bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain-age predicts subsequent dementia in memory clinic patients
Authors: Biondo Francesca , Jewell Amelia , Pritchard Megan , Aarsland Dag , Steves Claire J. , Mueller Christoph , Cole James H.
Published: April 2021

INTRODUCTION

Research into quantitative neuroimaging biomarkers of dementia risk rarely uses data representative of everyday clinic practice.

METHODS

We analysed T1-weighted MRI scans from memory clinic patients (n=1140; 60.2% female and mean [SD] age of 70.0 [10.8] years) to derive ‘brain-age’, an index of age-related brain health. We determined which patients went on to develop dementia (n=476) via linkage to electronic health records.

RESULTS

Cox regression indicated a 3% increased risk of dementia per brain-PAD year (brain-PAD = brain-age minus chronological age), HR(95% CI)=1.03(1.02, 1.04), p<0.001, adjusted for age, age2, sex, MMSE and normalised brain volume. Brain-PAD remained significant even with a minimum time-to-diagnosis of 3 years (HR=1.06) and with MMSE score ≥ 27 (HR=1.03).

DISCUSSION

Memory clinic patients with older-appearing brains are more likely to receive a subsequent dementia diagnosis. These results from a ‘real-world’ dataset suggest quantitative neuroimaging biomarkers like brain-age could be readily used in the clinic.

Research in Context

SYSTEMATIC REVIEW

Multiple previous studies were identified that have modelled dementia risk using quantitative neuroimaging, however, screening of participants based on comorbidities and contraindications alongside sociodemographic and healthcare sampling biases, limits the generalisation of these studies to real-world clinical settings. To facilitate better translation from research to the clinic, datasets that are more representative of dementia patient groups are warranted.

INTERPRETATION

Brain-age is an index of ‘biological’ age based on a quantitative analysis of T1-weighted MRI scans. Memory clinic patients with biologically older-appearing brains are more likely to receive a subsequent dementia diagnosis, independent of medical history, age, sex, MMSE score and normalised brain volumes. These findings suggest that brain-age has potential to be used early-on in memory clinics as a biomarker to aid detection of patients at high-risk of developing dementia.

FUTURE DIRECTIONS

Does the addition of T2-weighted MRI scan information and/or localised brain-age values improve dementia prediction?
A Discernable Increase in the Severe Acute Respiratory Syndrome Coronavirus 2 R.1 Lineage Carrying an E484K Spike Protein Mutation in Japan
Authors: Sekizuka Tsuyoshi , Itokawa Kentaro , Hashino Masanori , Okubo Kazuhiro , Ohnishi Asami , Goto Keiko , Tsukagoshi Hiroyuki , Ehara Hayato , Nomoto Ryohei , Ohnishi Makoto , Kuroda Makoto ,   Virus Diagnosis Group (NIID Toyama) and COVID-19 Genomic Surveillance Network in Japan (COG-JP).
Published: April 2021

Three COVID-19 waves in Japan have been characterized by the presence of distinct PANGO lineages (B.1.1. 162, B.1.1.284, and B.1.1.214). Recently, in addition to the B.1.1.7 lineage, which shows 25% abundance, an R.1 lineage carrying the E484K mutation in the spike protein was found to show up to 40% predominance.
Injuries and fatalities in Colombian mining emergencies (2005 - 2018)
Authors: Gheorghe Gloria C. , Manrique-Hernández Edgar F. , Idrovo Alvaro J.
Published: April 2021

Background

During the last decades several developed countries reported a decrease in the occurrence of mining injuries. Mining is a very important sector of Colombia’s economy without analyses of injuries and fatalities in mining emergencies.

Objective

This study describes the occurrence of mining emergencies in Colombia between 2005 and 2018, and their principal characteristics.

Methods

An ecological study was performed with the mining emergencies registered by the National Mining Agency between 2005 and 2018. The study described the place of occurrence, type of event, legal status and type of mines, mineral extracted, and number of injuries and fatalities. Benford’s law was used to explore the quality of the data.

Results

A total of 1,235 emergencies occurred, with 751 injured workers and 1,364 fatalities. The majority of emergencies were from collapses, polluted air, and explosions, most of which occurred in coal (77.41%), gold (18.06%), and emerald (1.38%) mines. Many emergencies occurred in illegal mines (27.21%), most of which were gold, construction materials, emerald, and coal. Illegal mines had a higher relative proportion of injuries and fatalities than legal mines (p<0.05). Mining disasters are likely to be underreported given that Benford’s Law was not satisfied.

Conclusions

Colombia is a country with increasing mining activity, where the occurrence of mining emergencies, injuries, and fatalities is growing. This is the first one full description of mining emergencies in Colombia with the few available data.
Monitoring carbon dioxide to quantify the risk of indoor airborne transmission of COVID-19
Authors: Bazant Martin Z. , Kodio Ousmane , Cohen Alexander E. , Khan Kasim , Gu Zongyu , Bush John W. M.
Published: April 2021

A new guideline for mitigating indoor airborne transmission of COVID-19 prescribes a limit on the time spent in a shared space with an infected individual (Bazant and Bush, 2021). Here, we rephrase this safety guideline in terms of occupancy time and mean exhaled carbon dioxide concentration in an indoor space, thereby enabling the use of CO2monitors in the risk assessment of airborne transmission of respiratory diseases. While CO2concentration is related to airborne pathogen concentration (Rudnick and Milton, 2003), the guideline developed here accounts for the different physical processes affecting their evolution, such as enhanced pathogen production from vocal activity and pathogen removal via face-mask use, filtration, sedimentation and deactivation. Critically, transmission risk depends on the total infectious dose, so necessarily depends on both the pathogen concentration and exposure time. The transmission risk is also modulated by the fractions of susceptible, infected and immune persons within a population, which evolve as the pandemic runs its course. A mathematical model is developed that enables a prediction of airborne transmission risk from real-time CO2measurements. Illustrative examples of implementing our guideline are presented using data from CO2monitoring in university classrooms and office spaces.

Impact Statement

There is mounting scientific evidence that COVID-19 is primarily transmitted through indoor airborne transmission, as arises when a susceptible person inhales virus-laden aerosol droplets exhaled by an infectious person. A safety guideline to limit indoor airborne transmission (Bazant and Bush, 2021) has recently been derived that complements the public health guidelines on surface cleaning and social distancing. We here recast this safety guideline in terms of total inhaled carbon dioxide, as can be readily monitored in most indoor spaces. Our approach paves the way for optimizing air handling systems by balancing health and financial concerns, informs policy for safely re-opening schools and businesses as the pandemic runs its course, and may be applied quite generally in the mitigation of airborne respiratory illnesses, including influenza.
The trends in maternal age distribution and the estimated live birth and population prevalence of Down’s syndrome in China: 1985-2012
Authors: Kang Jing , Wu Jianhua
Published: April 2021

This study aims to investigate the trends in maternal age distribution and estimate the live birth and population prevalence of Down’s syndrome in China.

Using population survey data, we demonstrated the change of maternal age over the past three decades and its effect on the live birth prevalence of Down’s syndrome. We also integrated the live birth prevalence and the survival rate to estimate the population prevalence of Down’s syndrome. Chi-square test was used to compare the maternal age distributions across survey years.

The results show that the maternal age has been rising over the past 30 years in China at national level. The proportion of mothers aged 35 and over increased from 3.62% in 1985 to 14.40% in 2010. The estimated live birth prevalence of Down’s syndrome has mirrored the same increase of the maternal age from 1.07 per 1000 live births in 1985 to 2.36 per 1000 live births in 2010. At City level, the change of maternal age and live birth prevalence of Down’s syndrome were more significant than at Town and County levels. The proportion of mothers aged 35 and over increased from 2.17% in 1995 to about 16% in 2010 at City level, while it increased from 2.03% to 13.65% at County level. The total estimated number of people with Down’s syndrome who were still alive in 2012 and aged below 27 was 611,053, and the estimated population prevalence is 0.45 per 1000.

To conclude, this study provides a clear message about the rising trend in maternal age in both urban and rural areas in China since 1985 and its effect on the estimated birth prevalence with Down’s syndrome. The regional differences should be taken into account for planning population policy and allocating medical resources to reduce the burden of family with Down’s syndrome.
cellxgene: a performant, scalable exploration platform for high dimensional sparse matrices
Authors: Megill Colin , Martin Bruce , Weaver Charlotte , Bell Sidney , Prins Lia , Badajoz Seve , McCandless Brian , Pisco Angela Oliveira , Kinsella Marcus , Griffin Fiona , Kiggins Justin , Haliburton Genevieve , Mani Arathi , Weiden Matthew , Dunitz Madison , Lombardo Maximilian , Huang Timmy , Smith Trent , Chambers Signe , Freeman Jeremy , Cool Jonah , Carr Ambrose
Published: April 2021

Quickly and flexibly exploring high-dimensional datasets, such as scRNAseq data, is underserved but critical for hypothesis generation, dataset annotation, publication, sharing, and community reuse. cellxgene is a highly generalizable, web-based interface for exploring high dimensional datasets along categorical, continuous and spatial dimensions, as well as feature annotation. cellxgene is differentiated by its ability to performantly handle millions of observations, and bridges a critical gap by enabling computational and experimental biologists to iteratively ask questions of private and public datasets. In doing so, cellxgene increases the utility and reusability of datasets across the single-cell ecosystem.

The codebase can be accessed athttps://github.com/chanzuckerberg/cellxgene. For questions and inquiries, please contactcellxgene@chanzuckerberg.com.
On the many advantages of using the VariantExperiment class to store, exchange and analyze SARS-CoV-2 genomic data and associated metadata
Authors: Ambroise Jérôme , Gatto Laurent , Hurel Julie , Bearzatto Bertrand , Gala Jean-Luc
Published: April 2021

On Friday, 19 March 2021, WHO organized a virtual global workshop highlighting the need for a globally coordinated plan to increase SARS-CoV-2 genetic sequencing capacities to detect SARS-CoV-2 mutations and variants, and to monitor virus genomic evolution worldwide. One week later, in another virtual meeting, it focused on sero epidemiology for SARS-CoV-2 variants of concern and variants of interest. Efficient monitoring of the virus relies on the storage, handling and sharing of the genomic data and the associated metadata. In this manuscript, we demonstrate how the Bioconductor VariantExperiment class addresses these needs, offering a robust and efficient solution to the requirements laid out by the WHO.
HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of CNV, CNVR and ROH
Authors: Zhou Jinghang , Liu Liyuan , Lopdell Thomas J. , Garrick Dorian J. , Shi Yuangang
Published: April 2021

Here we present an R package for summarizing, annotating, converting, comparing and visualizing CNV (copy number variants) and ROH (runs of homozygosity) detected from SNP (single nucleotide polymorphism) genotyping data. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving and user friendly for research in humans and most diploid livestock species.

Availability and Implementation

The source code, demo data and vignettes can be found athttps://github.com/JH-Zhou/HandyCNV
Warped Bayesian Linear Regression for Normative Modelling of Big Data
Authors: Fraza Charlotte J. , Dinga Richard , Beckmann Christian F. , Marquand Andre F.
Published: April 2021

Normative modelling is becoming more popular in neuroimaging due to its ability to make predictions of deviation from a normal trajectory at the level of individual participants. It allows the user to model the distribution of several neuroimaging modalities, giving an estimation for the mean and centiles of variation. With the increase in the availability of big data in neuroimaging, there is a need to scale normative modelling to big data sets. However, the scaling of normative models has come with several challenges.

So far, most normative modelling approaches used Gaussian process regression, and although suitable for smaller datasets (up to a few thousand participants) it does not scale well to the large cohorts currently available and being acquired. Furthermore, most neuroimaging modelling methods that are available assume the predictive distribution to be Gaussian in shape. However, deviations from Gaussianity can be frequently found, which may lead to incorrect inferences, particularly in the outer centiles of the distribution. In normative modelling, we use the centiles to give an estimation of the deviation of a particular participant from the ‘normal’ trend. Therefore, especially in normative modelling, the correct estimation of the outer centiles is of utmost importance, which is also where data are sparsest.

Here, we present a novel framework based on Bayesian Linear Regression with likelihood warping that allows us to address these problems, that is, to scale normative modelling elegantly to big data cohorts and to correctly model non-Gaussian predictive distributions. In addition, this method provides also likelihood-based statistics, which are useful for model selection.

To evaluate this framework, we use a range of neuroimaging-derived measures from the UK Biobank study, including image-derived phenotypes (IDPs) and whole-brain voxel-wise measures derived from diffusion tensor imaging. We show good computational scaling and improved accuracy of the warped BLR for certain IDPs and voxels if there was a deviation from normality of these parameters in their residuals.

The present results indicate the advantage of a warped BLR in terms of; computational scalability and the flexibility to incorporate non-linearity and non-Gaussianity of the data, giving a wider range of neuroimaging datasets that can be correctly modelled.
Regulation of DIM-2-dependent repeat-induced point mutation (RIP) by the recombination-independent homologous DNA pairing inNeurospora crassa
Authors: Carlier Florian , Nguyen Tinh-Suong , Mazur Alexey K. , Gladyshev Eugene
Published: April 2021

Repeat-induced point mutation (RIP) is a genetic process that creates cytosine-to-thymine (C-to-T) transitions in duplicated genomic sequences in fungi. RIP detects duplications irrespective of their origin, particular sequence, coding capacity, or genomic positions. Previous studies suggested that RIP involves a cardinally new mechanism of sequence recognition that operates on intact double-stranded DNAs. In the fungusNeurospora crassa, RIP can be mediated by a putative C5-cytosine methyltransferase (CMT) RID or/and a canonical CMT DIM-2. These distinct RIP pathways feature opposite substrate preferences: RID-dependent RIP is largely limited to the duplicated sequences, whereas DIM-2-dependent RIP preferentially mutates adjacent non-repetitive regions. Using DIM-2-dependent RIP as a principal readout of repeat recognition, here we show that GC-rich repeats promote stronger RIP compared to AT-rich repeats (independently of their intrinsic propensities to become mutated), with the relative contribution of AT base-pairs being close to zero. We also show that direct repeats promote much more efficient DIM-2-dependent RIP than inverted repeats; both the spacer DNA between the repeat units (the linker) and the flanking regions are similarly affected by this process. These and other results support the idea that repeat recognition for RIP involves formation of many short interspersed quadruplexes between homologous double-stranded DNAs, which need to undergo concomitant changes in their linking number to accommodate pairing.

During repeat-induced point mutation (RIP) gene-sized duplications of genomic DNA are detected by a mechanism that likely involves direct pairing of homologous double-stranded DNAs. We show that DIM-2-dependent RIP, triggered by closely-positioned duplications, is strongly affected by their relative orientations (direct versus inverted). We also show that GC-rich repeats promote RIP more effectively than AT-rich repeats. These results support a model in which homologous dsDNAs can pair by establishing interspersed quadruplex-based contacts with concomitant changes in their supercoiling status.
Differential effects of cerebellar degeneration on feedforward versus feedback control across speech and reaching movements
Authors: Parrell Benjamin , Kim Hyosub E. , Breska Assaf , Saxena Arohi , Ivry Richard B.
Published: April 2021

Errors that result from a mismatch between predicted movement outcomes and sensory afference are used to correct ongoing movements through feedback control and to adapt feedforward control of future movements. The cerebellum has been identified as a critical part of the neural circuit underlying implicit adaptation across a wide variety of movements (reaching, gait, eye movements, and speech). The contribution of this structure to feedback control is less well understood: although it has recently been shown in the speech domain that individuals with cerebellar degeneration produce even larger online corrections for sensory perturbations than control participants, similar behavior has not been observed in other motor domains. Currently, comparisons across domains are limited by different population samples and potential ceiling effects in existing tasks. To assess the relationship between changes in feedforward and feedback control associated with cerebellar degeneration across motor domains, we evaluated adaptive (feedforward) and compensatory (feedback) responses to sensory perturbations in reaching and speech production in human participants of both sexes with cerebellar degeneration and neurobiologically healthy controls. As expected, the cerebellar group demonstrated impaired adaptation in both reaching and speech. In contrast, the groups did not differ in their compensatory response in either domain. Moreover, compensatory and adaptive responses in the cerebellar group were not correlated within or across motor domains. These results point to a general impairment in feedforward control with spared feedback control in cerebellar degeneration. However, the magnitude of feedforward impairments and potential changes in feedback-based control manifest in a domain-specific manner across individuals.

Significance Statement

The cerebellum contributes to feedforward updating of movement in response to sensory errors, but its role in feedback control is less understood. Here, we tested individuals with cerebellar degeneration (CD), using sensory perturbations to assess adaptation of feedforward control and feedback gains during reaching and speech production tasks. The results confirmed that CD leads to reduced adaption in both domains. However, feedback gains were unaffected by CD in either domain. Interestingly, measures of feedforward and feedback control were not correlated across individuals within or across motor domains. Together, these results indicate a general impairment in feedforward control with spared feedback control in CD. However, the magnitude of feedforward impairments manifests in a domain-specific manner across individuals.
The Up state of the SARS-COV-2 Spike homotrimer favors an increased virulence for new variants
Authors: Giron Carolina Corrêa , Laaksonen Aatto , da Silva Fernando Luís Barroso
Published: April 2021

The COVID-19 pandemic has spread widely worldwide. However, as soon as the vaccines were released – the only scientifically verified and efficient therapeutic option thus far – a few mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged raising doubts about their efficiency. Therefore, this work aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor binding domain (RBD) and Angiotensin Converting Enzyme 2 (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state (the one in which the virus can interact with the cellular receptor ACE2) than due to alterations in the complexation RBD-ACE2, once the increased observed in the free energy values is small. Conversely, the South African variant (B.1.351), when compared with the wild type SARS-CoV-2, is much more stable in the opened state (either with one or two RBDs in the up position) than in the closed state (with the three RBDs in the down position). Such results contribute to the understanding of the natural history of disease and also to indicate possible strategies to both develop new therapeutic molecules and to adjust the vaccine doses for a higher production of B cells antibodies.

Graphical Abstract
Sobp modulates Six1 transcriptional activation and is required during craniofacial development
Authors: Tavares Andre L. P. , Jourdeuil Karyn , Neilson Karen M. , Majumdar Himani D. , Moody Sally A.
Published: April 2021

Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, craniofacial and/or renal defects. Mutations in the transcription factor Six1 and its cofactor Eya1, both required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 cofactor andSOBPmutations in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-IP and immunofluorescence experiments demonstrate that Sobp binds to and co-localizes with Six1 in the cell nucleus. Luciferase assays show that Sobp represses Six1+Eya1 transcriptional activation. Experimentsin Xenopusembryos that either knockdown or increase expression show that Sobp is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression ofXenopusSobp containing the human mutation disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function, is required for vertebrate craniofacial development, and identifies Sobp as a potential candidate gene for BOR and other deafness syndromes.

Summary statement

Sobp interacts with Six1 in the cell nucleus and represses the Six1+Eya1 transcriptional activation. InXenopusembryos, Sobp functions during early stages of inner ear development.
Nutrient Responsive O-GlcNAcylation Dynamically Modulates Galectin 3 Secretion
Authors: Mathew Mohit P. , Donaldson Julie G. , Hanover John A.
Published: April 2021

Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and in fact, characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about the molecular mechanisms underlying how these signals are integrated and transduced into biological effects. Galectins are proteins that bind glycans that are secreted by a poorly characterized non-classical secretory mechanism. Once outside the cell, galectins bind to terminal galactose residues of cell surface glycans and modulate numerous extracellular functions like clathrin independent endocytosis (CIE). Originating in the cytoplasm, galectins are predicted substrates for O-GlcNAc addition and removal. This study shows that galectin 3 is O-GlcNAcylated, and that changes in O-GlcNAc cycling alters its secretion. Moreover, we determined that there is a significant difference in O-GlcNAcylation status between cytoplasmic and secreted galectin 3. We observed dramatic alterations in galectin 3 secretion in response to nutrient conditions and that these changes were dependent on dynamic O-GlcNAcylation. Finally, we showed that alterations in galectin 3 secretion via disrupted O-GlcNAcylation drove changes in CIE. These results indicate that dynamic O-GlcNAcylation of galectin 3 plays a role in modulating its secretion and can tune its function of transducing nutrient sensing information coded in cell surface glycosylation into biological effects.
Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia
Authors: Medina-Carbonero Marta , Sanz-Alcázar Arabela , Britti Elena , Delaspre Fabien , Cabiscol Elisa , Ros Joaquim , Tamarit Jordi
Published: April 2021

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease, caused by partial deficiency of frataxin, a mitochondrial protein. This deficiency is caused by the presence of a GAA triplet expansion in the first intron of the frataxin gene or, in some patients, by point mutations. Generating mouse models mimicking FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. In the present work, we have characterized a new mouse model of FA (FXNI151F) based on a pathological point mutation (I154F) present in some FA patients. These mice present very low frataxin levels in all tissues and display neurological deficits resembling those observed in FA patients. We have also observed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in the antioxidant defenses. Remarkably, these biochemical alterations precede the appearance of neurological symptoms and present a different profile in heart and brain or cerebellum. The FXNI151Fmouse is an excellent tool for analyzing the consequences of frataxin deficiency in different tissues and for testing new therapies.
Brassica rapadomestication: untangling wild and feral forms and convergence of crop morphotypes
Authors: McAlvay Alex C. , Ragsdale Aaron P. , Mabry Makenzie E. , Qi Xinshuai , Bird Kevin A. , Velasco Pablo , An Hong , Pires J. Chris , Emshwiller Eve
Published: April 2021

The study of domestication contributes to our knowledge of evolution and crop genetic resources. Human selection has shaped wildBrassica rapainto diverse turnip, leafy, and oilseed crops. Despite its worldwide economic importance and potential as a model for understanding diversification under domestication, insights into the number of domestication events and initial crop(s) domesticated inB. rapahave been limited due to a lack of clarity about the wild or feral status of conspecific non-crop relatives. To address this gap and reconstruct the domestication history ofB. rapa, we analyzed 68,468 genotyping-by-sequencing-derived SNPs for 416 samples in the largest diversity panel of domesticated and weedyB. rapato date. To further understand the center of origin, we modeled the potential range of wildB. rapaduring the mid-Holocene. Our analyses of genetic diversity acrossB. rapamorphotypes suggest that non-crop samples from the Caucasus, Siberia, and Italy may be truly wild, while those occurring in the Americas and much of Europe are feral. Clustering, tree-based analyses, and parameterized demographic inference further indicate that turnips were likely the first crop type domesticated, from which leafy types in East Asia and Europe were selected from distinct lineages. These findings clarify the domestication history and nature of wild crop genetic resources forB. rapa, which provides the first step toward investigating cases of possible parallel selection, the domestication and feralization syndrome, and novel germplasm forBrassicacrop improvement.
Dynamic task-belief is an integral part of decision-making
Authors: Xue Cheng , Kramer Lily E. , Cohen Marlene R.
Published: April 2021

Natural decisions involve two seemingly separable processes: inferring the relevant task (task-belief) and performing the believed-relevant task. The assumed separability has led to the traditional practice of studying task-switching and perceptual decision-making individually. Here, we used a novel paradigm to manipulate and measure macaque monkeys’ task-belief, and demonstrated inextricable neuronal links between flexible task-belief and perceptual decision-making. We showed that in animals, but not artificial networks that performed as well or better than the animals, stronger task-belief is associated with better perception. Correspondingly, recordings from neuronal populations in cortical areas 7a and V1 revealed that stronger task-belief is associated with better discriminability of the believed-relevant but not the believed-irrelevant feature. Perception also impacts belief updating: noise fluctuations in V1 help explain how task-belief is updated. Our results demonstrate that complex tasks and multi-area recordings can reveal fundamentally new principles of how biology affects behavior in health and disease.
The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress
Authors: Yang Yoon-Mo , Karbstein Katrin
Published: April 2021

Although ribosome assembly is quality controlled to maintain protein homeostasis, different ribosome populations have been described. How these form, especially under stress conditions that impact energy levels and stop the energy-intensive production of ribosomes, remains unknown. Here we demonstrate how a physiologically relevant ribosome population arises during high Na+and pH stress via dissociation of Rps26 from fully assembled ribosomes to enable a translational response to these stresses. The chaperone Tsr2 releases Rps26 in the presence of high Na or pHin vitroand is required for Rps26 releasein vivo. Moreover, Tsr2 stores free Rps26 and promotes re-incorporation of the protein, thereby repairing the subunit after the stress subsides. Our data implicate a residue in Rps26 involved in Diamond Blackfan Anemia in mediating the effects of Na+. These data demonstrate how different ribosome populations can arise rapidly, without major energy input, and without bypass of quality control mechanisms.

Graphical Abstract

Highlights

Tsr2 releases Rps26 from mature ribosomes to remodel ribosome populations

Tsr2 stores released Rps26 and allows for ribosome repair after stress

Rps26 exploits a Mg binding site linked to Diamond Blackfan Anemia (DBA)

Chaperone-mediated ribosome remodeling might be common for chaperoned RPs
An Autoantigen-ome from HS-Sultan B-Lymphoblasts Offers a Molecular Map for Investigating Autoimmune Sequelae of COVID-19
Authors: Wang Julia Y. , Zhang Wei , Roehrl Victor B. , Roehrl Michael W. , Roehrl Michael H.
Published: April 2021

To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID-autoantigens (autoAgs). Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical ANAs and ENAs of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. Furthermore, B-cell-specific IgM-associated ER complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design.
Decreasing Mitochondrial RNA Polymerase Activity Reverses Biased Inheritance of Hypersuppressive mtDNA
Authors: Corbi Daniel , Amon Angelika
Published: April 2021

Faithful inheritance of mitochondrial DNA (mtDNA) is crucial for cellular respiration/oxidative phosphorylation and mitochondrial membrane potential. However, how mtDNA is transmitted to progeny is not fully understood. We utilized hypersuppressive mtDNA, a class of respiratory deficientSaccharomyces cerevisiaemtDNA that is preferentially inherited over wild-type mtDNA (rho+), to uncover the factors governing mtDNA inheritance. We found that regions ofrho+mtDNA persisted after hypersuppressive takeover indicating that hypersuppressive preferential inheritance may partially be due to active destruction ofrho+mtDNA. From a multicopy suppression screen, we found that overexpression of putative mitochondrial RNA exonucleasePET127reduced hypersuppressive biased inheritance. This suppression requiredPET127binding to the mitochondrial RNA polymeraseRPO41but notPET127exonuclease activity. A temperature-sensitive allele ofRPO41improvedrho+mtDNA inheritance relative to hypersuppressive mtDNA at semi-permissive temperatures revealing a previously unknown role forrho+transcription in promoting hypersuppressive mtDNA inheritance.
The neuroprotective effect of meloxicam in a transient ischemia model involves an increase in axonal sprouting but a decrease in new neuron formation after 7 days of reperfusion
Authors: Ugidos IF , González-Rodríguez P , Santos-Galdiano M , Font-Belmonte E , Anuncibay-Soto B , Pérez-Rodríguez D , Fernández-López A
Published: April 2021

The inflammatory response plays an important role in neuroprotection and regeneration after ischemic insult. The use of non-steroidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects. In this context, the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stroke, but its ability to inhibit both cyclooxygenase isoforms (1 and 2) could be a promising strategy to modulate post-ischemic inflammation. This study analyzed the effect of the anti-inflammatory agent meloxicam in a transient focal ischemia model in rats, measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area. We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia. Moreover, meloxicam treatment modulated glial scar reactivity, which matched with an increase in axonal sprouting. However, this treatment decreased the formation of neuronal progenitor cells. This study discusses the dual role of anti-inflammatory treatments after stroke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.

Abstract Figure
Soil, ocean, hot spring, and host-associated environments reveal unique selection pressures on genomic features of bacteria in microbial communities
Authors: Chuckran Peter F. , Hungate Bruce , Schwartz Egbert , Dijkstra Paul
Published: April 2021

Free-living bacteria in nutrient limited environments often exhibit small genomes which curb the cost of reproduction – a phenomenon known as genomic streamlining. Streamlining has been associated with a suite of traits such as reduced GC content, fewer 16S rRNA copies, and a lower abundance of regulatory genes, such as sigma (σ) factors. Here, we analyzed these traits from 116 publicly available metagenomes derived from marine, soil, host associated, and thermophilic communities. In marine and thermophilic communities, genome size and GC content declined in parallel, but GC content was higher in thermophilic communities. In soils, the relationship between genome size and GC content was negative, suggesting a different selection pressure on genome size and GC content in soil bacteria. The abundance of σ-factors varied with average genome size, ecosystem type, and the specific functions regulated by the sigma factor. In marine environments, housekeeping and heat-shock σ-factor genes (rpoDandrpoHrespectively) increased as genome size declined, and σ-factor responsible for flagella biosynthesis (fliA) decreased, suggesting a trade-off between nutrient conservation and chemotaxis. In soils, a high abundance offliAand the stress response σ-factor gene (rpoS) was associated with smaller average genome size and often located in harsh and/or carbon-limited environments such as deserts or agricultural fields – suggesting an increased capacity for stress response and mobility in nutrient-poor soils. This work showcases how ecosystem-specific environmental constraints force trade-offs which are then embedded in the genomic features of bacteria in microbial communities, specifically genome size, GC content, and regulatory genes, and further highlights the importance of considering these features in microbial community analysis.
Defined diets for freshwater planarians
Authors: Abel Chris , Powers Kaleigh , Gurung Gargi , Pellettieri Jason
Published: April 2021

Planarian flatworms are popular invertebrate models for basic research on stem cell biology and regeneration. These animals are commonly maintained on a diet of homogenized calf liver or boiled egg yolk in the laboratory, introducing a source of uncontrolled experimental variability. Here, we report the development of defined diets, prepared entirely from standardized, commercially sourced ingredients, for the freshwater speciesSchmidtea mediterranea, Dugesia japonica, andGirardia dorotocephala. These food sources provide an opportunity to test the effects of specific nutritional variables on biological phenomena of interest. Defined diet consumption was not sufficient for growth and only partially induced the increase in stem cell division that normally accompanies feeding, suggesting these responses are not solely determined by caloric intake. While our defined diet formulations do not support long-term planarian maintenance, they do enable delivery of double-stranded RNA for gene knockdown in a manner that provides unique advantages in some experimental contexts. We also present a new approach for preserving tissue integrity during hydrogen peroxide bleaching of liver-fed animals. These tools will empower research on the connections between diet, metabolism, and stem cell biology in the experimentally tractable planarian system.
Genetic Encoding of a Highly Photostable, Long Lifetime Fluorescent Amino Acid for Imaging in Mammalian Cells
Authors: Jones Chloe M. , Robkis D. Miklos , Blizzard Robert J. , Munari Mika , Venkatesh Yarra , Mihaila Tiberiu S. , Eddins Alex J. , Mehl Ryan A. , Zagotta William N. , Gordon Sharona E. , Petersson E. James
Published: April 2021

Acridonylalanine (Acd) is a fluorescent amino acid that is highly photostable, with a high quantum yield and long fluorescence lifetime in water. These properties make it superior to existing genetically encodable fluorescent amino acids for monitoring protein interactions and conformational changes through fluorescence polarization or lifetime experiments, including fluorescence lifetime imaging microscopy (FLIM). Here, we report the genetic incorporation of Acd using engineered pyrrolysine tRNA synthetase (RS) mutants that allow for efficient Acd incorporation in bothE. coliand mammalian cells. We compare protein yields and amino acid specificity for these Acd RSs to identify an optimal construct. We also demonstrate the use of Acd in FLIM, where its long lifetime provides strong contrast compared to endogenous fluorophores and engineered fluorescent proteins, which have lifetimes less than 5 ns.
Exploration of synergistic action of cell wall-degrading enzymes againstMycobacterium tuberculosis
Authors: van Schie Loes , Borgers Katlyn , Michielsen Gitte , Plets Evelyn , Vuylsteke Marnik , Tiels Petra , Festjens Nele , Callewaert Nico
Published: April 2021

Synopsis

Background

The major global health threat tuberculosis is caused byMycobacterium tuberculosis(Mtb). Mtb has a complex cell envelope – a partially covalently linked composite of polysaccharides, peptidoglycan and lipids, including a mycolic acid layer – which conveys pathogenicity but also protects against antibiotics. Given previous successes in treating gram-positive and -negative infections with cell wall degrading enzymes, we investigated such approach for Mtb.

Objectives

(i) Development of an Mtb microtiter growth inhibition assay that allows undisturbed cell envelope formation, to overcome the invalidation of results by typical clumped Mtb-growth in surfactant-free assays. (ii) Exploring anti-Mtb potency of cell wall layer-degrading enzymes. (iii) Investigation of the concerted action of several such enzymes.

Methods

We inserted a bacterial luciferase-operon in an auxotrophic Mtb strain to develop a microtiter assay that allows proper evaluation of cell wall degrading anti-Mtb enzymes. We assessed growth-inhibition by enzymes (recombinant mycobacteriophage mycolic acid esterase (LysB), fungal α-amylase and human and chicken egg white lysozymes) and combinations thereof, in presence or absence of biopharmaceutically acceptable surfactant.

Results

Our biosafety level-2 assay identified both LysB and lysozymes as potent Mtb-inhibitors, but only in presence of surfactant. Moreover, most potent disruption of the mycolic acid hydrophobic barrier was obtained by the highly synergistic combination of LysB, α-amylase and polysorbate 80.

Conclusions

Synergistically acting cell wall degrading enzymes are potently inhibiting Mtb – which sets the scene for the design of specifically tailored antimycobacterial (fusion) enzymes. Airway delivery of protein therapeutics has already been established and should be studied in animal models for active TB.
COVID-19 Time-varying Reproduction Numbers Worldwide: An Empirical Analysis of Mandatory and Voluntary Social Distancing
Authors: Chudik Alexander , Pesaran M. Hashem , Rebucci Alessandro
Published: April 2021

This paper estimates time-varying COVID-19 reproduction numbers worldwide solely based on the number of reported infected cases, allowing for under-reporting. Estimation is based on a moment condition that can be derived from an agent-based stochastic network model of COVID-19 transmission. The outcomes in terms of the reproduction number and the trajectory of per-capita cases through the end of 2020 are very diverse. The reproduction number depends on the transmission rate and the proportion of susceptible population, or the herd immunity effect. Changes in the transmission rate depend on changes in the behavior of the virus, re-flecting mutations and vaccinations, and changes in people’s behavior, reflecting voluntary or government mandated isolation. Over our sample period, neither mutation nor vaccination are major factors, so one can attribute variation in the transmission rate to variations in behavior. Evidence based on panel data models explaining transmission rates for nine European countries indicates that the diversity of outcomes resulted from the non-linear interaction of mandatory containment measures, voluntary precautionary isolation, and the economic incentives that gov-ernments provided to support isolation. These effects are precisely estimated and robust to various assumptions. As a result, countries with seemingly different social distancing policies achieved quite similar outcomes in terms of the reproduction number. These results imply that ignoring the voluntary component of social distancing could introduce an upward bias in the estimates of the effects of lock-downs and support policies on the transmission rates.

JEL Classification

D0, F6, C4, I120, E7
Advancing quality-control for NGS measurement of actionable mutations in circulating tumor DNA
Authors: Willey James C. , Morrison Tom , Austermiller Brad , Crawford Erin L. , Craig Daniel J. , Blomquist Thomas M. , Jones Wendell D. , Wali Aminah , Lococo Jennifer S. , Haseley Nathan , Richmond Todd A. , Novoradovskaya Natalia , Kusko Rebecca , Chen Guangchun , Li Quan-Zhen , Johann Don , Deveson Ira W. , Mercer Tim , Wu Leihong , Xu Joshua
Published: April 2021

The primary objective of the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) project is to develop standard analysis protocols and quality control metrics for use in DNA testing to enhance scientific research and precision medicine. This study reports a targeted next generation sequencing (NGS) method that enables more accurate detection of actionable mutations in circulating tumor DNA (ctDNA) clinical specimens. This advancement was enabled by designing a synthetic internal standard spike-in for each actionable mutation target, suitable for use in NGS following hybrid-capture enrichment and unique molecular index (UMI) or non-UMI library preparation. When mixed with contrived ctDNA reference samples, internal standards enabled calculation of technical error rate, limit of blank, and limit of detection for each variant at each nucleotide position, in each sample. True positive mutations with variant allele fraction too low for detection by current practice were detected with this method, thereby increasing sensitivity.