counties are clustered in relatively few areas of the country.
Pan[dem]ic! Rational Risk Avoidance During a Health Pandemic
Authors: Okeke Edward N.
Published: May 2021

During a health pandemic health workers have to balance two competing objectives: their own welfare vs. that of their patients. Intuitively, attending to sick patients during a pandemic poses risks to health workers because some of these patients could be infected. One way to reduce risk is by reducing contact with patients. These changes could be on the extensive margin, e.g., seeing fewer patients; or, more insidiously, on the intensive margin, by reducing the duration/intensity of contact. This paper studies risk avoidance behavior during the Covid-19 pandemic and examines implications for patient welfare. Using primary data on thousands of patient-provider interactions between January 2019 and October 2020 in Nigeria, I present evidence of risk compensation by health workers along the intensive margin. For example, the probability that a patient receives a physical examination has dropped by about a third. I find suggestive evidence of negative effects on health outcomes.
UV-A and UV-B Can Neutralize SARS-CoV-2 Infectivity
Authors: Biasin Mara , Strizzi Sergio , Bianco Andrea , Macchi Alberto , Utyro Olga , Pareschi Giovanni , Loffreda Alessia , Cavalleri Adalberto , Lualdi Manuela , Trabattoni Daria , Tacchetti Carlo , Mazza Davide , Clerici Mario
Published: May 2021

We performed an in-depth analysis of the virucidal effect of discrete wavelengths: UV-C (278 nm), UV-B (308 nm), UV-A (366 nm) and violet (405 nm) on SARS-CoV-2. By using a highly infectious titer of SARS-CoV-2 we observed that the violet light-dose resulting in a 2-log viral inactivation is only 10−4 times less efficient than UV-C light. Moreover, by qPCR and fluorescence in situ hybridization (FISH) approach we verified that the viral titer typically found in the sputum of COVID-19 patients can be completely inactivated by the long UV-wavelengths corresponding to UV-A and UV-B solar irradiation. The comparison of the UV action spectrum on SARS-CoV-2 to previous results obtained on other pathogens suggests that RNA viruses might be particularly sensitive to long UV wavelengths. Our data extend previous results showing that SARS-CoV-2 is highly susceptible to UV light and offer an explanation to the reduced incidence of SARS-CoV-2 infection seen in the summer season.

SYNOPSIS

UV-A, UV-B and violet wavelengths kill SARS-CoV-2, supporting the sterilizing effects of the solar pump on human pathogens and the explanation of the seasonality of the COVID-19 pandemic.
The UGT2A1/UGT2A2 locus is associated with COVID-19-related anosmia
Authors: Shelton Janie F. , Shastri Anjali J. ,   The 23andMe COVID-19 Team, Aslibekyan Stella , Auton Adam
Published: May 2021

Loss of sense of smell is a characteristic symptom of infection with SARS-CoV-2. However, specific mechanisms linking infection with loss of smell are poorly understood. Using self-reported symptom data from the 23andMe COVID-19 study, we describe the demographic patterns associated with COVID-19 related anosmia, and find the symptom is more often reported in women and younger respondents, and less often by those of East Asian and African American ancestry compared to those of European ancestry. We ran a trans-ethnic genome-wide association study (GWAS) comparing loss of smell or taste (n=47,298) with no loss of smell or taste (n=22,543) among those with a positive SARS-CoV-2 test result. We identified an association (rs7688383) in the vicinity of the UGT2A1 and UGT2A2 genes (OR=1.115, p-value=4×10−15), which have been linked to olfactory function. These results may shed light on the biological mechanisms underlying COVID-19 related anosmia.
Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic
Authors: Smith Leon G. , Mendoza Nicolas , Dobesh David , Smith Stephen M.
Published: May 2021

Introduction

This observational study looked at 255 COVID19 patients who required invasive mechanical ventilation (IMV) during the first two months of the US pandemic. Through comprehensive, longitudinal evaluation and new consideration of all the data, we were able to better describe and understand factors affecting outcome after intubation.

Methods

All vital signs, laboratory values, and medication administrations (time, date, dose, and route) were collected and organized. Further, each patient’s prior medical records, including PBM data and available ECG, were reviewed by a physician. These data were incorporated into time-series database for statistical analysis.

Results

By discharge or Day 90, 78.2% of the cohort expired. The most common pre-existing conditions were hypertension, (63.5%), diabetes (59.2%) and obesity (50.4%). Age correlated with death. Comorbidities and clinical status on presentation were not predictive of outcome. Admission markers of inflammation were universally elevated (>96%). The cohort’s weight range was nearly 7-fold. Causal modeling establishes that weight-adjusted HCQ and AZM therapy improves survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum levels.

Discussion

This detailed approach gives us better understanding of risk factors, prognostic indicators, and outcomes of Covid patients needing IMV. Few variables were related to outcome. By considering more factors and using new methods, we found that when increased doses of co-administered HCQ and AZM were associated with >100% increase in survival. Comparison of absolute with weight-adjusted cumulative doses proves administration ≥80 mg/kg of HCQ with > 1 gm AZM increases survival in IMV-requiring Covid patients by over 100%. According to our data, HCQ is not associated with prolongation. Studies, which reported QTc prolongation secondary to HCQ, need to be re-evaluated more stringently and with controls.

The weight ranges of Covid patient cohorts are substantially greater than those of most antibiotic RCTs. Future clinical trials need to consider the weight variance of hospitalized Covid patients and need to study therapeutics more thoughtfully.
f-statistics estimation and admixture graph construction with Pool-Seq or allele count data using the R package poolfstat
Authors: Gautier Mathieu , Vitalis Renaud , Flori Laurence , Estoup Arnaud
Published: May 2021

By capturing various patterns of the structuring of genetic variation across populations, f -statistics have proved highly effective for the inference of demographic history. Such statistics are defined as covariance of SNP allele frequency differences among sets of populations without requiring haplotype information and are hence particularly relevant for the analysis of pooled sequencing (Pool-Seq) data. We here propose a reinterpretation of the F (and D) parameters in terms of probability of gene identity and derive from this unified definition unbiased estimators for both Pool-Seq and standard allele count data obtained from individual genotypes. We implemented these estimators in a new version of the R package poolfstat, which now includes a wide range of inference methods: (i) three-population test of admixture; (ii) four-population test of treeness; (iii) F4-ratio estimation of admixture rates; and (iv) fitting, visualization and (semi-automatic) construction of admixture graphs. A comprehensive evaluation of the methods implemented in poolfstat on both simulated Pool-Seq (with various sequencing coverages and error rates) and allele count data confirmed the accuracy of these approaches, even for the most cost-effective Pool-Seq design involving low sequencing coverages. We further analyzed a real Pool-Seq data made of 14 populations of the invasive species Drosophila suzukii which allowed refining both the demographic history of native populations and the invasion routes followed by this emblematic pest. Our new package poolfstat provides the community with a user-friendly and efficient all-in-one tool to unravel complex population genetic histories from large-size Pool-Seq or allele count SNP data.
Ankyrin repeats in context with human population variation
Authors: Utgés Javier S. , Tsenkov Maxim I. , Dietrich Noah J. M. , MacGowan Stuart A. , Barton Geoffrey J.
Published: May 2021

Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy individuals across this family. Population variants are not randomly distributed across the genome but are constrained by gene essentiality and function. Accordingly, we interpret the population variants in context with evolutionary constraint and structural features including secondary structure, accessibility and protein-protein interactions across 383 three-dimensional structures of ankyrin repeats. We find five positions that are highly conserved across homologs and also depleted in missense variants within the human population. These positions are significantly enriched in intra-domain contacts and so likely to be key for repeat packing. In contrast, a group of evolutionarily divergent positions are found to be depleted in missense variants in human but significantly enriched in protein-protein interactions. Our analysis also suggests the domain has three, not two surfaces, each with different patterns of enrichment in protein-substrate interactions and missense variants. Our findings will be of interest to those studying or engineering ankyrin-repeat containing proteins as well as those interpreting the significance of disease variants.

Author Summary

Comparison of variation at each position of the amino acid sequence for a protein across different species is a powerful way to identify parts of the protein that are important for its structure and function. Large-scale DNA sequencing of healthy people has recently made it possible to study normal genetic variation within just one species. Our work combines information on genetic differences between over 100,000 people with in-depth analysis of all available three-dimensional structures for Ankyrin repeats which are a widespread family of binding proteins formed by units with similar amino acid sequence that are found in tandem. Our combined analysis identifies sites critical for ankyrin stability as well as the positions most important for substrate interactions and hence function. Although focused only on the Ankyrins, the principles developed in our work are general and can be applied to any protein family.
An Investigation of Neural Mechanisms Underlying Verb Morphology Deficits in Aphasia
Authors: Pifer Madeline , Brodbeck Christian , Faroqi-Shah Yasmeen
Published: May 2021

Agrammatic aphasia is an acquired language disorder characterized by slow, non-fluent speech that include primarily content words. It is well-documented that people with agrammatism (PWA) have difficulty with production of verbs and verb morphology, but it is unknown whether these deficits occur at the single word-level, or are the result of a sentence-level impairment. The first aim of this paper is to determine the linguistic level that verb morphology impairments exist at by using magnetoencephalography (MEG) scanning to analyze neural response to two language tasks (one word-level, and one sentence-level). It has also been demonstrated that PWA benefit from a morphosemantic intervention for verb morphology deficits, but it is unknown if this therapy induces neuroplastic changes in the brain. The second aim of this paper is to determine whether or not neuroplastic changes occur after treatment, and explore the neural mechanisms by which this improvement occurs.
Reconstructing unobserved cellular states from paired single-cell lineage tracing and transcriptomics data
Authors: Ouardini Khalil , Lopez Romain , Jones Matthew G. , Prillo Sebastian , Zhang Richard , Jordan Michael I. , Yosef Nir
Published: May 2021

Abstract

Novel experimental assays now simultaneously measure lineage relationships and transcriptomic states from single cells, thanks to CRISPR/Cas9-based genome engineering. These multimodal measurements allow researchers not only to build comprehensive phylogenetic models relating all cells but also infer transcriptomic determinants of consequential subclonal behavior. The gene expression data, however, is limited to cells that are currently present (“leaves” of the phylogeny). As a consequence, researchers cannot form hypotheses about unobserved, or “ancestral”, states that gave rise to the observed population. To address this, we introduce TreeVAE: a probabilistic framework for estimating ancestral transcriptional states. TreeVAE uses a variational autoencoder (VAE) to model the observed transcriptomic data while accounting for the phylogenetic relationships between cells. Using simulations, we demonstrate that TreeVAE outperforms benchmarks in reconstructing ancestral states on several metrics. TreeVAE also provides a measure of uncertainty, which we demonstrate to correlate well with its prediction accuracy. This estimate therefore potentially provides a data-driven way to estimate how far back in the ancestor chain predictions could be made. Finally, using real data from lung cancer metastasis, we show that accounting for phylogenetic relationship between cells improves goodness of fit. Together, TreeVAE provides a principled framework for reconstructing unobserved cellular states from single cell lineage tracing data.
No evidence of human genome integration of SARS-CoV-2 found by long-read DNA sequencing
Authors: Smits Nathan , Rasmussen Jay , Bodea Gabriela O. , Amarilla Alberto A. , Gerdes Patricia , Sanchez-Luque Francisco J. , Ajjikuttira Prabha , Modhiran Naphak , Liang Benjamin , Faivre Jamila , Deveson Ira W. , Khromykh Alexander A. , Watterson Daniel , Ewing Adam D. , Faulkner Geoffrey J.
Published: May 2021

A recent study proposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into the DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we applied deep (>50×) long-read Oxford Nanopore Technologies (ONT) sequencing to HEK293T cells infected with SARS-CoV-2, and did not find the virus integrated into the genome. By examining ONT data from separate HEK293T cultivars, we completely resolved 78 L1 insertions arisingin vitroin the absence of L1 overexpression systems. ONT sequencing applied to hepatitis B virus (HBV) positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution of retrotransposon and exogenous virus insertions via ONT sequencing. That we found no evidence of SARS-CoV-2 integration suggests such events are, at most, extremely rarein vivo, and therefore are unlikely to drive oncogenesis or explain post-recovery detection of the virus.
Partitioning the temporal changes in abundance-based beta diversity into loss and gain components
Authors: Tatsumi Shinichi , Iritani Ryosuke , Cadotte Marc W.
Published: May 2021

Ecologists have long recognized that the losses and gains in local species abundances can either decrease or increase spatial beta diversity, phenomena often referred to as biotic homogenization and differentiation, respectively. However, quantifying such dynamic impacts of species abundances on beta diversity has remained a methodological challenge.

Here, we develop a numerical method to additively partition the temporal changes in beta diversity into distinct components that reflect the losses and gains in local species abundances. Our method is based on Ružička and Bray–Curtis indices and the normalized abundance-based Whittaker’s beta diversity. The temporal changes in these measures are partitioned into components that represent biotic homogenization and differentiation driven by abundance losses and gains at both species and community levels.

Application of the method to a Swedish fish community dataset revealed decreases in beta diversity between 1990 and 2018. The homogenization of fish communities was explained by gains, but not losses, in species abundances across sites. Species-level partitioning further showed that the homogenization was largely caused by the increased population sizes of a particular species in sites where it was already present.

The results highlight that our partitioning method effectively identifies local population and community processes embedded in regional biodiversity patterns. We believe that explicit analyses of the losses and gains in species abundances should bring deeper insights into the dynamics of beta diversity.
Now you see it, now you don’t: optimal parameters for interslice stimulation in concurrent TMS-fMRI
Authors: Scrivener C. L. , Jackson J. B. , Correia M. M. , Mada M. , Woolgar A
Published: May 2021

The powerful combination of transcranial magnetic stimulation (TMS) concurrent with functional magnetic resonance imaging (fMRI) provides rare insights into the causal relationships between brain activity and behaviour. Despite a recent resurgence in popularity, TMS-fMRI remains technically challenging. Here we examined the feasibility of applying TMS during short gaps between fMRI slices to avoid incurring artefacts in the fMRI data. We quantified signal dropout and changes in temporal signal-to-noise ratio (tSNR) for TMS pulses presented at timepoints from 100ms before to 100ms after slice onset. Up to 3 pulses were delivered per volume using MagVenture’s MR-compatible TMS coil. We used a spherical phantom, two 7-channel TMS-dedicated surface coils, and a multiband (MB) sequence (factor=2) with interslice gaps of 100ms and 40ms, on a Siemens 3T Prisma-fit scanner. For comparison we repeated a subset of parameters with a more standard single-channel TxRx (birdcage) coil, and with a human participant and surface coil set up. We found that, even at 100% stimulator output, pulses applied at least - 40ms/+50ms from the onset of slice readout avoid incurring artifacts. This was the case for all three setups. Thus, an interslice protocol can be achieved with a frequency of up to ~10 Hz, using a standard EPI sequence (slice acquisition time: 62.5ms, interslice gap: 40ms). Faster stimulation frequencies would require shorter slice acquisition times, for example using in-plane acceleration. Interslice TMS-fMRI protocols provide a promising avenue for retaining flexible timing of stimulus delivery without incurring TMS artifacts.
Ocellar spatial vision in Myrmecia ants
Authors: Penmetcha Bhavana , Ogawa Yuri , Ryan Laura A , Hart Nathan S , Narendra Ajay
Published: May 2021

In addition to the compound eyes insects possess simple eyes known as ocelli. Input from the ocelli modulates optomotor responses, flight-time initiation and phototactic responses, behaviours that are predominantly mediated by the compound eyes. In this study, using pattern electroretinography (pERG), we investigated the contribution of the compound eyes to ocellar spatial vision in the diurnal Australian bull ant, Myrmecia tarsata by measuring the contrast sensitivity and spatial resolving power of the ocellar second-order neurons under various occlusion conditions. Furthermore, in four species of Myrmecia ants active at different times of the day and in European honeybee, Apis mellifera, we characterized the ocellar visual properties when both visual systems were available. Among the ants, we found that the time of activity had no significant effect on ocellar spatial vision. Comparing day-active ants and the honeybee we did not find any significant effect of locomotion on ocellar spatial vision. In M. tarsata, when the compound eyes were occluded, the amplitude of the pERG signal from the ocelli reduced by three times compared to conditions when the compound eyes were available. The signals from the compound eyes maintained the maximum contrast sensitivity of the ocelli as 13 (7.7%), and the spatial resolving power as 0.29 cpd. We conclude that ocellar spatial vison improves significantly with input from the compound eyes, with a noticeably larger improvement in contrast sensitivity than in spatial resolving power.
Parameter exploration improves the accuracy of long-read genome assembly
Authors: Priyam Anurag , Witwicka Alicja , Brahma Anindita , Stolle Eckart , Wurm Yannick
Published: May 2021

Long-molecule sequencing is now routinely applied to generate high-quality reference genome assemblies. However, datasets differ in repeat composition, heterozygosity, read lengths and error profiles. The assembly parameters that provide the best results could thus differ across datasets. By integrating four complementary and biologically meaningful metrics, we show that simple fine-tuning of assembly parameters can substantially improve the quality of long-read genome assemblies. In particular, modifying estimates of sequencing error rates improves some metrics more than two-fold. We provide a flexible software, CompareGenomeQualities, that automates comparisons of assembly qualities for researchers wanting a straightforward mechanism for choosing among multiple assemblies.
Adaptive spectroscopic visible-light optical coherence tomography for human retinal oximetry
Authors: Rubinoff Ian , Kuranov Roman V. , Ghassabi Zeinab , Wang Yuanbo , Beckmann Lisa , Miller David A. , Tayebi Behnam , Wollstein Gadi , Ishikawa Hiroshi , Schuman Joel S. , Zhang Hao F.
Published: May 2021

Alterations in the retinal oxygen saturation (sO2) and oxygen consumption are associated with nearly all blinding diseases. A technology that can accurately measure retinal sO2has the potential to improve ophthalmology care significantly. Recently, visible-light optical coherence tomography (vis-OCT) showed great promise for noninvasive, depth-resolved measurement of retinal sO2as well as ultra-high resolution anatomical imaging. We discovered that spectral contaminants (SC), if not correctly removed, could lead to incorrect vis-OCT sO2measurements. There are two main types of SCs associated with vis-OCT systems and eye conditions, respectively. Their negative influence on sO2accuracy is amplified in human eyes due to stringent laser power requirements, eye motions, and varying eye anatomies. We developed an adaptive spectroscopic vis-OCT (Ads-vis-OCT) method to iteratively remove both types of SCs. We validated Ads-vis-OCT inex vivobovine blood samples against a blood-gas analyzer. We further validated Ads-vis-OCT in 125 unique retinal vessels from 18 healthy subjects against pulse-oximeter readings, setting the stage for clinical adoption of vis-OCT.
ILORA: A database of alien vascular flora of India
Authors: Pant Vidushi , Patwardhan Chinmay , Patil Kshitij , Bhowmick Amiya Ranjan , Mukherjee Abhishek , Banerjee Achyut Kumar
Published: May 2021

1) Biological invasions pose an unprecedented threat to biodiversity and ecosystems at different spatial scales, especially for a biodiversity-rich developing nation like India. While country-level checklists of alien taxa are important, databases having their biological and ecological attributes are of paramount importance for facilitating research activities and developing policy interventions. Such a comprehensive database for alien flora is lacking in India.

2) We have curated data for 14 variables related to ecology, biogeography, introduction pathway, socio-economy and distribution of 1747 alien vascular plant species from 22 national and global sources to produce the Indian Alien Flora Information (ILORA) version 1.0 database. This paper describes the detailed methodology of curating these data along with the rationale behind selecting these variables.

3) The database, the first of its kind for the Indian alien flora, will provide easy access to high quality data and offer a ready reference to comprehend the existing scenario of alien plant species in the country. The database is dynamic and will be updated regularly. It has a provision to incorporate user submitted data, which will allow increasing the resolution of the database as well as the expansion of its capacity.

4) The database is envisaged to become a nationwide collaborative platform for a wide spectrum of stakeholders. It is freely accessible via an online data repository as well as through a dedicated website (https://ilora2020.wixsite.com/ilora2020).
Broadening a SARS-CoV-1 neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution
Authors: Zhao Fangzhu , Yuan Meng , Keating Celina , Shaabani Namir , Limbo Oliver , Joyce Collin , Woehl Jordan , Barman Shawn , Burns Alison , Zhu Xueyong , Ricciardi Michael , Peng Linghang , Smith Jessica , Huang Deli , Briney Bryan , Sok Devin , Nemazee David , Teijaro John R. , Wilson Ian A. , Burton Dennis R. , Jardine Joseph G.
Published: May 2021

The emergence of SARS-CoV-2 underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents and to help guide vaccine design. Here, we demonstrate that engineering approaches can be used to refocus an existing neutralizing antibody to a related but resistant virus. Using a rapid affinity maturation strategy, we engineered CR3022, a SARS-CoV-1 neutralizing antibody, to bind SARS-CoV-2 receptor binding domain with >1000-fold improved affinity. The engineered CR3022 neutralized SARS-CoV-2 and provided prophylactic protection from viral challenge in a small animal model of SARS-CoV-2 infection. Deep sequencing throughout the engineering process paired with crystallographic analysis of an enhanced antibody elucidated the molecular mechanisms by which engineered CR3022 can accommodate sequence differences in the epitope between SARS-CoV-1 and SARS-CoV-2. The workflow described provides a blueprint for rapid broadening of neutralization of an antibody from one virus to closely related but resistant viruses.
Effect of SSRI discontinuation on anxiety-like behaviours in mice
Authors: Collins Helen M , Pinacho Raquel , Ozdemir Dersu , Bannerman David M , Sharp Trevor
Published: May 2021

Background

Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms including anxiety. Surprisingly little is known of the behavioural effect of SSRI discontinuation in animals.

Aim

Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice.

Methods

Experiments were based on a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5 day period using the elevated plus maze (EPM) and other anxiety tests.

Results

An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open arm exploration but this was dissociable from effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days treatment but was absent after 7 days treatment. A discontinuation response was not decernable in other anxiety and fear-learning tests applied 3-5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity.

Conclusion

Overall, the current study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
A cost-effective way to design a two layered cell trapping microfluidic device
Authors: Lázaro-Guevara José M.
Published: May 2021

When studying cells population, sometimes is necessary to isolate a specific subset to perform a timeline analysis or determinate the evolution on cell progeny. Microfluidic devices are being used for fulfill this function in multiple designs. However, the design and fabrication of this type of devices involve multiple challenges and high cost. Miniaturization tends to be the primarily challenge where those devices below 10um tends to be so expensive that needs special facilities for fabrication, but using techniques as multilayer fabrication those problems can be overcome. In this work are stated techniques (photolithography, soft-lithography) that helps solving that limitations, from using inexpensive materials, to alignment techniques that does not requires high-tech equipment’s, and a practical design for microfluidic cell trapping array. Where multiple cell types could be seeded and trapped in small cluster (varying on cell size) to be retrieved later on in an easy and practical way.
Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR
Authors: Scherer Michael , Gasparoni Gilles , Rahmouni Souad , Shashkova Tatiana , Arnoux Marion , Louis Edouard , Nostaeva Arina , Avalos Diana , Dermitzakis Emmanouil T. , Aulchenko Yurii S. , Lengauer Thomas , Lyons Paul A. , Georges Michel , Walter Jörn
Published: May 2021

Background

Understanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL) but also for discriminating general from cell-type-specific effects.

Results

Here, we present a two-step computational framework MAGAR, which fully supports identification of methQTLs from matched genotyping and DNA methylation data, and additionally the identification of quantitative cell-type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T-cells, B-cells) from healthy individuals and demonstrate the discrimination of common from cell-type-specific methQTLs. We experimentally validate both types of methQTLs in an independent dataset comprising additional cell types and tissues. Finally, we validate selected methQTLs (PON1, ZNF155, NRG2) by ultra-deep local sequencing. In line with previous reports, we find cell-type-specific methQTLs to be preferentially located in enhancer elements.

Conclusions

Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell-type-specific epigenomic variation.
High Dimensionality Reduction by Matrix Factorization for Systems Pharmacology
Authors: Mehrpooya Adel , Saberi-Movahed Farid , Azizizadeh Najmeh , Rezaei-Ravari Mohammad , Saberi-Movahed Farshad , Eftekhari Mahdi , Tavassoly Iman
Published: May 2021

The extraction of predictive features from the complex high-dimensional multi-omic data is necessary for decoding and overcoming the therapeutic responses in systems pharmacology. Developing computational methods to reduce high-dimensional space of features inin vitro, in vivoand clinical data is essential to discover the evolution and mechanisms of the drug responses and drug resistance. In this paper, we have utilized the Matrix Factorization (MF) as a modality for high dimensionality reduction in systems pharmacology. In this respect, we have proposed three novel feature selection methods using the mathematical conception of a basis for features. We have applied these techniques as well as three other matrix factorization methods to analyze eight different gene expression datasets to investigate and compare their performance for feature selection. Our results show that these methods are capable of reducing the feature spaces and find predictive features in terms of phenotype determination. The three proposed techniques outperform the other methods used and can extract a 2-gene signature predictive of a Tyrosine Kinase Inhibitor (TKI) treatment response in the Cancer Cell Line Encyclopedia (CCLE).

Key Points

Matrix Factorization (MF) is a useful framework for high dimensionality reduction in systems pharmacology.

Novel feature selection methods using the incorporation of the mathematical conception of a basis for features into MF increases the performance of feature selection process.

Feature selection based on the basis-concept in MF can provide predictive gene signatures for therapeutic responses in systems pharmacology.
Interaction between perineuronal nets and ketamine in antidepressant action
Authors: Young Calvin K. , Kinley Kachina G. , McNaughton Neil
Published: May 2021

Depression is highly prevalent, increases suicide risk, and is now the leading cause of disability worldwide. Our ability to treat depression is hampered by the lack of understanding of its biological underpinnings and of the mode of action of effective treatments. We hypothesised that the scaffolding proteins in the medial frontal cortex play a major role in effective antidepressant action. We implanted cannulae into the infralimbic cortex to inject chABC and locally remove perineuronal nets and then tested for antidepressant effects with the forced swim test. We further tested if systemic injections of ketamine had an additive effect. Our preliminary data indicate that neither the removal of these scaffolding proteins nor ketamine were sufficient to decrease depression-like behaviour, but may interact synergistically to decrease immobility time in the forced swim test.
"Smart Tanks": An Intelligent High-Throughput Intervention Testing Platform in Daphnia
Authors: Cho Yongmin , Jonas-Closs Rachael A. , Yampolsky Lev Y. , Kirschner Marc W. , Peshkin Leonid
Published: May 2021

We present a novel platform for testing the effect of interventions on life- and health-span of a short-lived semi transparent freshwater organism, sensitive to drugs with complex behavior and physiology – the planktonic crustacean Daphnia magna. Within this platform, dozens of complex behavioural features of both routine motion and response to stimuli are continuously accurately quantified for large homogeneous cohorts via an automated phenotyping pipeline. We build predictive machine learning models calibrated using chronological age and extrapolate onto phenotypic age. We further apply the model to estimate the phenotypic age under pharmacological perturbation. Our platform provides a scalable framework for drug screening and characterization in both life-long and instant assays as illustrated using long term dose response profile of metformin and short term assay of such well-studied substances as caffeine and alcohol.
Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution
Authors: Subramanian Ayshwarya , Vernon Katherine , Zhou Yiming , Marshall Jamie L. , Alimova Maria , Zhang Fan , Slyper Michal , Waldman Julia , Montesinos Monica S. , Dionne Danielle , Nguyen Lan T. , Cuoco Michael S. , Dubinsky Dan , Purnell Jason , Heller Keith , Sturner Samuel H. , Grinkevich Elizabeth , Ghoshal Ayan , Weins Astrid , Villani Alexandra-Chloe , Chang Steven L. , Rosenblatt-Rosen Orit , Shaw Jillian L. , Regev Aviv , Greka Anna
Published: May 2021

Mouse models are a tool for studying the mechanisms underlying complex diseases; however, differences between species pose a significant challenge for translating findings to patients. Here, we used single-cell transcriptomics and orthogonal validation approaches to provide cross-species taxonomies, identifying shared broad cell classes and unique granular cellular states, between mouse and human kidney. We generated cell atlases of the diabetic and obese kidney using two different mouse models, a high-fat diet (HFD) model and a genetic model (BTBR ob/ob), at multiple time points along disease progression. Importantly, we identified a previously unrecognized, expanding Trem2high macrophage population in kidneys of HFD mice that matched human TREM2high macrophages in obese patients. Taken together, our cross-species comparison highlights shared immune and metabolic cell-state changes.
Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia
Authors: Tuval Amos , Brilon Yardena , Azogy Hadas , Moshkovitz Yoni , Biezuner Tamir , Leshkowitz Dena , Salame Tomer M , Minden Mark D , Tal Perry , Rotter Varda , Oren Moshe , Kaushansky Nathali , Shlush Liran I
Published: May 2021

Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated.

Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs.

Intriguingly, a misfolded p53 was described in AML blasts that do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a “pseudomutant” conformations of p53.

By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudomutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent.

Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing.

Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.
Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi
Authors: Bernatchez Jean A. , Kil Yun-Seo , da Silva Elany Barbosa , Thomas Diane , McCall Laura-Isobel , Wendt Karen L. , Souza Julia M. , Ackermann Jasmin , McKerrow James H. , Cichewicz Robert H. , Siqueira-Neto Jair L.
Published: May 2021

Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi, are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/), and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi. Leucinostatin B also showed in vivo efficacy in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid T. brucei, our findings suggest a potential cross-trypanocidal compound class and provide a platform for further chemical derivatization of a potent chemical scaffold against T. cruzi.
BrainEXP-NPD: a database of transcriptomic profiles of human brains of six neuropsychiatric disorders
Authors: Xia Cuihua , Ma Teng , Jiao Chuan , Chen Chao , Liu Chunyu
Published: May 2021

Background

Spatio-temporal gene expression has been widely used to study gene functions and biological mechanisms in diseases. Numerous microarray and RNA sequencing data focusing on brain transcriptomes in neuropsychiatric disorders have accumulated. However, their consistency, reproducibility has not been properly evaluated. Except for a few psychiatric disorders, like schizophrenia, bipolar disorder and autism, most have not been compared to each other for cross-disorder comparisons.

Methods

We organized 48 human brain transcriptome datasets from six sources. The original brain donors include patients with schizophrenia (SCZ, N=427), bipolar disorder (BD, N=312), major depressive disorder (MDD, N=219), autism spectrum disorder (ASD, N=53), Alzheimer’s disease (AD, N=765), Parkinson’s disease (PD, N=163) as well as controls as unaffected by such disorders (CTRL, N=6,378), making it a total of 8,317 samples. Raw data included multiple brain regions of both sexes, with ages ranging from embryonic to seniors. After standardization, quality control, filtering and removal of known and unknown covariates, we performed comprehensive meta- and mega-analyses, including gene differential expression and gene co-expression network.

Results

A total of 6922, 3011, 2703, 4389, 3507, 4279 significantly differentially expressed genes (FDR q < 0.05) were detected in the comparisons of 6 brain regions of SCZ-CTRL, 5 brain regions of BD-CTRL, 6 brain regions of MDD-CTRL, 4 brain regions of ASD-CTRL, 7 brain regions of AD-CTRL, and 6 brain regions of PD-CTRL, respectively. Most differentially expressed genes were brain region-specific and disease-specific. SCZ and BD have a maximal transcriptome similarity in striatum (ρ=0.42) among the four brain regions, as measured by Spearman’s correlation of differential expression log2 FC values. SCZ and MDD have a maximal transcriptome similarity in hippocampus (ρ=0.30) among the five brain regions. BD and MDD have a maximal transcriptome similarity in frontal cortex (ρ=0.45) among the five brain regions. Other disease pairs have a less transcriptome similarity (ρ<0.1) in all brain regions. PD is negatively correlated with SCZ, BD, and MDD in cerebellum and striatum. We also performed coexpression network analyses for different disorders and controls separately. We developed a database named BrainEXP-NPD (http://brainexpnpd.org:8088/BrainEXPNPD/), to provide a userfriendly web interface for accessing the data, and analytical results of meta- and mega-analyses, including gene differential expression and gene co-expression networks between cases and controls on different brain regions, sexes and age groups. Discussion: BrainEXP-NPD compiled the largest collection of brain transcriptomic data of major neuropsychiatric disorders and presented lists of differentially expressed genes and coexpression modules in multiple brain regions of six major disorders.
Micromorphy Offers Effective Defence Against Predation: Insights From The Cost-Benefit Analyses Of Micro Gastropod Predation Record
Authors: Chandroth Anupama , Chattopadhyay Devapriya
Published: May 2021

Predation, an important driver of natural selection, is studied in the fossil record using quantifiable traces like drill holes produced by gastropods and repair scars produced after durophagous attacks. Despite the abundance of such records in molluscan prey, predation records of micromolluscs (<5mm) remained unexplored. Using a Miocene assemblage of microgastropods from the Quilon Limestone, India, we established the predatory-prey dynamics with the help of cost-benefit analyses. The overall predation intensity is low (DF = 0.06, RF= 0.04) and does not depend on the relative abundance of prey groups suggesting a non-random prey selection regardless of the encounter frequency. The predation is selective in terms of taxonomy, ornamentation, and size of the prey. The smallest size class has the lowest DF and RF supporting a negative size refugia. Higher IDF in larger size class and ornamented groups implies morphological defense resulting in higher failure. Microgastropods show a lower predation intensity than their regular-sized counterparts in a global comparison of coeval records. Results of the cost-benefit analyses explain this difference; the net energy gain from predatory drilling is found to increase monotonically with increasing prey size making the small prey less beneficial. Because the predators try to maximize net energy gain from a predatory attack, the microgastropod prey characterized by relatively low net energy yield is not preferred in the presence of larger prey. Micromorphy, therefore, appears a viable strategy for the prey group to be adopted as an evolutionary response against predation, especially in resource-limited conditions that fail to support large body size.