bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission potential of vaccinated and unvaccinated persons infected with the SARS-CoV-2 Delta variant in a federal prison, July—August 2021
Authors: Salvatore Phillip P. , Lee Christine C. , Sleweon Sadia , McCormick David W. , Nicolae Lavinia , Knipe Kristen , Dixon Thomas , Banta Robert , Ogle Isaac , Young Cristen , Dusseau Charles , Salmonson Shawn , Ogden Charles , Godwin Eric , Ballom TeCora , Ross Tara , Wynn Nhien Tran , David Ebenezer , Bessey Theresa K. , Kim Gimin , Suppiah Suganthi , Tamin Azaibi , Harcourt Jennifer L. , Sheth Mili , Lowe Luis , Browne Hannah , Tate Jacqueline E. , Kirking Hannah L. , Hagan Liesl M.
Published: November 2021

Background

The extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons.

Methods

Consenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis.

Results

A total of 978 specimens were provided by 95 participants, of whom 78 (82%) were fully vaccinated and 17 (18%) were not fully vaccinated. No significant differences were detected in duration of RT-PCR positivity among fully vaccinated participants (median: 13 days) versus those not fully vaccinated (median: 13 days; p=0.50), or in duration of culture positivity (medians: 5 days and 5 days; p=0.29). Among fully vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p=0.048) or Janssen (p=0.003) vaccine recipients.

Conclusions

As this field continues to develop, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks.
Comparison of seven modelling algorithms for GABA-edited 1H-MRS
Authors: Craven Alexander R. , Bhattacharyya Pallab K. , Clarke William T. , Dydak Ulrike , Edden Richard A. E. , Ersland Lars , Mandal Pravat K. , Mikkelsen Mark , Murdoch James B. , Near Jamie , Rideaux Reuben , Shukla Deepika , Wang Min , Wilson Martin , Zöllner Helge , Hugdahl Kenneth , Oeltzschner Georg
Published: November 2021

Edited MRS sequences are widely used for studying GABA in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multi-site study.

GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate.

After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors’ hardware, presenting across algorithms. Scale differences across algorithms were also observed.

Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An inter-class correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases.

Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

Highlights

GABA-edited MRS data from 222 healthy adults across 20 research sites were analyzed

Data were modelled using seven different algorithms, yielding GABA+ and Glx estimates

Moderate agreement was seen across all the tested algorithms

Adding a component to represent co-edited macromolecule signals improved concordance

Baseline modelling emerged as major factor differentiating outcomes
Biogenic action of Lactobacillus plantarum SBT2227 promotes sleep in Drosophila melanogaster
Authors: Ko Taro , Murakami Hiroki , Kamikouchi Azusa , Ishimoto Hiroshi
Published: November 2021

Lactic acid bacteria (LAB) influence multiple aspects of host brain function via the production of active metabolites in the gut, which is known as the pre/pro-biotic action. However, little is known about the biogenic effects of LAB on host brain function. Here, we reported that the Lactobacillus plantarum SBT2227 promoted sleep in Drosophila melanogaster. Administration of SBT2227 primarily increased the amount of sleep and decreased sleep latency at the beginning of night-time. The sleep-promoting effects of SBT2227 were independent of the existing gut flora. Furthermore, heat treatment or mechanical crushing of SBT2227 did not suppress the sleep-promoting effects, indicative of biogenic action. Transcriptome analysis, and RNAi mini-screening for gut-derived peptide hormones revealed the requirement of neuropeptide F, a homologue of the mammalian neuropeptide Y, for the action of SBT2227. These biogenic effects of SBT2227 on the host sleep provide new insights into the interaction between the brain and gut bacteria.
Sensitive identification of known and unknown protease activities by unsupervised linear motif deconvolution
Authors: Uzozie Anuli C. , Smith Theodore G. , Chen Siyuan , Lange Philipp F.
Published: November 2021

The cleavage-site specificities for many proteases are not well-understood, restricting the utility of supervised classification methods. We present an algorithm and web interface to overcome this limitation through the unsupervised detection of overrepresented patterns in protein sequence data, providing insight into the mixture of protease activities contributing to a complex system.

Here, we apply the RObust LInear Motif Deconvolution (RoLiM) algorithm to confidently detect substrate cleavage patterns for SARS-CoV-2 Mpro protease in N terminome data of an infected human cell line. Using mass spectrometry-based peptide data from a case-control comparison of 341 primary urothelial bladder cancer cases and 110 controls, we identified distinct sequence motifs indicative of increased MMP activity in urine from cancer patients. Evaluation of N terminal peptides from patient plasma post-chemotherapy detected novel Granzyme B/Corin activity.

RoLiM will enhance unbiased investigation of peptide sequences to establish the composition of known and uncharacterized protease activities in biological systems.
Erasure of Biologically Meaningful Signal by Unsupervised scRNAseq Batch-correction Methods
Authors: Tyler Scott R , Guccione Ernesto , Schadt Eric E
Published: November 2021

Single cell RNAseq (scRNAseq) batches range from technical-replicates to multi-tissue atlases, thus requiring robust batch-correction methods that operate effectively across this spectrum of between-batch similarity. Commonly employed benchmarks quantifyremovalof batch effects and preservation ofwithin-batchvariation, the preservation of biologically meaningful differencesbetweenbatches has been under-researched. Here, we address these gaps, quantifying batch effects at the level of cluster composition and along overlapping topologies through the introduction of two new measures. We discovered that standard approaches of scRNAseq batch-correction erase cell-type and cell-state variation in real-world biological datasets, single cell gene expression atlases, andin silicoexperiments. We highlight through examples showing that these issues may create the artefactual appearance of external validation/replication of findings. Our results demonstrate that either biological effects, if known, must be balanced between batches (like bulk-techniques), or technical effects that vary between batches must be explicitly modeled to prevent erasure of biological variation by unsupervised batch correction approaches.
Studies of parenchymal texture added to mammographic breast density and risk of breast cancer: a systematic review of the methods used in the literature
Authors: Anandarajah Akila , Chen Yongzhen , Colditz Graham A. , Hardi Angela , Stoll Carolyn , Jiang Shu
Published: November 2021

This systematic review aimed to assess the methods used to classify mammographic breast parenchymal features in relation to prediction of future breast cancer including the time from mammogram to diagnosis of breast cancer, and methods for the identification of texture features and selection of features for inclusion in analysis. The databases including Medline (Ovid) 1946-,Embase.com1947-, CINAHL Plus 1937-, Scopus 1823-, Cochrane Library (including CENTRAL), andClinicaltrials.gov. were searched through October 2021 to extract published articles in English describing the relationship of parenchymal texture features with risk of breast cancer. Twenty-eight articles published since 2016 were included in the final review. Of these, 7 assessed texture features from film mammograms images, 3 did not report details of the image used, and the others used full field mammograms from Hologic, GE and other manufacturers. The identification of parenchymal texture features varied from using a predefined list to machine-driven identification. Reduction in number of features chosen for analysis in relation to cancer incidence then varied across statistical approaches and machine learning methods. The variation in approach and number of features identified for inclusion in analysis precluded generating a quantitative summary or meta-analysis of the value of these to improve predicting risk of future breast cancers. This updated overview of the state of the art revealed research gaps; based on these, we provide recommendations for future studies using parenchymal features for mammogram images to make use of accumulating image data, and external validation of prediction models that extend to 5 and 10 years to guide clinical risk management. By following these recommendations, we expect to improve risk classification and risk prediction for women to tailor screening and prevention strategies to level of risk.
Best BLAST hit alone cannot be used as evidence of fraud
Authors: Díaz-Arce Natalia , Rodríguez-Ezpeleta Naiara
Published: November 2021

In a recent study, Blanco-Fernandez, et al. 1 applied molecular tools to authenticate fish products and conclude evidence of “worrying international fraud”. They revealed mislabeling in recognizable and unrecognizable fish products labeled as anchovy, hake and tuna commercialized by European companies. Their analyses consisted on extracting DNA from the fish product to be authenticated followed by amplification and sequencing of a suite of DNA markers and on comparing the resulting sequences to the GenBank sequence database using BLAST (Basic Tool Alignment Search Tool) (https://blast.ncbi.nlm.nih.gov/Blast.cgi). By carefully reanalyzing their data, we identify errors in their species identification and conclude that best BLAST hit alone cannot be used as evidence of fraud.
Multi-ensemble coordination between the direct and indirect striatal pathways actuates perceptual decisions
Authors: Cui Lele , Tang Shunhang , Zhao Kai , Pan Jingwei , Zhang Zhaoran , Si Bailu , Xu Ning-long
Published: November 2021

Sensory-guided decision-making is a vital brain function critically depending on the striatum, a key brain structure transforming sensorimotor information into actions. However, how the two opposing striatal pathways work in concert to select actions during decision-making remains controversial. Here, using cell-type specific two-photon imaging and optogenetic perturbations from the posterior dorsal striatum during decision-making behavior in mice, we uncover the population coding and causal mechanisms of the direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) in decision-related action selection. Unexpected from prevailing models, we found that both dSPNs and iSPNs contain divergent subpopulations representing competing choices, and exhibit ensemble-level asymmetry: stronger contralateral dominance in dSPNs than in iSPNs. Such multi-ensemble competition/cooperation causally contributes to decision-related action selection, as supported by systematic optogenetic manipulations and verified by computational modeling. Our results unravel a multi-ensemble coordination mechanism in the striatum for action selection during decision-making.
FastQTLmapping: an ultra-fast package for mQTL-like analysis
Authors: Gao Xingjian , Li Jiarui , Liu Xinxuan , Peng Qianqian , Jing Han , Wang Sijia , Liu Fan
Published: November 2021

Here we describe fastQTLmapping, a C++ package that is computationally efficient not only for mQTL-like analysis but as a generic solver also for conducting exhaustive linear regressions involving extraordinarily large numbers of dependent and explanatory variables allowing for covariates. Compared to the state-of-the-art MatrixEQTL, fastQTLmapping was an order of magnitude faster with much lower peak memory usage. In a large dataset consisting of 3,500 individuals, 8 million SNPs, 0.8 million CpGs and 20 covariates, fastQTLmapping completed the mQTL analysis in 7 hours with 230GB peak memory usage.

Availability and Implementation

FastQTLmapping is implemented in C++ and released under a GPL license. FastQTLmapping can be downloaded from https://github.com/TianTTL/xQTLmapping.

Contact

liufan@big.ac.cn
The evolution of genomic, transcriptomic, and single-cell protein markers of metastatic upper tract urothelial carcinoma
Authors: Ohara Kentaro , Figueiredo Rendeiro André , Bhinder Bhavneet , Eng Kenneth Wha , Ravichandran Hiranmayi , Pisapia David , Vosoughi Aram , Fernandez Evan , Shohdy Kyrillus S. , Manohar Jyothi , Beg Shaham , Wilkes David , Robinson Brian D. , Khani Francesca , Bareja Rohan , Tagawa Scott T. , Sboner Andrea , Elemento Olivier , Faltas Bishoy M. , Mosquera Juan Miguel
Published: November 2021

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are unknown. The genomic and transcriptomic differences between primary and metastatic UTUC is not well described either. We combined whole-exome sequencing, RNA-sequencing, and Imaging Mass Cytometry™ (IMC™) of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. IMC enables spatially resolved single-cell analyses to examine the evolution of cancer cell, immune cell, and stromal cell markers using mass cytometry with lanthanide metal-conjugated antibodies. We discovered that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature were stable across primary and matched metastatic UTUC. Molecular and immune subtypes were consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single-cells. Molecular subtyping at the single cell level was highly conserved between primary and metastatic UTUC tumors within the same patient.
Tissue-specific impacts of aging and genetics on gene expression patterns in humans
Authors: Yamamoto Ryo , Chung Ryan , Vazquez Juan Manuel , Sheng Huanjie , Steinberg Philippa , Ioannidis Nilah M , Sudmant Peter H
Published: November 2021

Age is the primary risk factor for many common human diseases including heart disease, Alzheimer’s dementias, cancers, and diabetes. Determining how and why tissues age differently is key to understanding the onset and progression of such pathologies. Here, we set out to quantify the relative contributions of genetics and aging to gene expression patterns from data collected across 27 tissues from 948 humans. We show that age impacts the predictive power of expression quantitative trait loci across several tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find that the heritability (h2) of gene expression is largely consistent among tissues. In contrast, the average contribution of aging to gene expression variance varied by more than 20-fold among tissues with in 5 tissues. We find that the coordinated decline of mitochondrial and translation factors is a widespread signature of aging across tissues. Finally, we show that while in general the force of purifying selection is stronger on genes expressed early in life compared to late in life as predicted by Medawar’s hypothesis, a handful of highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression associated somatic mutations in cancer. In contrast, gene expression variation that is under genetic control is strongly enriched for genes under relaxed constraint. Together we present a novel framework for predicting gene expression phenotypes from genetics and age and provide insights into the tissue-specific relative contributions of genes and the environment to phenotypes of aging.
Identification, analysis, and confirmation of seed storability-related loci in Dongxiang wild rice (Oryza rufipogon Griff.)
Authors: Zhao Minmin , Hu Biaolin , Fan Yuanwei , Ding Gumu , Yang Wanling , Chen Yong , Chen Yanhong , Xie Jiankun , Zhang Fantao
Published: November 2021

Dongxiang wild rice (Oryza rufipogon Griff.) (DXWR) has strong seed storability and identifying its elite gene resources may facilitate genetic improvements in rice seed storability. In this study, we developed two backcross inbred lines (BILs) populations, with DXWR as a common donor parent and two rice varieties (F6 and R974) as recipient parents. Bulked segregant analysis via whole genome sequencing (BSA-seq) was used to identify seed storability-related loci in the DXWR and F6 population. Two main genomic regions containing 18,550,000–20,870,000 bp on chromosome 4 and 7,860,000–9,780,000 bp on chromosome 9 were identified as candidate loci of DXWR seed storability; these overlapped partially with seed storability-related quantitative trait loci (QTLs) discovered in previous studies, suggesting that these loci may provide important regions for isolating the responsible genes. In total, 448 annotated genes were predicted within the identified regions, of which 274 and 82 had nonsynonymous and frameshift mutations, respectively. We detected extensive metabolic activities and cellular processes during seed storability and confirmed the effects of the seed storability-related candidate loci using four BILs from DXWR and R974. These results may facilitate the cloning of DXWR seed storability-related genes, thereby elucidating rice seed storability and its improvement potential.
The sleep EEG envelope: a novel, neuronal firing-based human biomarker
Authors: Ujma Péter P. , Dresler Martin , Simor Péter , Fabó Dániel , Ulbert István , Erőss Loránd , Bódizs Róbert
Published: November 2021

Sleep EEG reflects instantaneous voltage differences relative to a reference, while its spectrum reflects the degree to which it is comprised of oscillations at various frequencies. In contrast, the envelope of the sleep EEG reflects the instantaneous amplitude of oscillations at specific frequencies, and its spectrum reflects the rhythmicity of the occurrence of these oscillations. The ordinary sleep EEG and its spectrum have been extensively studied and its individual stability and relationship to various demographic characteristics, psychological traits and pathologies is well known. In contrast, the envelope spectrum has not been extensively studied before. In two studies, we explored the generating mechanisms and utility of studying the envelope of the sleep EEG. First, we used human invasive data from cortex-penetrating microelectrodes and subdural grids to demonstrate that the sleep EEG envelope spectrum reflects local neuronal firing. Second, we used a large database of healthy volunteers to demonstrate that the scalp EEG envelope spectrum is highly stable within individuals, especially in NREM sleep, and that it is affected by age and sex. Multivariate models based on a learning algorithm could predict both age (r=0.6) and sex (r=0.5) with considerable accuracy from the EEG envelope spectrum. With age, oscillations characteristically shifted from a 4-5 second rhythm to higher rhythms. The envelope spectrum was not associated with general cognitive ability (IQ). Our results demonstrate that the sleep envelope spectrum is a promising, neuronal firing-based biomarker of various demographic and disease-related phenotypes.
Transcriptome network analysis implicates CX3CR1-positive type 3 dendritic cells in non-infectious uveitis
Authors: Hiddingh S. , Pandit A. , Verhagen F.H. , Rijken R. , Servaas N. H. , Wichers C.G.K. , Dam-van Loon N.H. ten , Imhof S.M. , Radstake T.R.D.J. , de Boer J.H. , Kuiper J.J.W.
Published: November 2021

Background

Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear.

Methods

We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations.

Results

We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed towards a gene module with the chemokine receptorCX3CR1as the key hub gene. We confirmed these results in an independent case-control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1-DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3-like cells can be detected in inflamed eyes of patients.

Conclusions

These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology.

Funding

The presented work is supported by UitZicht (project number #2014-4, #2019-10, an #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.
Influence network model uncovers relations between biological processes and mutational signatures
Authors: Amgalan Bayarbaatar , Wojtowicz Damian , Kim Yoo-Ah , Przytycka Teresa M.
Published: November 2021

There has been a growing appreciation recently that mutagenic processes can be studied through the lenses of mutational signatures, which represent characteristic mutation patterns attributed to individual mutagens. However, the causal link between mutagens and observed mutation patterns remains not fully understood, limiting the utility of mutational signatures. To gain insights into these relationships, we developed a network-based method, named GeneSigNetthat constructs a directed network among genes and mutational signatures. The approach leverages a sparse partial correlation among other statistical techniques to uncover dominant influence relations between the activities of network nodes. Applying GeneSigNetto cancer data sets, we uncovered important relations between mutational signatures and several cellular processes that can shed light on cancer related mutagenic processes. Our results are consistent with previous findings such as the impact of homologous recombination deficiency on a clustered APOBEC mutations in breast cancer. The network identified by GeneSigNetalso suggest an interaction between APOBEC hypermutation and activation of regulatory T Cells (Tregs) and a relation between APOBEC mutations and changes in DNA conformation. GeneSigNetalso exposed a possible link between the SBS8 signature of unknown aetiology and the nucleotide excision repair pathway. GeneSigNetprovides a new and powerful method to reveal the relation between mutational signatures and gene expression.

GeneSigNetis freely available athttps://github.com/ncbi/GeneSigNet.
Trajectory Recording and Analysis System for Cockroach Robot
Authors: Huai Ruituo , Zhu Haoran , Yang Shuo , Yu Zhihao , Wang Hui , Yang Junqing , Zhang Pingqiu , Shi Yong , Yan Rui
Published: November 2021

In this study, We design a trajectory recording and analysis system to record and analysis the changes in the movement behavior of the cockroach robot after stimulation. The external hardware of this system is an infrared touchpad as the experimental platform for the cockroach robot to crawl freely, and the infrared matrices densely distributed in the X and Y directions of the infrared touchpad are used to detect and locate the position of the cockroach robot. The cockroach robot’s movement trajectory is displayed visually through the projector’s interface projection on the infrared touchpad. The system software consists of three main parts: the electrical signal parameter setting module, the movement trajectory recording module, and the data analysis module. The electrical signal parameter setting module sets the stimulation parameters and configures the corresponding serial port to independently stimulate the left and right antenna and cercus of the cockroach; the trajectory recording module is used to record the trajectory of the cockroach robot through the coordinate positioning method. The data analysis module explores the change of motion behavior of the cockroach robot with time after receiving the stimulus by using the stage analysis method, and explores the change of motion of the cockroach robot with different voltage stimulus by using the module analysis method. The system is tested in experiments and the results demonstrated its applicability to the recording and analysis of the cockroach robot’s trajectories.
Adversarial domain translation networks for fast and accurate integration of large-scale atlas-level single-cell datasets
Authors: Zhao Jia , Wang Gefei , Ming Jingsi , Lin Zhixiang , Wang Yang ,   The Tabula Microcebus Consortium, Wu Angela Ruohao , Yang Can
Published: November 2021

The rapid emergence of large-scale atlas-level single-cell RNA-seq datasets presents remarkable opportunities for broad and deep biological investigations through integrative analyses. However, harmonizing such datasets requires integration approaches to be not only computationally scalable, but also capable of preserving a wide range of fine-grained cell populations. We created Portal, a unified framework of adversarial domain translation to learn harmonized representations of datasets. With innovation in model and algorithm designs, Portal achieves superior performance in preserving biological variation during integration, while achieving integration of millions of cells in minutes with low memory consumption. We show that Portal is widely applicable to integrating datasets across samples, platforms and data types (including scRNA-seq, snRNA-seq and scATAC-seq). Finally, we demonstrate the power of Portal by applying it to the integration of cross-species datasets with limited shared information among them, elucidating biological insights into the similarities and divergences in the spermatogenesis process among mouse, macaque and human.
Reduced Incidence of Long-COVID Symptoms Related to Administration of COVID-19 Vaccines Both Before COVID-19 Diagnosis and Up to 12 Weeks After
Authors: Simon Michael A. , Luginbuhl Ryan D. , Parker Richard
Published: November 2021

Both clinical trials and studies leveraging real-world data have repeatedly confirmed the three COVID-19 vaccines authorized for use by the Food and Drug Administration are safe and effective at preventing infection, hospitalization, and death due to COVID-19 and a recent observational study of self-reported symptoms provides support that vaccination may also reduce the probability of developing long-COVID. As part of a federated research study with the COVID-19 Patient Recovery Alliance, Arcadia.io performed a retrospective analysis of the medical history of 240,648 COVID-19-infected persons to identity factors influencing the development and progression of long-COVID. This analysis revealed that patients who received at least one dose of any of the three COVID vaccines prior to their diagnosis with COVID-19 were 7-10 times less likely to report two or more long-COVID symptoms compared to unvaccinated patients. Furthermore, unvaccinated patients who received their first COVID-19 vaccination within four weeks of SARS-CoV-2 infection were 4-6 times less likely to report multiple long-COVID symptoms, and those who received their first dose 4-8 weeks after diagnosis were 3 times less likely to report multiple long-COVID symptoms compared to those who remained unvaccinated. This relationship supports the hypothesis that COVID-19 vaccination is protective against long-COVID and that effect persists even if vaccination occurs up to 12 weeks after COVID-19 diagnosis. A critical objective of this study was hypothesis generation, and the authors intend to perform further studies to substantiate the findings and encourage other researchers to as well.
C-reactive protein and lactate dehydrogenase as prognostic indicators in COVID-2019 outpatients
Authors: Suzuki Keiko , Ichikawa Takaya , Suzuki Satoshi , Tanino Yoko , Kakinoki Yasutaka
Published: November 2021

Background

It is critical for clinicians seeing outpatients with coronavirus disease 2019 (COVID-19) to identify those who will require oxygen therapy after the hospital visit. Although studies on biomarkers predicting mortality or ventilator requirement in hospitalized patients with COVID-19 have been conducted, research on biomarkers predicting the need for oxygen therapy in outpatients is sparse.

Methods

Patients with COVID-19 who visited Asahikawa City Hospital on an outpatient basis were included in the study. In total, 287 new outpatients visited between April 2021 and September 2021, and 142 underwent blood testing. All blood tests were performed before any treatments for COVID-19 were started. Demographic information, laboratory data, and clinical treatment information were extracted from the electronic medical records. Risk factors associated with oxygen therapy were explored.

Results

In total, 40 of 142 patients who underwent blood testing required oxygen therapy within 7 days after blood samples were taken, and all other patients recovered without oxygen therapy. C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels were significantly higher in patients who required oxygen therapy, and their cutoffs were 36 mg/L (sensitivity, 0.802; specificity, 0.725) and 267 U/L (sensitivity, 0.713; specificity, 0.750), respectively. Multivariate logistic regression identified age, body mass index, CRP ≥ 36 mg/L, and LDH ≥ 267 U/L as significant risk factors for oxygen therapy requirement. This study suggests that elevated CRP and LDH levels are independent risk factors for oxygen therapy in outpatients with COVID-19. Further confirmatory studies are needed.
The output of interneurons in the primary visual cortex is best reflected by pre-synaptic activity, not somatic activity
Authors: Vroman Rozan , McKay Lawrie
Published: November 2021

Recent advances in 2-photon calcium-imaging in awake mice have made it possible to study the effect of different behavioural states on cortical circuitry. Many studies assume that somatic activity can be used as a measure for neuronal output. We set out to test the validity of this assumption by comparing somatic activity with the pre-synaptic activity of VIP (Vasoactive intestinal peptide)- and SST (Somatostatin)-positive interneurons in layer 2/3 of the primary visual cortex (V1). We used mice expressing genetically encoded calcium indicators in VIP/SST-interneurons across the whole cell (VIP/SST:GCaMP6f) or confined to pre-synapses (VIP/SST:SyGCaMP5). Mice were exposed to a full-field visual stimulation protocol consisting of 60-second-long presentations of moving Gabor gratings (0.04 cpd, 2 Hz) alternated by 30 seconds of grey screen. During imaging, mice were placed on an air-suspended Styrofoam ball, allowing them to run voluntarily. We compared neural activity during three 4-second time-windows: Before visual stimulation (−4 to 0 sec), during the initial onset (1 to 5 sec) and at the end of the stimulation (56 to 60 sec.). These were further compared while the mice were stationary and while they were voluntarily locomoting. Unlike VIP-somas, VIP-pre-synapses showed strong suppressive responses to the visual stimulus. Furthermore, VIP-somas were positively correlated with locomotion, whereas in VIP-synapses we observed a split between positive and negative correlations. In addition, a similar but weaker distinction was found between SST-somas and pre-synapses. The excitatory effect of locomotion in VIP-somas increased over the course of the visual stimulus but this property was only shared with the positively correlated VIP-pre-synapses. The remaining negatively correlated pre-synapses showed no relation to the overall activity of the Soma. Our results suggest that when making statements about the involvement of interneurons in V1 layer 2/3 circuitry it is crucial to measure from synaptic terminals as well as from somas.
Esrrγa regulates nephron development and ciliogenesis by controlling prostaglandin synthesis and cooperation with Ppargc1a
Authors: Wesselman Hannah M. , Flores-Mireles Ana L. , Wingert Rebecca A.
Published: November 2021

Cilia are essential for the ontogeny and function of many tissues, including the kidney. In mammals, Esrrγ has been previously established as a significant determinant of renal health, with decreased expression linked to age related dysfunction, cyst formation, and kidney disease. Here, we report that the Esrrγ vertebrate ortholog estrogen related receptor gamma a (esrrγa) is essential for proper cell fate choice within kidney functional units (nephrons) as well as ciliogenesis. Deficiency of esrrγa resulted in nephrons with alterations in proximodistal segmentation and a decreased multiciliated epithelial cell populace. Surprisingly, esrrγa deficiency disrupted renal ciliogenesis and caused a similar abrogation within the developing node and otic vesicle—all defects that occurred independently of changes in cell polarity or basal body organization. These phenotypes were consistent with interruptions in prostaglandin signaling, and we found that ciliogenesis was rescued in esrrγa deficient embryos with exogenous PGE2 or through overexpression of the cyclooxygenase enzyme Ptgs1. Through genetic interaction studies, we found that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (ppargc1a), which acts upstream of Ptgs1-mediated prostaglandin synthesis, has a synergistic relationship with esrrγa in the ciliogenic pathway. These data position esrrγa as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling and cooperation with ppargc1a, and highlight esrrγa as a potential new target for future ciliopathic treatments.
MAPR origins reveal a new class of prokaryotic cytochrome b5 proteins and possible role in eukaryogenesis
Authors: Tamarit Daniel , Teakel Sarah , Marama Michealla , Aragão David , Gerdes Svetlana Y. , Forwood Jade K. , Ettema Thijs J. G. , Cahill Michael A.
Published: November 2021

The multiple functions of PGRMC1, the archetypal heme-binding eukaryotic MAPR family member, include steroidogenic regulation, membrane trafficking, and steroid responsiveness. The interrelationships between these functions are currently poorly understood. Previous work has shown that different MAPR subclasses were present early in eukaryotic evolution, and that tyrosine phosphorylated residues appeared in the eumetazoan ancestor, coincident with a gastrulation organizer. Here we show that MAPR proteins are related to a newly recognized class of prokaryotic cytochrome-b5 domain proteins. Our first solved structure of this new class exhibits shared MAPR-like folded architecture and heme-binding orientation. We also report that a protein subgroup from Candidate Phyla Radiation bacteria shares MAPR-like heme-interacting tyrosines. Our results support bacterial origins for both PGRMC1 and CYP51A, that catalyze the meiosis-associated 14-demethylation of the first sterol lanosterol from yeast to humans. We propose that eukaryotic acquisition of a membrane-trafficking function related to sterol metabolism was associated with the appearance of MAPR genes early in eukaryotic evolution.
Net charges of the ribosomal proteins of theS10andspcclusters of halophiles are inversely related to the degree of halotolerance
Authors: Tirumalai Madhan R , Anane-Bediakoh Daniela , Rajesh Siddharth , Fox George. E.
Published: November 2021

Net positive charge(s) on ribosomal proteins (r-proteins) have been reported to influence the assembly and folding of ribosomes. A high percentage of r-proteins from extremely halophilic archaea are known to be acidic or even negatively charged. Those proteins that remain positively charged are typically far less so. Herein the analysis is extended to the non-archaeal halophilic bacteria, eukaryotes and halotolerant archaea. The net charges (pH 7.4) of r-proteins that comprise theS10-spcoperon/cluster from individual microbial and eukaryotic genomes were estimated and intercompared. It was observed that as a general rule, as the salt tolerance of the bacterial strains increased from 5 to 15%, the net charges of the individual proteins remained mostly basic. The most striking exceptions were the extremely halophilic bacterial strains,Salinibacter ruberSD01,Acetohalobium arabaticumDSM 5501 andSelenihalanaerobacter shriftiiATCC BAA-73, which are reported to require a minimum of 18%-21% of salt for their growth. All three strains have a higher number of acidicS10-spccluster r-proteins than what is seen in the moderate halophiles or the halotolerant strains. Of the individual proteins, only uL2 never became acidic. uS14 and uL16 also seldom became acidic. The net negative charges on several of theS10-spccluster r-proteins is a feature generally shared by all extremely halophilic archaea and bacteria. TheS10-spccluster r-proteins of halophilic fungi and algae (eukaryotes) were exceptions. They were positively charged despite the halophilicity of the organisms.

Importance

The net charges (at pH 7.4) of the ribosomal proteins (r-proteins) that comprise theS10-spccluster show an inverse relationship with the halophilicity/halotolerance levels in both bacteria and archaea. In non-halophilic bacteria, theS10-spccluster r-proteins are generally basic (positively charged), while the rest of the proteomes in these strains are generally acidic. On the other hand, the whole proteomes of the extremely halophilic strains are overall negatively charged including theS10-spccluster r-proteins. Given that the distribution of charged residues in the ribosome exit tunnel influences co-translational folding, the contrasting charges observed in theS10-spccluster r-proteins has potential implications for the rate of passage of these proteins through the ribosomal exit tunnel. Furthermore, the universal protein uL2 which lies in the oldest part of the ribosome is always positively charged irrespective of the strain/organism it belongs to. This has implications for its role in the prebiotic context.
Structural comparative modeling of multi-domain ΔF508 CFTR
Authors: McDonald Eli Fritz , Woods Hope , Smith Shannon T. , Kim Minsoo , Schoeder Clara T. , Plate Lars , Meiler Jens
Published: November 2021

Cystic Fibrosis (CF) is a common genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs - which increases the risk of infection and eventually causes death. CFTR is an ATP binding cassette (ABC) transporter composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (ΔF508), making ΔF508 CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain ΔF508 CFTR structure has been determined and few studies have modeled ΔF508 using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a ΔF508 model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and ΔF508 CFTR structural models. These models demonstrate the destabilizing effects of ΔF508 on NBD1 and the NBD1/TMD interface in both the closed and open conformation of CFTR. Furthermore, we modeled ΔF508/R1070W and ΔF508 bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of R1070W and VX-809 on multi-domain models of ΔF508 CFTR and pave the way for rational design of additional drugs that target ΔF508 CFTR for treatment of CF.

Author Summary

Protein’s three-dimension shape determines their function, so when genetic mutation compromises the shape of vital proteins, it may cause disease. Such is the case in Cystic Fibrosis, a chronic genetic disease caused by mutations in the protein Cystic Fibrosis Transmembrane Conductance Regulator. Here, we work backwards from the shape of the wild-type protein – found in healthy people, to computationally model the shape of the most common Cystic Fibrosis mutant. Our computer models reveal distinct defects in the shape of the mutant Cystic Fibrosis Transmembrane Conductance Regulator protein in the area surrounding the mutation. We also model an important FDA approved Cystic Fibrosis drug, VX-809, into the mutant protein structure and show how VX-809 stabilizes the protein around the location of the mutation. The method we developed will pave the way for computational drug design for Cystic Fibrosis.
Virtual reality validation of naturalistic modulation strategies to counteract fading in retinal stimulation
Authors: Thorn Jacob Thomas , Chenais Naïg Aurelia Ludmilla , Hinrichs Sandrine , Chatelain Marion , Ghezzi Diego
Published: November 2021

Objective

Temporal resolution is a key challenge in artificial vision. Several prosthetic approaches are limited by the perceptual fading of evoked phosphenes upon repeated stimulation from the same electrode. Therefore, implanted patients are forced to perform active scanning, via head movements, to refresh the visual field viewed by the camera. However, active scanning is a draining task, and it is crucial to find compensatory strategies to reduce it.

Approach

To address this question, we implemented perceptual fading in simulated prosthetic vision using virtual reality. Then, we quantified the effect of fading on two indicators: the time to complete a reading task and the head rotation during the task. We also tested if stimulation strategies previously proposed to increase the persistence of responses in retinal ganglion cells to electrical stimulation could improve these indicators.

Main results

This study shows that stimulation strategies based on interrupted pulse trains and randomisation of the pulse duration allows significant reduction of both the time to complete the task and the head rotation during the task.

Significance

The stimulation strategy used in retinal implants is crucial to counteract perceptual fading and to reduce active head scanning during prosthetic vision. In turn, less active scanning might improve the patient’s comfort in artificial vision.
Effects of food availability cycles on phase and period of activity/rest rhythm inDrosophila melanogaster
Authors: Singh Viveka Jagdish , Potdar Sheetal , Sheeba Vasu
Published: November 2021

Foraging and feeding are indispensable for survival and their timing depends not only on the metabolic state of the animal but also on the availability of food resources in their environment. Since both these aspects are subject to change over time, these behaviours exhibit rhythmicity in occurrence. As the locomotor activity of an organism is related to its disposition to acquire food, and peak feeding in fruit flies has been shown to occur at a particular time of the day, we asked if cyclic food availability can entrain their rhythmic activity. By subjecting flies to cyclic food availabilityi.e., feeding/starvation (FS) cycles, we provided food cues contrasting to the preferred activity times and observed if this imposed cycling in food availability could entrain the activity/rest rhythm. We found that phase control, which is a property integral to entrainment, was not achieved despite increasing starvation duration of FS cycles (FS12:12, FS10:14 and FS8:16). We also found that flies subjected to T21 and T26 FS cycles were unable to match period of the activity rhythm to short or long T-cycles. Taken together these results show that external food availability cycles do not entrain the activity/rest rhythm of fruit flies. However, we find that starvation induced hyperactivity causes masking which results in phase changes. Additionally, T-cycle experiments resulted in minor period changes during FS treatment. These findings highlight that food cyclicity by itself may not be a potent zeitgeber but may act in unison with other abiotic factors like light and temperature to help flies time their activity appropriately.
CRAFT: a bioinformatics software for custom prediction of circular RNA functions
Authors: Molin Anna Dal , Gaffo Enrico , Difilippo Valeria , Buratin Alessia , Parenzan Caterina Tretti , Bresolin Silvia , Bortoluzzi Stefania
Published: November 2021

Circular RNAs (circRNAs), transcripts generated by backsplicing, are particularly stable and pleiotropic molecules, whose dysregulation drives human diseases and cancer by modulating gene expression and signaling pathways. CircRNAs can regulate cellular processes by different mechanisms, including interaction with microRNAs (miRNAs) and RNA-binding proteins (RBP), and encoding specific peptides. The prediction of circRNA functions is instrumental to interpret their impact in diseases, and to prioritize circRNAs for functional investigation. Currently, circRNA functional predictions are provided by web databases that do not allow custom analyses, while self-standing circRNA prediction tools are mostly limited to predict only one type of function, mainly focusing on the miRNA sponge activity of circRNAs. To solve these issues, we developed CRAFT (CircRNA Function prediction Tool), a freely available computational pipeline that predicts circRNA sequence and molecular interactions with miRNAs and RBP, along with their coding potential. Analysis of a set of circRNAs with known functions has been used to appraise CRAFT predictions and to optimize its setting. CRAFT provides a comprehensive graphical visualization of the results, links to several knowledge databases, and extensive functional enrichment analysis. Moreover, it originally combines the predictions for different circRNAs. CRAFT is a useful tool to help the user explore the potential regulatory networks involving the circRNAs of interest and generate hypotheses about the cooperation of circRNAs into the modulation of biological processes.

Key points

CRAFT is a self standing tool for comprehensive circRNA function prediction.

CRAFT functions include circRNA sequence reconstruction, microRNA and RNA-binding protein response elements and coding potential prediction.

Predictions for multiple circRNAs are connected to infer possible cooperation networks and illustrate the potential impact of circRNAs on biological and disease processes.