bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyzing the Global Impact of COVID-19 Vaccination Progress: A Result-oriented Storytelling Approach
Authors: Dey Samrat Kumar , Rahman Md. Mahbubur , Siddiqi Umme Raihan , Howlader Arpita , Tushar Arifuzzaman
Published: March 2021

The next big step in combating the coronavirus disease 2019 (COVID-19) pandemic will be gaining widespread acceptance of a vaccination campaign for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but achieving high uptake need proper understandings. Many health professionals, researchers, statisticians, and programmers to track the viruses spread in different parts of the world have used various methods. However, the proliferation of vaccines produced by talented scientists around the world has sparked a strong desire to extract meaningful insights from available data. Until now, several vaccines against coronavirus disease (COVID-19) have been approved and are being distributed worldwide in various regions. This study aims to report the detailed data analysis and result-oriented storytelling of the COVID-19 vaccination program of different countries across the globe. To analyze the vaccination trend globally this research utilized two different open datasets provided by ourworldindata.org and worldometers.info. An exploratory data analysis (EDA) with interactive data visualization using various python libraries was conducted, and the results are presented in this article to better understand the impact of ongoing vaccination programs around the world. Apart from the valuable insights gained from the data of various countries, this investigation also included a comparison of the number of confirmed and death cases before and after vaccination to determine the efficacy of each vaccine in each country. The results show that a large number of people are still undecided about whether or not to get a COVID-19 vaccine, despite the virus’s continued devastating effects on communities. Overall, our findings contribute to ongoing research aimed at informing policy on how to persuade the unvaccinated to be vaccinated.
Fast and accurate annotation of acoustic signals with deep neural networks
Authors: Steinfath Elsa , Palacios Adrian , Rottschäfer Julian R , Yuezak Deniz , Clemens Jan
Published: March 2021

Acoustic signals serve communication within and across species throughout the animal kingdom. Studying the genetics, evolution, and neurobiology of acoustic communication requires annotating acoustic signals: segmenting and identifying individual acoustic elements like syllables or sound pulses. To be useful, annotations need to be accurate, robust to noise, and fast.

We here introduceDAS, a method that annotates acoustic signals across species based on a deep-learning derived hierarchical presentation of sound. We demonstrate the accuracy, robustness, and speed ofDASusing acoustic signals with diverse characteristics from insects, birds, and mammals.DAScomes with a graphical user interface for annotating song, training the network, and for generating and proofreading annotations. The method can be trained to annotate signals from new species with little manual annotation and can be combined with unsupervised methods to discover novel signal types.DASannotates song with high throughput and low latency, allowing realtime annotations for closed-loop experimental interventions. Overall,DASis a universal, versatile, and accessible tool for annotating acoustic communication signals.
High Gamma and Beta Temporal Interference Stimulation in the Human Motor Cortex Improves Motor Functions
Authors: Ma Ru , Xia Xinzhao , Zhang Wei , Lu Zhuo , Wu Qianying , Cui Jiangtian , Song Hongwen , Fan Chuan , Chen Xueli , Wei Junjie , Ji Gongjun , Wang Kai , Wang Xiaoxiao , Qiu Bensheng , Zhang Xiaochu
Published: March 2021

Background

Temporal interference (TI) stimulation is a new technique of noninvasive brain stimulation. Envelope-modulated waveforms with two high-frequency carriers can activate neurons in target brain regions without stimulating the overlying cortex, which has been validated in mouse brains. However, whether TI stimulation can work on the human brain has not been elucidate.

Objective

To assess the effectiveness and safety aspect of the envelope-modulated waveform of TI stimulation on human primary motor cortex (M1).

Methods

Participants attended three sessions of 30-min TI stimulation at 2 mA during a random reaction time task (RRTT) or a serial reaction time task (SRTT). Motor cortex excitability was measured before and after TI stimulation.

Results

In the RRTT experiment, only 70 Hz TI stimulation had a promoting effect on the reaction time (RT) performance and excitability of the motor cortex compared to sham stimulation. Meanwhile, compared with the sham condition, only 20 Hz TI stimulation significantly facilitated motor learning in the SRTT experiment, which was significantly positively correlated with the increase in motor evoked potential.

Conclusion

These results indicate that the envelope-modulated waveform of TI stimulation has a significant promoting effect on human motor functions, experimentally suggesting the effectiveness of TI stimulation in humans for the first time and pave the way for further explorations.
Association of stress-related neural activity and baseline interleukin-6 plasma levels in healthy adults
Authors: Voges Johanna F. , Müller-Pinzler Laura , Neis Miriam , Luebber Finn , Lange Tanja , Hundt Jennifer E. , Kasten Meike , Krämer Ulrike M. , Krach Sören , Rademacher Lena
Published: March 2021

Several studies suggest a link between acute changes in inflammatory parameters due to an endotoxin or (psychological) stressor and the brain’s stress response. The extent to which basal circulating levels of inflammatory markers are associated with the brain’s stress response has been hardly investigated so far. In the present study, baseline plasma levels of the cytokine interleukin (IL)-6 were obtained and linked to neural markers of psychosocial stress using a modified version of the Montreal Imaging Stress Task in a sample of N=65 healthy subjects (N=39 female). Of three a-priori defined regions of interest – the amygdala, anterior insula, and anterior cingulate cortex – baseline IL-6 was significantly and negatively associated with stress-related neural activation in the right amygdala and left anterior insula. Our results suggest that baseline cytokines might be related to differences in the neural stress response and that this relationship could be inverse to that previously reported for induced acute changes in inflammation markers.
Gene Expression Variation in Arabidopsis Embryos at Single-Nucleus Resolution
Authors: Kao Ping , Schon Michael A. , Mosiolek Magdalena , Nodine Michael D.
Published: March 2021

Soon after fertilization of egg and sperm, plant genomes become transcriptionally activated and drive a series of coordinated cell divisions to form the basic body plan during embryogenesis. Early embryonic cells rapidly diversify from each other, and investigation of the corresponding gene expression dynamics can help elucidate underlying cellular differentiation programs. However, current plant embryonic transcriptome datasets either lack cell-specific information or have RNA contamination from surrounding non-embryonic tissues. We have coupled fluorescence-activated nuclei sorting together with single-nucleus mRNA sequencing to construct a gene expression atlas ofArabidopsis thalianaearly embryos at single-cell resolution. In addition to characterizing cell-specific transcriptomes, we found evidence that distinct epigenetic and transcriptional regulatory mechanisms operate across emerging embryonic cell types. These datasets and analyses, as well as the approach we devised, are expected to facilitate the discovery of molecular mechanisms underlying pattern formation in plant embryos.

Summary statement

A transcriptome atlas of Arabidopsis embryos constructed from single nuclei reveals cell-specific epigenetic and transcriptional regulatory features.
Dynamic bi-directional phosphorylation events associated with the reciprocal regulation of synapses during homeostatic up- and down-scaling
Authors: Desch Kristina , Langer Julian D. , Schuman Erin M.
Published: March 2021

Homeostatic synaptic scaling allows for bi-directional adjustment of the strength of synaptic connections in response to changes in their input. Protein phosphorylation modulates many neuronal and synaptic processes, but it has not been studied on a global, proteome-wide scale during synaptic scaling. To examine this, we used LC-MS/MS analyses to measure changes in the phosphoproteome in response to up- or down-scaling in cultured cortical neurons over minutes to 24 hours. Out of 45,000 phosphorylation events measured, ~3,300 (associated with 1,280 phospho-proteins) were regulated by homeostatic scaling. The activity-sensitive phosphoproteins were predominantly located at synapses and involved in cytoskeletal reorganization. We identified many early transient phosphorylation events which could serve as sensors for the activity offset as well as late and/or persistent phosphoregulation that could represent effector mechanisms driving the homeostatic response. Much of the persistent phosphorylation was reciprocally regulated by up- or down-scaling, suggesting that the mechanisms underlying these two poles of synaptic regulation make use of a common signaling axis.
Bias correction for inverse variance weighting Mendelian randomization
Authors: Mounier Ninon , Kutalik Zoltán
Published: March 2021

Inverse-variance weighted two-sample Mendelian randomization (IVW-MR) is the most widely used approach that utilizes genome-wide association studies (GWAS) summary statistics to infer the existence and the strength of the causal effect between an exposure and an outcome. Estimates from this approach can be subject to different biases due to the use of weak instruments and winner’s curse, which can change as a function of the overlap between the exposure and outcome samples.

We developed a method (MRlap) that simultaneously considers weak instrument bias and winner’s curse, while accounting for potential sample overlap. Assuming spike-and-slab genomic architecture and leveraging LD-score regression and other techniques, we could analytically derive, reliably estimate, and hence correct for the bias of IVW-MR using association summary statistics only.

We tested our approach using simulated data for a wide range of realistic settings. In all the explored scenarios, our correction reduced the bias, in some situations by as much as 30 folds. Additionally, our results are consistent with the fact that the strength of the biases will decrease as the sample size increases and we also showed that the overall bias is also dependent on the genetic architecture of the exposure, and traits with low heritability and/or high polygenicity are more strongly affected. ApplyingMRlapto obesity-related exposures revealed significant differences between IVW-based and corrected effects, both for non-overlapping and fully overlapping samples.

Our method not only reduces bias in causal effect estimation but also enables the use of much larger GWAS sample sizes, by allowing for potentially overlapping samples.
MLG: Multilayer graph clustering for multi-condition scRNA-seq data
Authors: Lu Shan , Conn Daniel J. , Chen Shuyang , Johnson Kirby D. , Bresnick Emery H. , Keleş Sündüz
Published: March 2021

Single-cell transcriptome sequencing (scRNA-seq) enabled investigations of cellular heterogeneity at exceedingly higher resolutions. Identification of novel cell types or transient developmental stages across multiple experimental conditions is one of its key applications. Linear and non-linear dimensionality reduction for data integration became a foundational tool in inference from scRNA-seq data. We presentMultiLayerGraph Clustering (MLG) as an integrative approach for combining multiple dimensionality reduction of multi-condition scRNA-seq data. MLG generates a multilayer shared nearest neighbor cell graph with higher signal-to-noise ratio and outperforms current best practices in terms of clustering accuracy across large-scale bench-marking experiments. Application of MLG to a wide variety of datasets from multiple conditions highlights how MLG boosts signal-to-noise ratio for fine-grained sub-population identification. MLG is widely applicable to settings with single cell data integration via dimension reduction.
Flow cytometry-based determination of ploidy from dried leaf specimens in genomically complex collections of the tropical forage grass Urochloa s. l
Authors: Tomaszewska Paulina , Pellny Till K. , Hernández Luis Miguel , Mitchell Rowan A. C. , Castiblanco Valheria , de Vega José J. , Schwarzacher Trude , Heslop-Harrison Pat (J.S.)
Published: March 2021

We aimed to develop an optimized approach to determine ploidy for dried leaf material in a germplasm collection of a tropical forage grass group, including approaches to collect, dry and preserve plant samples for flow cytometry analysis. Urochloa (including Brachiaria, Megathyrus and some Panicum) tropical grasses are native to Africa and are now, after selection and breeding, planted worldwide, particularly in South America, as important forages with huge potential for further sustainable improvement and conservation of grasslands. The methods enable robust identification of ploidy levels (coefficient of variation, CV, typically <5%). Ploidy of some 353 forage grass accessions (ploidy range from 2 to 9), from international genetic resource collections, showing variation in basic chromosome numbers and reproduction modes (apomixis and sexual), were determined using our defined standard protocol. Two major Urochloa agamic complexes used in the current breeding programs at CIAT and EMBRAPA: the ‘brizantha’ and ‘humidicola’ agamic complexes are variable, with multiple ploidy levels and DNA content. U. brizantha has odd level of ploidy (x=5), and the relative differences in nuclear DNA content between adjacent cytotypes is reduced, thus more precise examination of this species is required. Ploidy measurement of U. humidicola revealed some aneuploidy.
Silk-based antimicrobial peptide mixed with recombinant spidroin creates functionalized spider silk
Authors: Liu Frank Y.C.
Published: March 2021

1.

Surgical site infection (SSI) from sutures is a global health emergency because of the antibiotic crisis. Methicillin-resistant S. aureus and other emerging strains are difficult to treat with antibiotics, so drug-free sutures with antimicrobial properties are a solution. Functionalized spider silk protein (spidroin) is a candidate for its extraordinary strength because it has a large repetitive region (150Rep) that forms crosslinked beta-sheets. The antimicrobial peptide HNP-1 can be connected to recombinant spidroin to create antimicrobial silk. Ni-NTA purified 2Rep-HNP1 fusion protein was mixed with recombinant NT2RepCT spidroin at 1:25, 1:20, 1:10 ratios, and spun into silk fibers by syringe-pumping protein into a 100% isopropanol bath. Beta-sheet crosslinking of the identical 2Rep regions tagged the 2Rep-HNP1 permanently onto the resultant silk. Silk showed no sign of degradation in an autoclave, PBS, or EtOH. The tagged 2Rep-HNP1 retained broad-spectrum antimicrobial activity >90% against S. aureus and E. coli as measured by log reduction and radial diffusion assay. Furthermore, a modified expression protocol increased protein yield of NT2RepCT 2.8-fold, and variable testing of the spinning process demonstrated the industrial viability of silk production. We present a promising suture alternative in antimicrobial recombinant spider silk.
Neonatal 6-OHDA lesion of the SNc induces striatal compensatory sprouting from surviving SNc dopaminergic neurons without VTA contribution
Authors: Tanguay William , Ducrot Charles , Giguère Nicolas , Bourque Marie-Josée , Trudeau Louis-Eric
Published: March 2021

Dopamine (DA) neurons of thesubstantia nigra pars compacta(SNc) are uniquely vulnerable to neurodegeneration in Parkinson’s disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10- and 90-days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared to the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability.

Graphical abstract text

We describe a technique to induce the loss of approximately 50% of SNc DA neurons in neonate mice using unilateral intranigral 6-OHDA (left panel).

Compensatory axonal sprouting was observed in the striatum as early as 10 days following the lesion (at P15), with effects lasting until adulthood (P90).

Conditional AAV-mediated expression of eYFP (green) reveals SNc DA neurons, projecting to the dorsal striatum (middle panel), and not VTA DA neurons, projecting to the ventral striatum (right panel), as the main source of compensatory axonal sprouting.

Graphical abstract
On the predictability of postoperative complications for cancer patients: a Portuguese cohort study
Authors: Gonçalves Daniel , Henriques Rui , Lara Santos Lúcio , Costa Rafael S
Published: March 2021

Postoperative complications following cancer surgeries are still hard to predict despite the historical efforts towards the creation of standard clinical risk scores. The differences among score calculators, contribute for the creation of highly specialized tools, with poor reusability in foreign contexts, resulting in larger prediction errors in clinical practice.

This work aims to predict postoperative complications risk for cancer patients, offering two major contributions. First, to develop and evaluate a machine learning-based risk score, specific for the Portuguese population using a retrospective cohort of 847 cancer patients undergoing surgery between 2016 and 2018, predicting 4 outcomes of interest: i) existence of postoperative complications, ii) severity level of complications, iii) number of days in the Intermediate Care Unit (ICU), and iv) postoperative mortality within 1 year. An additional cohort of 137 cancer patients was used to validate the models. Second, to support the study with relevant findings and improve the interpretability of predictive models.

In order to achieve these objectives, a robust methodology for the learning of risk predictors is proposed, offering new perspectives and insights into the clinical decision process. For postoperative complications the mean Receiver Operating Characteristic Curve (AUC) was 0.69, for complications’ severity mean AUC was 0.65, for the days in the ICU the Mean Absolute Error (MAE) was 1.07 days, and for one-year postoperative mortality the mean AUC was 0.74, calculated on the development cohort.

In this study, risk predictive models which may help guide physicians at estimating cancer patient’s risk of developing surgical complications were developed. Additionally, a web-based decision support system is further provided to this end.
Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by Supervised Molecular Dynamics simulation
Authors: Sohraby Farzin , Aryapour Hassan
Published: March 2021

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and discover the reasons for the lack of inhibitory activity against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98′ and Phe67/Phe67′ in the HTLV-1 protease could make strong π-Stacking interactions with Indinavir, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and more selective inhibitors for the HTLV-1 protease.
Generation and first characterization of TRDC-Knockout pigs lacking γδ T cells
Authors: Petersen Bjoern , Kammerer Robert , Frenzel Antje , Hassel Petra , Dau Tung Huy , Becker Roswitha , Breithaupt Angele , Ulrich Reiner Georg , Lucas-Hahn Andrea , Meyers Gregor
Published: March 2021

The TRDC-Locus encodes the T cell receptor delta constant region, one component of the γδ T cell receptor which is essential for development of γδ T cells. In contrast to peptide recognition by αβ T cells, antigens activating γδ T cells are mostly MHC independent and not well characterized. Therefore, the function of γδ T cells and their contribution to protection against infections is still unclear. Higher numbers of circulating γδ T cells compared to mice, render the pig a suitable animal model to study γδ T cells. Knocking-out the porcine TRDC-locus by intracytoplasmic microinjection and somatic cell nuclear transfer resulted in healthy living γδ T cell deficient offspring. Flow cytometric analysis revealed that TRDC-KO pigs lack γδ T cells in peripheral blood mononuclear cells (PBMC) and spleen cells. The composition of the remaining leucocyte subpopulations was not affected by the depletion of γδ T cells. Genome-wide transcriptome analyses in PBMC revealed a pattern of changes reflecting the impairment of known or expected γδ T cell dependent pathways. Histopathology did not reveal developmental abnormalities of secondary lymphoid tissues. However, in a vaccination experiment the KO pigs stayed healthy but had a significantly lower neutralizing antibody titer as the syngenic controls.
Desiccation stress acts as cause as well as cost of dispersal inDrosophila melanogaster
Authors: Mishra Abhishek , Tung Sudipta , Sruti V.R. Shree , Shreenidhi P.M. , Dey Sutirth
Published: March 2021

Environmental stress is one of the important causes of biological dispersal. At the same time, the process of dispersal itself can incur and/or increase susceptibility to stress for the dispersing individuals. Therefore, in principle, stress can serve as both a cause and a cost of dispersal.

Desiccation stress is an environmentally relevant stress faced by many organisms, known to shape their population dynamics and distribution. However, the potentially contrasting roles of desiccation stress as a cause and a cost of dispersal have not been investigated. Furthermore, while desiccation stress often affects organisms in a sex-biased manner, it is not known whether the desiccation-dispersal relationship varies between males and females.

We studied the role of desiccation stress as a cause and cost of dispersal in a series of experiments usingD. melanogasteradults in two-patch dispersal setups. We were interested in knowing whether (a) dispersers are the individuals that are more susceptible to desiccation stress, (b) dispersers pay a cost in terms of reduced resistance to desiccation stress, (c) dispersal evolution alters the desiccation cost of dispersal, and (d) females pay a reproductive cost of dispersal. For this, we modulated the degree of desiccation stress faced by the flies as well as the provision of rest following a dispersal event.

Our data showed that desiccation stress served as a significant cause of dispersal in both sexes. Further investigation revealed an increase in both male and female dispersal propensity with increasing desiccation duration. Next, we found a male-biased cost of dispersal in terms of reduced desiccation resistance. This trend was preserved in dispersal-selected and non-selected controls as well, where the desiccation cost of dispersal in females was very low compared to the males. Finally, we found that the females instead paid a significant reproductive cost of dispersal.

Our results highlight the complex relationship between desiccation stress and dispersal, whereby desiccation resistance can show both a positive and a negative association with dispersal. Furthermore, the sex differences observed in these trait associations may translate into differences in movement patterns, thereby giving rise to sex-biased dispersal.
Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2
Authors: Fatouros Peter R. , Roy Urmi , Sur Shantanu
Published: March 2021

The spike protein in the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the receptor Angiotensin Converting Enzyme 2 (ACE2) on the host cell to facilitate the viral uptake. Angiotensin II (Ang II) peptide, which has a naturally high affinity for ACE2, may be useful in inhibiting this interaction. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the ACE2 receptor. The peptide in the ACE2-peptide complex was coordinated to zinc in the ACE2 cleft. Exploratory molecular dynamics (MD) simulations were used to measure the time-based stability of the native and mutant peptides and their receptor complexes. The MD-generated root-mean-square deviation (RMSD) values are mostly similar between the native and seven mutant peptides considered in this work, although the values for free peptides demonstrated higher variation, and often were higher in amplitude than peptides associated with the ACE2 complex. An observed lack of a strong secondary structure in the short peptides is attributed to the latter’s greater flexibility and movement. The strongest binding energies within the ACE2-peptide complexes were observed in the native Ang II and only one of its mutant variants, suggesting ACE2 cleft is designed to provide optimal binding to the native sequence. An examination of the S1 binding site on ACE2 suggests that complex formation alone with these peptides may not be sufficient to allosterically inhibit the binding of SARS-CoV-2 spike proteins. However, it opens up the potential for utilizing AngII-ACE2 binding in the future design of molecular and supramolecular structures to prevent spike protein interaction with the receptor through creation of steric hindrance.
The link between static and dynamic brain functional network connectivity and genetic risk of Alzheimer’s disease
Authors: Sendi Mohammad S. E. , Zendehrouh Elaheh , Ellis Charles A. , Chen Jiayu , Miller Robyn L. , Mormino Elizabeth , Salat David H. , Calhoun Vince D.
Published: March 2021

Apolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimer’s disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a reproducible, data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N=894) between 42 to 95 years of age (mean = 70 years). We divided individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the amount of time each subject spent in each state, called occupancy rate or OCR. We compared both sFNC and OCR, estimated from dFNC, across individuals with different genetic risk and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. Additionally, we found that AD genetic risk affects whole-brain sFNC and dFNC in women but not in men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.
Effects of sequence motifs in the yeast 3′ untranslated region determined from massively-parallel assays of random sequences
Authors: Savinov Andrew , Brandsen Benjamin M. , Angell Brooke E. , Cuperus Josh T. , Fields Stanley
Published: March 2021

The 3′ untranslated region (UTR) plays critical roles in determining the level of gene expression, through effects on activities such as mRNA stability and translation. The underlying functional elements within this region have largely been identified through analyses of the limited number of native genes. To explore the effects of sequence elements when not present in biologically evolved sequence backgrounds, we analyzed hundreds of thousands of random 50-mers inserted into the 3′ UTR of a reporter gene in the yeastSaccharomyces cerevisiae. We determined relative protein expression levels from the fitness of a library of transformants in a growth selection. We find that the consensus 3′ UTR efficiency element significantly boosts expression, independent of sequence context; on the other hand, the consensus positioning element has only a small effect on expression. Some sequence motifs that are binding sites for Puf proteins substantially increase expression in this random library, despite these proteins generally being associated with post-transcriptional downregulation when bound to native mRNAs. Thus, the regulatory effects of 3′ UTR sequence features like the positioning element and Puf binding sites appear to be strongly dependent on their context within native genes, where they exist alongside co-evolved sequence features. Our measurements also allowed a systematic examination of the effects of point mutations within efficiency element motifs across diverse sequence backgrounds. These mutational scans reveal the relativein vivoimportance of individual bases in the efficiency element, which likely reflects their roles in binding the Hrp1 protein involved in cleavage and polyadenylation.
High-dimensional profiling demonstrates complexity, tissue imprinting, and lineage-specific precursors within the mononuclear phagocyte compartment of the human intestine
Authors: Fenton Thomas M. , Wulff Line , Jones Gareth-Rhys , Vandamme Julien , Jørgensen Peter B. , Bain Calum C. , Lee Julie , Izarzugaza Jose MG. , Belling Kirstine G. , Ho Gwo-Tzer , Nielsen Ole H. , Riis Lene B. , Pers Tune H. , Jakobsen Henrik L. , Mowat Allan M. , Brunak Søren , Agace William W.
Published: March 2021

Mononuclear phagocytes (MNP), including macrophages and classical dendritic cells (cDC), are highly heterogeneous cells with distinct functions. Understanding MNP complexity in the intestinal lamina propria (LP), particularly in humans, has proved difficult due to the expression of overlapping phenotypic markers and the inability to isolate these cells without contamination from gut-associated lymphoid tissues (GALT). Here, we exploited our novel method for isolation of human GALT-free LP to carry out single-cell (sc)RNA-seq, CITE-seq and flow cytometry analysis of human ileal and colonic LP MNPs. As well as classical monocytes, non-classical monocytes, mature macrophage subsets, cDC1s, and cDC2s, we identified a CD1c+cDC subset with features of both cDC2 and monocytes, which were transcriptionally similar to the recently described cDC3. While similar MNP subsets were present in both ileal and colonic LP, the proportions and transcriptional profiles of these populations differed between these sites and in diseased states, indicating local specialization and environmental imprinting. Using computational trajectory tools, we identified putative early committed pre-cDC subsets and developmental intermediates of mature cDC1, cDC2 and cDC3, as well as monocyte–to-macrophage trajectories. Collectively, our results provide novel insights into the heterogeneity and development of intestinal LP MNP and an important framework for studying the role of these populations in intestinal homeostasis and disease.

One sentence summary

Fenton and Wulffet al. use single-cell methods to explore the complexity of the mononuclear phagocyte compartment of the human intestinal lamina propria, identifying distinct dendritic cell and macrophage subsets, site-specific transcriptional signatures, and lineage-specific precursors.
Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived neurons and astrocytes
Authors: Kesavan Jaideep , Watters Orla , Dinkel Klaus , Hamacher Michael , Prehn Jochen H.M. , Henshall David C. , Engel Tobias
Published: March 2021

The P2X7 receptor (P2X7R) is a cation membrane channel activated by extracellular adenosine 5′-triphosphate. Activation of this receptor results in numerous downstream events including the modulation of neurotransmission, release of pro-inflammatory mediators, cell proliferation or cell death. While the expression of P2X7Rs is well documented on microglia and oligodendrocytes, the presence of functional P2X7Rs on neurons and astrocytes remains debated. Furthermore, to date, functional studies on the P2X7R are mostly limited to studies in cells from rodents and immortalised cell lines expressing human P2X7Rs. To assess the functional expression of P2X7Rs in human neurons and astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into forebrain cortical neurons that co-express FOXG1 and βIII-tubulin as well as S100 β-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining on the soma and processes of hiPSC-derived neurons and astrocytes. In addition, our data show that stimulation with the potent nonselective P2X7R agonist BzATP induces robust calcium rises in hiPSC-derived neurons and astrocytes, which were blocked by the selective P2X7R antagonist AFC-5128. Together, our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived forebrain cortical neurons and astrocytes demonstrating that these cells offer the potential for investigating P2X7R-mediated pathophysiology and drug screening in vitro.
The Effect of Attention Load on Balance Control Performance
Authors: Mirloo Sheida , Parpanchi Behzad , Baghdadi Golnaz
Published: March 2021

Posture balance control is an essential ability that is affected by the attention load. We investigated the effect of attention load on posture balance control experimentally and computationally. Fifteen young individuals participated in an experiment containing simultaneous performing of a balance control task and an auditory task. A previous computational model was extended by introducing the effect of attention load as a gain in a Proportional-Integral-Derivative (PID) controller. Results demonstrated that the sensitivity of the posture balance control to the attention load should be considered besides other influential factors in designing sport or physical rehabilitation exercises. Simulations suggested that the issues of joint impedance stiffness or viscosity might also be compensated by changing the attention load.
Combining evolutionary and assay-labelled data for protein fitness prediction
Authors: Hsu Chloe , Nisonoff Hunter , Fannjiang Clara , Listgarten Jennifer
Published: March 2021

Predictive modelling of protein properties has become increasingly important to the field of machine-learning guided protein engineering. In one of the two existing approaches, evolutionarily-related sequences to a query protein drive the modelling process, without any property measurements from the laboratory. In the other, a set of protein variants of interest are assayed, and then a supervised regression model is estimated with the assay-labelled data. Although a handful of recent methods have shown promise in combining the evolutionary and supervised approaches, this hybrid problem has not been examined in depth, leaving it unclear how practitioners should proceed, and how method developers should build on existing work. Herein, we present a systematic assessment of methods for protein fitness prediction when evolutionary and assay-labelled data are available. We find that a simple baseline approach we introduce is competitive with and often outperforms more sophisticated methods. Moreover, our simple baseline is plug-and-play with a wide variety of established methods, and does not add any substantial computational burden. Our analysis highlights the importance of systematic evaluations and sufficient baselines.
Strain diversity of plant-associated Lactiplantibacillus plantarum
Authors: Yu Annabelle O. , Goldman Elissa A. , Brooks Jason T. , Golomb Benjamin L. , Yim Irene S. , Gotcheva Velitchka , Angelov Angel , Kim Eun Bae , Marco Maria L.
Published: March 2021

The intraspecific phenotypic and genetic diversity of Lactiplantibacillus plantarum (formerly Lactobacillus plantarum) was examined for five strains isolated from fermented olives and eight strains from cactus fruit, fermented tomatoes, teff injera, wheat boza, and wheat sourdough starter sources. Carbohydrate utilization and stress tolerance characteristics showed that the olive isolates grew more robustly in galactose and raffinose, showed higher tolerance to 12% v/v EtOH, and exhibited a greater capacity to inhibit an olive spoilage strain of Saccharomyces cerevisiae than L. plantarum from the other plant sources. Certain traits were variable between fermented olive isolates such as the capacity for biofilm formation and survival at pH 2 or 50 °C. By comparison, all L. plantarum from fruit sources grew better at a pH of 3.5 than the strains from fermented grains. Multi-locus sequence typing and genome sequencing indicated that strains from the same source type tended to be genetically related. Comparative genomics was unable to resolve strain differences, with the exception of the most phenotypically impaired and robust isolates. The findings show that L. plantarum is adapted for growth on specific plants or plant food types, but that intraspecific variation may be important for ecological fitness of L. plantarum within individual habitats.
Whole genome duplications and the diversification of the Globin-X genes of vertebrates
Authors: Hoffmann Federico G. , Storz Jay F. , Kuraku Shigehiro , Vandewege Mike W. , Opazo Juan C.
Published: March 2021

The globin superfamily of vertebrate genes is a textbook example of how the interplay between local gene duplications, whole-genome duplications, and regulatory changes can facilitate the evolution of novel protein functions. Almost every vertebrate examined possesses copies of hemoglobin and myoglobin in their genomes, and both cytoglobin and neuroglobin are present in the vast majority of vertebrate genomes surveyed as well. The phylogenetic distribution of globin-E, globin-Y and globin-X (GbX), however, is more spotty, suggesting multiple independent gene losses. Globin-X is an enigmatic globin with a wide phyletic distribution that spans protostomes and deuterostomes. Unlike canonical globins such as hemoglobins and myoglobins, functional data suggest that GbX does not have a primary respiratory function. Instead, available evidence suggests that GbX may play a role in protecting cells from oxidative damage and in reducing nitrite and it is predicted to be bound to the cell membrane. Recently released genomes from key vertebrate taxa provide an excellent opportunity to address questions about the early stages of evolution of these genes in vertebrates. In the current study, we integrate bioinformatic, synteny and phylogenetic analyses to characterize the diversity of GbX genes in non-teleost ray-finned fishes, resolve relationships between the GbX genes of cartilaginous fish and the GbX genes of bony vertebrates, and demonstrate that the GbX genes of cyclostomes and gnathostomes have independent duplicative histories. Our study highlights the role that whole genome duplications (WGDs) have played in expanding the repertoire of genes in vertebrate genomes. Our results indicate that GbX paralogs have a remarkably high rate of retention following WGDs in comparison to other globin genes, and also provide an evolutionary framework for interpreting results of experiments that examine functional properties of GbX and patterns of tissue-specific expression. By identifying GbX genes products of different WGDs in the vertebrate tree of life, our results can guide the design of experimental work to explore whether gene duplicates that originate via WGDs have evolved novel functional properties or expression profiles relative to singleton or tandemly duplicated copies of GbX.
Unravelling the shared genetic mechanisms underlying 18 autoimmune diseases using a systems approach
Authors: Gokuladhas Sreemol , Schierding William , Golovina Evgeniia , Fadason Tayaza , O’Sullivan Justin
Published: March 2021

Autoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. While these studies have identified a handful of pleiotropic loci that confer risk to multiple AiDs, they lack the power to detect shared genetic factors residing outside of these loci. Here, we integrated chromatin contact, expression quantitative trait loci and protein-protein interaction (PPI) data to identify genes that are regulated by both pleiotropic and non-pleiotropic SNPs. The PPI analysis revealed complex interactions between the shared and disease-specific genes. Furthermore, pathway enrichment analysis demonstrated that the shared genes co-occur with disease-specific genes within the same biological pathways. In conclusion, our results are consistent with the hypothesis that genetic risk loci associated with multiple AiDs converge on a core set of biological processes that potentially contribute to the emergence of polyautoimmunity.
Pulse labeling reveals the tail end of protein folding by proteome profiling
Authors: Zhu Mang , Kuechler Erich R. , Stoynov Nikolay , Gsponer Joerg , Mayor Thibault
Published: March 2021

Accurate and efficient folding of nascent protein sequences into their native state requires support from the protein homeostasis network. Herein we probed which newly translated proteins are less thermostable to infer which polypeptides require more time to fold within the proteome. Specifically, we determined which of these proteins were more susceptible to misfolding and aggregation under heat stress using pulse SILAC coupled mass spectrometry. These proteins are abundant, short, and highly structured. Notably these proteins display a tendency to form β-sheet structures, a configuration which typically requires more time for folding, and were enriched for Hsp70/Ssb and TRiC/CCT binding motifs, suggesting a higher demand for chaperone-assisted folding. These polypeptides were also more often components of stable protein complexes in comparison to other proteins. All evidence combined suggests that a specific subset of newly translated proteins requires more time following synthesis to reach a thermostable native state in the cell.
OpenCell: proteome-scale endogenous tagging enables the cartography of human cellular organization
Authors: Cho Nathan H. , Cheveralls Keith C. , Brunner Andreas-David , Kim Kibeom , Michaelis André C. , Raghavan Preethi , Kobayashi Hirofumi , Savy Laura , Li Jason Y. , Canaj Hera , Kim James Y.S. , Stewart Edna M. , Gnann Christian , McCarthy Frank , Cabrera Joana P. , Brunetti Rachel M. , Chhun Bryant B. , Dingle Greg , Hein Marco Y. , Huang Bo , Mehta Shalin B. , Weissman Jonathan S. , Gómez-Sjöberg Rafael , Itzhak Daniel N. , Royer Loic A. , Mann Matthias , Leonetti Manuel D.
Published: March 2021

Elucidating the wiring diagram of the human cell is a central goal of the post-genomic era. We combined genome engineering, confocal live-cell imaging, mass spectrometry and data science to systematically map the localization and interactions of human proteins. Our approach provides a data-driven description of the molecular and spatial networks that organize the proteome. Unsupervised clustering of these networks delineates functional communities that facilitate biological discovery, and uncovers that RNA-binding proteins form a specific sub-group defined by unique interaction and localization properties. Furthermore, we discover that remarkably precise functional information can be derived from protein localization patterns, which often contain enough information to identify molecular interactions. Paired with a fully interactive website opencell.czbiohub.org, we provide a resource for the quantitative cartography of human cellular organization.
The CTEXT complex inSaccharomyces cerevisiaeplays a crucial role in degrading distinct sets of aberrant mRNAs by the nuclear exosome
Authors: Saha Upasana , Gaine Rajlaxmi , Paira Sunirmal , Das Satarupa , Das Biswadip
Published: March 2021

InSaccharomyces cerevisiae, DRN (Decay ofRNA in theNucleus) requiring Cbc1/2p, Tif4631p, and Upf3p promotes the exosomal degradation of aberrantly long 3′-extended-, export-defective transcripts and a small group of normal (special) mRNAs. In this study, using a systematic proteomic analysis we show that each of the known components interacts with one another and they exist as a separate complex, which was dubbed CTEXT (CBC-Tif4631p-dependentEXosomeTargeting). We also identified a DEAD-box RNA helicase Dbp2p as an additional novel component of CTEXT during this analysis which was further bolstered by the finding that genomic deletions of Dbp2p led to the stabilization of all the signature nuclear messages. Interestingly, the RRM domain of Tif4631p located at the extreme N-termini of this polypeptide was found to play a vital role in in mediating the interaction of the CTEXT with the core exosome complex. These inferences were substantiated by the finding that deletion of this domain led to the functional impairment of the CTEXT complex. Thus, the CTEXT constitutes an independent complex that assists the nuclear exosome in degrading the select classes of nuclear transcripts inSaccharomyces cerevisiae.