bluuebunny/crossref_metadata_2025 huggingface dataset:
Returning to nursing during the COVID-19 pandemic: experiences and needs of re-entering nurses
Authors: Noorland Sofie A. , Hoekstra Trynke , Kok Maarten O.
Published: February 2021

Aim

Assessing the needs and experiences of re-entering nurses during the COVID-19 pandemic.

Background

During the COVID-19 outbreak in the Netherlands, thousands of former nurses have returned to nursing to support healthcare staff. After a period of absence and with little time to prepare, these former nurses re-entered during a challenging, uncertain and rapidly evolving pandemic. Little is known about the experiences and needs of these re-entering nurses.

Design

Qualitative study

Methods

We conducted semi-structured interviews with 20 purposively selected nurses who had re-entered nursing during the first wave of the COVID-19 pandemic in the Netherlands. Interviews were transcribed verbatim and analysed via thematic content analysis. This study followed the COREQ guidelines.

Results

Participants mentioned that a lack of a clear job description led to unclarity about the kind of tasks that re-entering nurses were expected and allowed to perform. This unclarity was especially notable in the newly established COVID-19 departments. Re-entering nurses mentioned to wish for an easily accessible mentorship structure and an individualised and practical training program. Re-entering nurses felt supported by a positive team dynamic, which was shaped by the sense of urgency and relevance of their work and helped them deal with stressful experiences.

Conclusion

The results indicate that a rapid and safe return to nursing during a pandemic could be facilitated by: a clear description of roles and responsibilities; an individualised assessment determining the competences and knowledge disparities of re-entering nurses; practical training focussing on competencies needed during a pandemic; and a collaborative mentorship structure to guide re-entering nurses.

Relevance to clinical practice

The rapid recruitment of former nurses to mitigate an acute shortage of qualified nurses could play a vital role during a pandemic. To deploy these nurses effectively, safely and sustainably, it is important to address the needs of these re-entering nurses.

What does this paper contribute towards the wider global clinical community?

This research showed the need to prepare a flexible individualised training programme which could support re-entering nurses during crisis situations, such as a pandemic.

A responsive mentorship structure helps to provide support to re-entering nurses in a dynamic, uncertain and rapidly evolving situation.

In a rapidly evolving situation, it is essential to continue to create clarity about the roles and responsibilities of re-entering nurses.
Mandatory public health measures for COVID-19 are associated with improved mortality, equity and economic outcomes
Authors: Lundberg Brita E. , McDonald Kathyrn
Published: February 2021

We review approaches to the COVID-19 pandemic in a systematic way by comparing countries/states representative of the mandatory vs. voluntary approach to non-pharmaceutical interventions in Europe and the US. We use a comparative tabular format to examine differences in mortality, economic impact and equity between regions with mandatory versus voluntary policies. Mandatory shelter-in-place policies were associated with 3 to 4 fold lower population adjusted mortality in the US model and 11 fold lower in the European one. We conclude that voluntary policies are less effective, based on historical precedent and the current analysis. Moreover, effects on health equity mirrored the increased mortality outcomes of voluntary policies and there was no apparent economic benefit associated with voluntary measures.
The association of CREBRF variant rs373863828 with body composition in adult Samoans
Authors: Hawley Nicola L. , Duckham Rachel L. , Carlson Jenna C. , Naseri Take , Reupena Muagututia Sefuiva , Lameko Viali , Pomer Alysa , Wetzel Abigail , Selu Melania , Lupematisila Vaimoana , Unasa Folla , Vesi Lupesina , Fatu Tracy , Unasa Seipepa , Faasalele-Savusa Kima , Viali Satupaitea , Rivara Anna C. , Russell Emily M. , Deka Ranjan , Kershaw Erin E. , Minster Ryan L. , Weeks Daniel E. , McGarvey Stephen T.
Published: February 2021

Objective

The minor allele of rs373863828, a missense variant in CREBRF, is associated with higher BMI but lower odds of type 2 diabetes in Pacific Islanders.

Methods

To test if this protective effect operates through metabolically favorable body fat distribution, we examined the association of the minor A allele with body composition, measured using dual-energy x-ray absorptiometry (DXA), in a cross-sectional study of n=421 Samoan adults.

Results

We replicated our earlier finding that this allele was associated with higher weight and BMI, although it was statistically significant only in women. There was no significant association of genotype with percent body fat, visceral adiposity or fat distribution, although in women, the A allele was associated with greater total fat mass (p=0.02), android (p=0.009) and trunk fat (p=0.01). In both sexes, age- and height-adjusted average lean mass was significantly greater per copy of the A allele: 2.16 kg/copy in women and 1.73 kg/copy in men.

Conclusions

These data do not support a primary role of fat distribution in mediating the association between rs373863828 genotype and type 2 diabetes risk. We suggest an alternative hypothesis: those with the A allele may more efficiently regulate blood glucose because of their greater absolute lean mass.
Noncommunicable Diseases, Sociodemographic Vulnerability, and the Risk of Mortality in Hospitalized Children and Adolescents with COVID-19 in Brazil: A Syndemic in Play
Authors: Sousa Braian Lucas Aguiar , Maria Brentani Alexandra Valeria , Ribeiro Cecilia Claudia Costa , Dolhnikoff Marisa , Ellero Grisi Sandra Josefina Ferraz , Ferrer Ana Paula Scoleze , Ferraro Alexandre Archanjo
Published: February 2021

Background

Although many studies identify the presence of comorbidities and socioeconomic vulnerabilities as risk factors for worse COVID-19 outcomes, few have addressed this issue in children. We aimed to study how these factors have impacted COVID-19 mortality in Brazilian children and adolescents.

Methods

This is an observational study using publicly available data from the Brazilian Ministry of Health. We studied 5,857 patients younger than 20 years old, all of them hospitalized with laboratory-confirmed COVID-19. We used multilevel mixed-effects generalized linear models to study mortality, stratifying the analysis by age, region of the country, presence of noncommunicable diseases, ethnicity, and socioeconomic development.

Findings

Individually, most of the comorbidities included were risk factors. Having more than one comorbidity increased almost tenfold the risk of death (OR 9·67 95%CI 6·89-13·57). Compared to White children, Indigenous, Pardo (mixed), and East Asian had a significantly higher risk of mortality. We also found a regional effect (higher mortality in the North), and a socioeconomic effect (higher mortality among children from less socioeconomically developed municipalities).

Interpretation

Besides the impact of comorbidities, we identified ethnic, regional, and socioeconomic effects shaping the mortality of children hospitalized with COVID-19 in Brazil. Putting these findings together, we propose that there is a syndemic among COVID-19 and noncommunicable diseases, driven and fostered by large-scale sociodemographic inequalities. Facing COVID-19 in Brazil must also include addressing these structural issues. Our findings also identify risk groups among children that should be prioritized for public health measures, such as vaccination.

Funding

None.
Development of a new Aerosol Barrier Mask for mitigation of spread of SARS-CoV-2 and other infectious pathogens
Authors: Karam Karam Abi , Hota Piyush , Mora S. Jimena , Lowell Amelia , McKay Kelly , Xian Xiaojun , Patel Bhavesh , Forzani Erica
Published: February 2021

The COVID-19 pandemic has caused huge impact on public health and significantly changed our lifestyle. This is due to the fast airborne oro-nasal transmission of SARS-CoV-2 from the infected individuals. The generation of liquid aerosolized particles occurs when the COVID-19 patients speak, sing, cough, sneeze, or simply breathe. We have developed a novel aerosol barrier mask (ABM) to mitigate the spread of SARS-CoV-2 and other infectious pathogens. This Aerosol Barrier Mask is designed for preventing SARS-CoV-2 transmission while transporting patients within hospital facilities. This mask can constrain aerosol and droplet particles and trap them in a biofilter, while the patient is normally breathing and administrated with medical oxygen. The system can be characterized as an oxygen delivery and mitigation mask which has no unfiltered exhaled air dispersion. The mask helps to prevent the spread of SARS-CoV-2, and potentially other infectious respiratory pathogens and protects everyone in general, especially healthcare professionals.
Clinician Readiness to Adopt A.I. for Critical Care Prioritisation
Authors: Kennedy Georgina , Gallego Blanca
Published: February 2021

There is a wide chasm between what has been shown to be feasible in the application of artificial intelligence to data from the electronic medical record, and what is currently available. The reasons for this are complex and understudied, and vary across technical, ethical and sociocultural domains. This work addresses the gap in the literature for studies that determine the readiness of clinical end-users to adopt such tools and the way in which they are perceived to affect clinical practice itself.

In this study, we present a novel, credible AI system for predicting in-patient deterioration to likely end users. We gauge their readiness to adopt this technology using a modified version of the technology adoption model.

Users are found to be moderately positive towards the potential introduction of this technology in their workflow, although they demonstrate particular concern for the appropriateness of the clinical setting into which it is deployed.
Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning
Authors: Makielski Kelly M. , Donnelly Alicia J. , Khammanivong Ali , Scott Milcah C. , Ortiz Andrea R. , Galvan Dana C. , Tomiyasu Hirotaka , Amaya Clarissa , Ward Kristi , Montoya Alexa , Garbe John R. , Mills Lauren J. , Cutter Gary R. , Fenger Joelle M. , Kisseberth William C. , O’Brien Timothy D. , Weigel Brenda J. , Spector Logan G. , Bryan Brad A. , Subramanian Subbaya , Modiano Jaime F.
Published: February 2021

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal mRNAs. The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by qRT-PCR, while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups (“healthy”, “osteosarcoma”, “other bone tumor”, or “non-neoplastic disease”). Pre-treatment samples from osteosarcoma cases were used as the training set and a validation set from post-treatment samples was used for testing, classifying as “osteosarcoma–detected” or “osteosarcoma–NOT detected”. Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma–NOT detected” had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof-of-concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.

Abstract Figure
A robust method of nuclei isolation for single-cell RNA sequencing of solid tissues from the plant genusPopulus
Authors: Conde Daniel , Triozzi Paolo M. , Balmant Kelly M. , Doty Andria L. , Miranda Mariza , Boullosa Anthony , Schmidt Henry W. , Pereira Wendell J. , Dervinis Christopher , Kirst Matias
Published: February 2021

Single-cell transcriptome analysis has been extensively applied in humans and animal models to uncover gene expression heterogeneity between the different cell types of a tissue or an organ. It demonstrated its capability to discover the key regulatory elements that determine cell fate during developmental programs such as brain or heart development. Single-cell analysis requires the isolation and labeling of the messenger RNA (mRNA) derived from each cell. These challenges were primarily addressed in mammals by developing microfluidic-based approaches. For plant species whose cells contain cell walls, these approaches have generally required the generation of isolated protoplasts. Many plant tissues’ secondary cell wall hinders enzymatic digestion required for individual protoplast isolation, resulting in an unequal representation of cell types in a protoplast population. This limitation is especially critical for cell types located in the inner layers of a tissue or the inner tissues of an organ. Consequently, single-cell RNA sequencing (scRNA-seq) studies using microfluidic approaches in plants have mainly been restricted toArabidopsisroots, for which well-established procedures of protoplast isolation are available. Here we present a simple alternative approach to generating high-quality protoplasts from plant tissue by characterizing the mRNA extracted from individual nuclei instead of whole cells. We developed the protocol using two different plant materials with varying cellular complexity levels and cell-wall structure,Populusshoot apices, and more lignified stems. Using the 10× Genomics Chromium technology, we show that this procedure results in intact mRNA isolation and limited leakage, with a broad representation of individual cell transcriptomes.
CTP regulates membrane-binding activity of the nucleoid occlusion protein Noc
Authors: Jalal Adam S. B. , Tran Ngat T. , Wu Ling J. , Ramakrishnan Karunakaran , Rejzek Martin , Gobbato Giulia , Stevenson Clare E. M. , Lawson David M. , Errington Jeff , Le Tung B. K.
Published: February 2021

ATP and GTP-dependent molecular switches are extensively used to control functions of proteins in a wide range of biological processes. However, CTP switches are rarely reported. Here, we report that a nucleoid occlusion protein Noc is a CTPase enzyme whose membrane-binding activity is directly regulated by a CTP switch. InBacillus subtilis, Noc nucleates on 16-bpNBSsites before associating with neighboring non-specific DNA to form large membrane-associated nucleoprotein complexes to physically occlude assembly of the cell division machinery. Byin vitroreconstitution, we show that (i) CTP is required for Noc to form theNBS-dependent nucleoprotein complex, and (ii) CTP binding, but not hydrolysis, switches Noc to a membrane-active state. Overall, we suggest that CTP couples membrane-binding activity of Noc to nucleoprotein complex formation to ensure productive recruitment of DNA to the bacterial cell membrane for nucleoid occlusion activity.
Evidence for Multiple Teosinte Hybrid Zones in Central Mexico
Authors: Hufnagel David E. , Kananen Kathryn , Glaubitz Jeffrey C. , de Jesuś Sánchez-González José , Doebley John F. , Hufford Matthew B.
Published: February 2021

1

Hybrid zones provide an excellent opportunity for studying population dynamics and whether hybrid genetic architectures are locally adaptive. The genus Zea contains many diverse wild taxa collectively called teosinte.Zea maysssp.parviglumis, the lowland progenitor of maize (Zea maysssp.mays), and its highland relativeZea maysssp.mexicanalive parapatrically and, while putative hybrids have been identified in regions of range overlap, these have never been deeply explored.

Here we use a broadly sampled SNP data set to identify and confirm 112 hybrids betweenZea maysssp.parviglumisandZea maysssp.mexicana, mostly clustered in three genetically and geographically distinct hybrid groups in Central Mexico.

These hybrid groups inhabit intermediate environments relative to parental taxa. We demonstrate that these individuals are true hybrids and not products of isolation by distance or ancestral to parviglumis and mexicana. This work expands on previous studies, clearly identifying hybrid zones inZea, genetically characterizing hybrid groups, and showing what appear to be unique genetic architectures of hybridization in distinct hybrid groups.

With the potential for local adaptation, variable hybrid zone dynamics, and differential architectures of hybridization, we present these teosinte hybrids and parental taxa as a promising model system for studying hybridization and hybrid zones.
Destabilization of the holo-DNA Polδ by loss of Pol32 confers conditional lethality that can be suppressed by stabilizing Pol31-Pol3 interaction
Authors: Shimada Kenji , Tsai-Pflugfelder Monika , Motlagh Niloofar Davoodi Vijeh , Delgoshaie Neda , Fuchs Jeannette , Gasser Susan M.
Published: February 2021

DNA Polymerase δ plays an essential role in genome replication and in the preservation of genome integrity. InS. cerevisiae, Polδ consists of three subunits: Pol3 (the catalytic subunit), Pol31 and Pol32. We have constructedpol31mutants by alanine substitution at conserved amino acids, and identified three alleles that do not confer any disadvantage on their own, but which suppress the cold-, HU- and MMS-hypersensitivity of yeast strains lacking Pol32. We have shown that Pol31 and Pol32 are both involved in translesion synthesis, error-free bypass synthesis, and in preservation of replication fork stability under conditions of HU arrest. We identified a solvent exposed loop in Pol31 defined by two alanine substitutions at T415 and W417. Whereas pol31-T4l5A compromises polymerase stability at stalled forks,pol31-W417A is able to suppress many, but not all, of the phenotypes arising frompol32Δ. ChIP analyses showed that the absence of Pol32 destabilizes Pole and Polα at stalled replication forks, but does not interfere with checkpoint kinase activation. We show that the Pol31-W417A-mediated suppression of replicationstress sensitivity inpol32Δ stems from enhanced interaction between Pol3 and Pol31, which stabilizes a functional Polδ.
Crystal structure of a bacterial CNNM magnesium transporter
Authors: Chen Yu Seby , Kozlov Guennadi , Armitano Joshua , Moeller Brandon E. , Fakih Rayan , Rohaim Ahmed , Roux Benoit , Burke John E. , Gehring Kalle
Published: February 2021

CBS-pair domain divalent metal cation transport mediators (CNNMs) are a broadly conserved family of integral membrane proteins with close to 90,000 protein sequences known. CNNM proteins are associated with Mg2+transport but it is not known if they mediate transport themselves or regulate other transporters. Here, we determined the crystal structure of an archaeal CNNM protein with Mg2+-ATP bound. The structure reveals a novel transmembrane fold for the DUF21 domain, the largest family of domains of unknown function. The protein has a negatively charged cavity that penetrates halfway through the membrane suggesting it functions as a cation transporter. The cytosolic portion of the protein is comprised of highly charged four-helix bundle and a CBS-pair domain. HDX-MS experiments, molecular dynamics, and additional crystal structures show that the cytosolic domains undergo large conformational changes upon nucleotide binding suggesting a mechanism of regulation shared between human and bacterial orthologs. The molecular characterization of CNNM proteins has profound implications for understanding their biological functions in human diseases, including cancer, and in animals, bacteria and plants.
Polygenic prediction of type 2 diabetes in continental Africa
Authors: Chikowore Tinashe , Ekoru Kenneth , Vujkovic Marijana , Gill Dipender , Pirie Fraser , Young Elizabeth , Sandhu Manjinder S , McCarthy Mark , Rotimi Charles , Adeyemo Adebowale , Motala Ayesha , Fatumo Segun
Published: February 2021

Objective

Polygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans.

Research Design and Methods

Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls).

Results

The African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10thdecile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile.

Conclusions

African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.
The same ultra-rapid parallel brain dynamics underpin the production and perception of speech
Authors: Fairs Amie , Michelas Amandine , Dufour Sophie , Strijkers Kristof
Published: February 2021

The temporal dynamics by which linguistic information becomes available is one of the key properties to understand how language is organised in the brain. An unresolved debate between different brain language models is whether words, the building blocks of language, are activated in a sequential or parallel manner. In this study we approached this issue from a novel perspective by directly comparing the time course of word component activation in speech production versus perception. In an overt object naming task and a passive listening task we analysed with mixed linear models at the single-trial level the event-related brain potentials elicited by the same lexico-semantic and phonological word knowledge in the two language modalities. Results revealed that both word components manifested simultaneously as early as 75 ms after stimulus onset in production and perception; differences between the language modalities only became apparent after 300 ms of processing. The data provide evidence for ultra-rapid parallel dynamics of language processing and are interpreted within a neural assembly framework where words recruit the same integrated cell assemblies across production and perception. These word assemblies ignite early on in parallel and only later on reverberate in a behaviour-specific manner.
Longitudinal analysis of the faecal microbiome in pigs fedCyberlindnera jadiniiyeast as a protein source during the weanling period followed by a rapeseed- and faba bean-based grower-finisher diet
Authors: Iakhno S. , Delogu F. , Umu Ö.C.O. , Kjos N.P. , Håkenåsen I.M. , Mydland L.T. , Øverland M. , Sørum H.
Published: February 2021

The porcine gut microbiome is closely connected to diet and is central to animal health and growth. The gut microbiota composition in relation toCyberlindnera jadiniiyeast as a protein source in a weanling diet was studied previously. Also, there is a mounting body of knowledge regarding the porcine gut microbiome composition in response to the use of rapeseed (Brassica napussubsp.napus) meal, and faba beans (Vicia faba) as protein sources during the growing/finishing period. However, there is limited data on how the porcine gut microbiome respond to a combination ofC. jadiniiyeast in the weanling phase and rapeseed meal and faba beans in the growing/finishing phase. This work investigated how the porcine faecal microbiome was changing in response to a novel yeast diet with a high inclusion of yeast proteins (40% of crude protein) in a weanling diet followed by a diet based on rapeseed meal and faba beans during the growing/finishing period. The feacal microbiomes of the weanling pigs fed yeast were more diverse with higher relative abundance ofFirmicutesoverBacteroidetescompared with those of soybean meal-based diet fed weanlings. Reduced numbers ofPrevotellain the yeast fed faecal microbiomes remained a microbiome characteristic up until two weeks after the yeast diet was changed to the rapeseed/faba bean growing finishing diet. A number of differentially abundant bacterial phylotypes along with distinct co-occurrence patterns observed during the growing/finishing period indicated the presence of a “carry-over” effect of the yeast weanling diet onto the faecal microbiomes of the grower/finisher pigs.
gbpAandchiAgenes are not uniformly distributed amongst diverseVibrio cholerae
Authors: Fennell Thea G. , Blackwell Grace A. , Thomson Nicholas R. , Dorman Matthew J.
Published: February 2021

Members of the bacterial genusVibrioutilise chitin both as a metabolic substrate and a signal to activate natural competence.Vibrio choleraeis a bacterial enteric pathogen, sub-lineages of which can cause pandemic cholera. However, the chitin metabolic pathway inV. choleraehas been dissected using only a limited number of laboratory strains of this species. Here, we survey the complement of key chitin metabolism genes amongst 195 diverseV. cholerae.We show that the gene encoding GbpA, known to be an important colonisation and virulence factor in pandemic isolates, is not ubiquitous amongstV. cholerae.We also identify a putatively novel chitinase, and present experimental evidence in support of its functionality. Our data indicate that the chitin metabolic pathway within theV. choleraespecies is more complex than previously thought, and emphasise the importance of considering genes and functions in the context of a species in its entirety, rather than simply relying on traditional reference strains.

Impact statement

It is thought that the ability to metabolise chitin is ubiquitous amongstVibriospp., and that this enables these species to survive in aqueous and estuarine environmental contexts. Although chitin metabolism pathways have been detailed in several members of this genus, little is known about how these processes vary within a singleVibriospecies. Here, we present the distribution of genes encoding key chitinase and chitin-binding proteins across diverseVibrio cholerae, and show that our canonical understanding of this pathway in this species is challenged when isolates from non-pandemicV. choleraelineages are considered alongside those linked to pandemics. Furthermore, we show that genes previously thought to be species core genes are not in fact ubiquitous, and we identify novel components of the chitin metabolic cascade in this species, and present functional validation for these observations.

Data summary

The authors confirm that all supporting data, code, and protocols have been provided within the article or through supplementary data files.

No whole-genome sequencing data were generated in this study. Accession numbers for the publicly-available sequences used for these analyses are listed in Supplementary Table 1, Table 2, and the Methods.

All other data which underpin the figures in this manuscript, including pangenome data matrices, modified and unmodified sequence alignments and phylogenetic trees, original images of gels and immunoblots, raw fluorescence data, amplicon sequencing reads, and the R code used to generate Figure 7, are available in Figshare:https://dx.doi.org/10.6084/m9.figshare.13169189

(Note for peer-review: Figshare DOI is inactive but will be activated upon publication, please use temporary URLhttps://figshare.com/s/7795a2d80c13f694f8fafor review).
White-box Deep Neural Network Prediction of Genome-Wide Transcriptome Signatures
Authors: Magnusson Rasmus , Tegnér Jesper N. , Gustafsson Mika
Published: February 2021

Prediction algorithms for protein or gene structures, including transcription factor binding from sequence information, have been transformative in understanding gene regulation. Here we ask whether human transcriptomic profiles can be predicted solely from the expression of transcription factors (TFs). To this end, we explore whether a neural network (NN) could predict the transcriptome from TFs. Using at least one hidden layer, we find that the expression of 1,600 TFs can explain >95% of variance in 25,000 genes. Using the light-up technique to inspect the trained NN, we find an overrepresentation of known TF-gene regulations. Furthermore, the learned prediction network has a hierarchical organization. A smaller set of around 125 core TFs could explain close to 80% of the variance. Interestingly, reducing the number of TFs below 500 induces a rapid decline in prediction performance. Next, we evaluated the prediction model using transcriptional data from 22 human diseases. The TFs were sufficient to predict the target genes’ dysregulation (rho=0.61, P < 10−216). By inspecting the model, key causative TFs could be extracted for subsequent validation using disease-associated genetic variants. In conclusion, we demonstrate the construction of an interpretable neural network predictor. Analysis of the predictors revealed key TFs that were inducing transcriptional changes during disease.
Cooperative virulence can emerge via horizontal gene transfer but is stabilized by transmission
Authors: Bakkeren Erik , Gül Ersin , Huisman Jana S. , Steiger Yves , Rocker Andrea , Hardt Wolf-Dietrich , Diard Médéric
Published: February 2021

Intestinal inflammation fuelsSalmonellaTyphimurium (S.Tm) transmission despite a fitness cost associated with the expression of virulence. Cheater mutants can emerge that profit from inflammation without enduring this cost. Intestinal virulence inS.Tm is therefore a cooperative trait, and its evolution a conundrum. Horizontal gene transfer (HGT) of cooperative alleles may facilitate the emergence of cooperative virulence, despite its instability. To test this hypothesis, we clonedhilD, coding for a master regulator of virulence, into a conjugative plasmid that is highly transferrable during intestinal colonization. We demonstrate that virulence can emerge byhilDtransfer between avirulent strainsin vivo. However, this was indeed unstable andhilDmutant cheaters arose within a few days. The timing of cheater emergence depended on the cost. We further show that stabilization of cooperative virulence inS.Tm is dependent on transmission dynamics, strengthened by population bottlenecks, leading cheaters to extinction and allowing cooperators to thrive.
Hyper-connectivity between the left motor cortex and prefrontal cortex is associated with the severity of dysfunction of the descending pain modulatory system in fibromyalgia
Authors: de Oliveira Franco Álvaro , Fernandes Camila , Vicunha Paul , Bandeira Janete , Aratanha Maria Adelia , da Silva Torres Iraci Lucena , Fregni Felipe , Caumo Wolnei
Published: February 2021

The impaired cortical function likely plays a critical role in chronic pain maintenance and fibromyalgia symptoms. Functional connectivity (FC), as assessed by functional near-infrared spectroscopy (fNIRS), is a promising approach that evaluates cortical activation through hemodynamic response estimation. This study compared the FC of bilateral motor and prefrontal cortices between responders and nonresponders to the conditioned pain modulation test (CPM-test) induced by hand immersion in cold water (0–1°C). We included 37 women with fibromyalgia according to the American College of Rheumatology diagnoses criteria (n = 23 responders to CPM-test and n = 14 nonresponders). After the adjustment for multiple comparisons, we found that nonresponders relative to responders showed higher FC between the left motor cortex (LMC) with the left prefrontal cortex (LPFC) and right prefrontal cortex (RPFC). The psychiatric diagnoses were also positively associated with a higher FC in LMC–LPFC and LMC–RPFC. These results indicate that the increased connectivity between the left motor and bilateral prefrontal cortex might be a neural marker of DPMS dysfunction and an intermediate in the interplay between fibromyalgia and psychiatric disorders.
Motor planning under uncertainty
Authors: Alhussein Laith , Smith Maurice A.
Published: February 2021

Actions often require the selection of a specific goal amongst a range of possibilities, like when a softball player must precisely position her glove to field a fast-approaching ground ball. Previous studies have suggested that during goal uncertainty, the brain prepares for all potential goals in parallel and averages the corresponding motor plans to command an intermediate movement that is progressively refined as additional information becomes available. Although intermediate movements are widely observed, they could instead reflect a neural decision about the single best action choice at each point in time given the remaining uncertainty. Here we systematically dissociate these possibilities using novel experimental manipulations, and find that when confronted with uncertainty, humans generate a single motor plan that optimizes task performance, rather than averaging potential motor plans. In addition to accurate predictions of population-averaged changes in motor output, a novel computational model based on this performance-optimization theory accounted for a remarkable 80-90% of the variance for individual differences between participants. Our findings resolve a long-standing question about how the brain selects an action to execute during goal uncertainty, providing fundamental insight into motor planning in the nervous system.
Re-investigation of classic T cell subsets and identification of novel cell subpopulations by single-cell RNA sequencing
Authors: Wang Xuefei , Shen Xiangru , Chen Shan , Liu Hongyi , Hong Ni , Chen Xi , Jin Wenfei
Published: February 2021

Classic T cell subsets are defined by a small set of cell surface markers, while single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets remain unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naïve and CD8 Naïve were mainly clustered into their scCPop counterparts, while cells from the other T cell subsets were assigned to multiple scCPops including mucosal-associated invariant T cells and natural killer T cells. The multiple T cell subsets that form a single scCPop exhibited similar expression pattern, but not vice versa, indicating scCPops are much homogeneous cell populations with similar cell states. Interestingly, we discovered and named IFNhiT, a new T cell subpopulation that highly expressed Interferon Signaling Associated Genes (ISAGs). We further enriched IFNhiT by FACS sorting of BST2 for scRNA-seq analyses. IFNhiT cluster disappeared on tSNE plot after removing ISAGs, while IFNhiT cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhiT cluster. BST2+ T cells and BST2− T cells showing different efficiencies of T cell activation indicates high level of ISAGs may contribute to quick immune responses.
Plasma Aβ ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
Authors: O’Connor Antoinette , Pannee Josef , Poole Teresa , Arber Charles , Portelius Erik , Swift Imogen , Heslegrave Amanda J , Abel Emily , Willumsen Nanet , Rice Helen , Weston Philip SJ , Ryan Natalie S , Polke James M , Nicholas Jennifer M , Frost Chris , Mead Simon , Wray Selina , Chávez-Gutiérrez Lucía , Blennow Kaj , Zetterberg Henrik , Fox Nick C
Published: February 2021

In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(p<0.001) and non-carriers (p<0.001); higher Aβ38:40 inAPPversusPSEN1(p<0.001) and non-carriers (p<0.001), while Aβ42:40 was higher inAPPandPSEN1compared to non-carriers (both p<0.001). Aβ profiles were reasonably consistent in plasma and cell lines. WithinPSEN1, sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO.In-vivodifferences in Aβ processing betweenAPPandPSEN1provide insights into ADAD pathophysiology which can inform therapy development.
siRNA enrichment in Argonaute 2-depletedBlattella germanica
Authors: Montañés José Carlos , Rojano Carlos , Ylla Guillem , Piulachs Maria Dolors , Maestro José Luis
Published: February 2021

Background

RNA interference (RNAi) is a cellular mechanism used to fight various threats, including transposons, aberrant RNA, and some types of viruses. It relies on dsRNA detection and, through a mechanism involving Dicer-2 (Dcr-2) and Argonaute 2 (AGO2), together with a small RNA fragment (siRNA) as a complementary guide, binds to an RNA and cleaves it.

Methods

Using the cockroachBlattella germanicaas a model, we examined AGO2 activity by depleting its mRNA levels using RNAi and analyzing the phenotypes produced.

Results

SilencingAGO2expression had no remarkable effect on nymphal development or reproduction. dsRNA treatment triggered an immediate and transitory increase inAGO2expression, independently of Dcr-2 action. In addition, we analyzed the siRNAs generated after injecting a heterologous dsRNA in control andAGO2-depleted animals. The results revealed that siRNAs were distributed non-uniformly along the dsRNA sequence. InAGO2-depleted animals, the proportion of 22 nucleotide reads was higher and accumulations of reads appeared in areas less well-represented in the controls. We also detected a slight preference for cytosine as the first nucleotide in controls to be lost inAGO2-depleted individuals.

Conclusions/General significance

The siRNAs produced from a dsRNA are heterogeneously distributed along the length of the dsRNA and this arrangement depends on the sequence. AGO2 exerts its role as nuclease on the siRNA duplexes independently of its action on the homologous mRNA. This study sheds light on an extremely useful process for reverse genetics in laboratories, in addition to the design of more effective, specific, and eco-friendly pest-control strategies.

Highlights

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RNA interference is used to fight cellular threats including transposons and viruses

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Silencing AGO2 inBlattella germanicadoes not affect development or reproduction

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siRNA distribution along the dsRNA sequence is non-uniform and sequence dependent

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AGO2 depletion increased the proportion of 22 nt reads in certain areas
Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics
Authors: Ma Peijun , He Lorrie L. , Pironti Alejandro , Laibinis Hannah H. , Ernst Christoph M. , Manson Abigail L. , Bhattacharyya Roby P. , Earl Ashlee M. , Livny Jonathan , Hung Deborah T.
Published: February 2021

In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of “last resort,” inKlebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as it is a determinant of a strain’s propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance inK. pneumoniaewith important implications for diagnosing and treating this important class of pathogens.
Dlc1controls cardio-vascular development downstream of Vegfa/Kdrl/Nrp1 signaling in the zebrafish embryo
Authors: Linnerz Tanja , Bertrand Julien Y.
Published: February 2021

The family ofdeleted-in-liver-cancer (dlc)genes encodes RhoGTPases and plays pivotal roles in cardiovascular development, but animal models for studying their functions are sparse due to early embryonic lethality. Gain and loss of function ofdlc1anddlc3severely altered the growth of intersegmental vessels in the trunk of zebrafish embryos. Additionally, overexpression ofdlc1affected the growth of the common cardinal veins, but could rescue the arrest of angiogenesis induced by Vegfr2 inhibition, placingdlc1downstream ofkdrlsignaling. Loss ofdlc1negatively affected the lumenization of the first aortic arch arteries and the lateral dorsal aortae.dlc1mutants displayed a full obstruction in the early outflow tract during cardiac morphogenesis, which models to alterations in DLC1 detected in congenital heart defects in human patients. This study provides a functionalin vivocharacterization ofdlc1anddlc3during vertebrate embryogenesis and placesdlc1as a key gene to control vascular development.
Dorsal striatal dopamine induces fronto-cortical hypoactivity and implies reduced anxiety and compulsive behaviors in rats
Authors: Casado-Sainz Agata , Gudmundsen Frederik , Baerentzen Simone L. , Lange Denise , Ringsted Annemette , Martinez-Tajada Isabel , Medina Siria , Lee Hedok , Svarer Claus , Keller Sune H. , Schain Martin , Kjaerby Celia , Fisher Patrick M. , Cumming Paul , Palner Mikael
Published: February 2021

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervating the rat dorsal striatum. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement, as expected from dopamine release, rearings and time spend in center, while it also lowered self-grooming and increased prepulse inhibition in females. Remarkably, we observed reduced [18F]FDG metabolism in frontal cortex, following dopamine activation in the dorsal striatum, yet total glutamate levels-in this region were increased. A finding which may help explain the contradiction in some clinical studies of increased [18F]FDG metabolism and lower glutamate levels in diseases like OCD. Taken together, these results establish the importance of nigro-striatal dopamine transmission for modulating CSTC function, especially with respect to fronto-cortical activity, glutamate levels and behaviors related anxiety and compulsive actions.

One Sentence Summary

Dorsal striatum dopamine induce fronto-cortical hypoactivity and reduce compulsive behaviors in rats
Cytidine triphosphate promotes efficient ParB-dependent DNA condensation by facilitating one-dimensional spreading fromparS
Authors: de Asis Balaguer Francisco , Aicart-Ramos Clara , Fisher Gemma LM , de Bragança Sara , Pastrana Cesar L. , Dillingham Mark S. , Moreno-Herrero Fernando
Published: February 2021

Faithful segregation of bacterial chromosomes relies on the ParABS partitioning system and the SMC complex. In this work, we used single molecule techniques to investigate the role of cytidine triphosphate (CTP) binding and hydrolysis in the critical interaction between centromere-likeparSDNA sequences and the ParB CTPase. Using a combined dual optical tweezers confocal microscope, we observe the specific interaction of ParB withparSdirectly. Binding aroundparSis enhanced 4-fold by the presence of CTP or the non-hydrolysable analogue CTPγS. However, ParB proteins are also detected at a lower density in distal non-specific regions of DNA. This requires the presence of aparSloading site and is prevented by roadblocks on DNA, consistent with one dimensional diffusion by a sliding clamp. Magnetic tweezers experiments show that the spreading activity, which has an absolute requirement for CTP binding but not hydrolysis, results in the condensation ofparS-containing DNA molecules at low nanomolar protein concentrations. We propose a model in which ParB-CTP-Mg2+complexes move along DNA following loading atparSsites and protein:protein interactions result in the localised condensation of DNA within ParB networks.