bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of cross progeny variance genomic prediction using simulations and experimental data in winter elite bread wheat
Authors: Oget-Ebrad Claire , Heumez Emmanuel , Duchalais Laure , Goudemand-Dugué Ellen , Oury François-Xavier , Elsen Jean-Michel , Bouchet Sophie
Published: September 2023

The utilization of genomic prediction is increasing in crop breeding to parental selection and mating. The Usefulness Criterion (UC) that considers Parental Mean (PM), progeny Standard Deviation (SD) and selection intensity has been shown to increase the likelihood to get outstanding progenies compared to mating using PM alone while maintaining more diversity in the germplasm for next generations.

This study estimates our ability to predict UC and its two components (PM and SD) using simulations and experimental data (73-101 winter bread wheat crosses depending on the trait, with 54.8 progenies on average) including heading date, plant height, grain protein content and yield evaluation. The training population comprises 2,146 French varieties registered during the last 20 years and INRAE-AO breeding lines.

According to simulations, prediction ability increases with heritability and progeny size and decreases with QTL number, most notably for SD. We used as a reference a TRUE scenario,i.e. an optimal situation where TP is infinite and where marker effects are perfectly estimated. SD was strongly impacted by the quality of marker effect estimates. In simulations, considering the error in marker effect estimates improved SD predictions for quantitative traits with low heritability. In experimental data, the interest of this method was limited.

PM and UC were reasonably predicted for all traits, while SD was more challenging. This pioneering study experimentally validates genomic prediction of progeny variance. The ability of prediction depends on trait architecture while the realization of cross potential in the field necessitates a sufficient number of progenies.

Key message

From simulations and experimental data, the quality of cross progeny variance genomic predictions may be high, but depends on trait architecture and necessitates sufficient number of progenies.
Individuals learning to drive solo before age 18 have superior spatial navigation ability compared with those who learn later
Authors: Yavuz Emre , Manley Ed , Gahnstrom Christoffer J. , Goodroe Sarah , Coutrot Antoine , Hornberger Michael , Spiers Hugo
Published: September 2023

A challenge associated with driving vehicles can be navigating to the destination. While driving experience would seem beneficial for improving navigation skill, it remains unclear how driving experience relates to wayfinding ability. Using the mobile video game-based wayfinding task Sea Hero Quest, which is predictive of real-world navigation, we measured wayfinding ability in US-based participants (n = 694, 291 men, 403 women, mean age = 26.8 years, range = 18-52 years). We also asked travel-related self-report questions, including the age one started learning to drive, the age one started driving solo and weekly driving hours. A multivariate linear regression model found that those who started driving solo below aged 18 had significantly better wayfinding ability than those starting to drive solo aged 18 and above. Other driving-related self-report measures were not associated with wayfinding ability. Future studies should determine the directionality of the association between driving experience and wayfinding ability.
Full-Length Single-Molecule Protein Fingerprinting
Authors: Filius Mike , van Wee Raman , de Lannoy Carlos , Westerlaken Ilja , Li Zeshi , Kim Sung Hyun , de Agrela Pinto Cecilia , Wu Yunfei , Boons Geert-Jan , Pabst Martin , de Ridder Dick , Joo Chirlmin
Published: September 2023

Proteins are the primary functional actors of the cell. Hence, their identification is pivotal to advance our understanding of cell biology and disease. Current protein analysis methods are of limited use for distinguishing proteoforms. In particular, mass spectrometric methods often provide only ambiguous information on post-translational modification sites, and sequences of co-existing modifications may not be resolved. Here we demonstrate FRET-based single-molecule protein fingerprinting to map the location of individual amino acids and a post-translational modification within single full-length protein molecules. Using an approach that relies on transient binding of fluorescently labeled DNA strands to probe the amino acids on a protein one by one we show that we can fingerprint intrinsically disordered proteins as well as folded globular proteins with sub-nanometer resolution. We anticipate that this technology will be used for proteoform identification in biological and translational research with ultimate sensitivity.
Reduced discrimination between signals of danger and safety but not overgeneralization is linked to exposure to childhood adversity in healthy adults
Authors: Klingelhöfer-Jens Maren , Hutterer Katharina , Schiele Miriam A. , Leehr Elisabeth J. , Schümann Dirk , Rosenkranz Karoline , Böhnlein Joscha , Repple Jonathan , Deckert Jürgen , Domschke Katharina , Dannlowski Udo , Lueken Ulrike , Reif Andreas , Romanos Marcel , Zwanzger Peter , Pauli Paul , Gamer Matthias , Lonsdorf Tina B.
Published: September 2023

Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of ‘exposure’. Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and cognitive processes and ultimately behavior. 1402 healthy participants underwent a fear conditioning paradigm (acquisition training, generalization), while acquiring skin conductance responses (SCRs) and ratings (arousal, valence, and contingency). Childhood adversity was operationalized as (1) dichotomization, and following (2) the specificity model, (3) the cumulative risk model, and (4) the dimensional model. Individuals exposed to childhood adversity showed blunted physiological reactivity in SCRs, but not ratings, and reduced CS+/CS-discrimination during both phases, mainly driven by attenuated CS + responding. The latter was evident across different operationalizations of ‘exposure’ following the different theories. None of the theories tested showed clear explanatory superiority. Notably, a remarkably different pattern of increased responding to the CS-is reported in the literature for anxiety patients, suggesting that individuals exposed to childhood adversity may represent a specific sub-sample. We highlight that theories linking childhood adversity to (vulnerability to) psychopathology need refinement.
The wheat powdery mildew resistance genePm4also confers resistance to wheat blast
Authors: O’Hara Tom , Steed Andrew , Goddard Rachel , Gaurav Kumar , Arora Sanu , Quiroz-Chávez Jesús , Ramírez-González Ricardo , Badgami Roshani , Gilbert David , Sánchez-Martín Javier , Wingen Luzie , Feng Cong , Jiang Mei , Cheng Shifeng , Dreisigacker Susanne , Keller Beat , Wulff Brande B.H. , Uauy Cristóbal , Nicholson Paul
Published: September 2023

Wheat blast, caused by the fungusMagnaporthe oryzae, threatens global cereal production since its emergence in Brazil in 1985 and recently spread to Bangladesh and Zambia. Here we demonstrate that theAVR-Rmg8effector, common in wheat-infecting isolates, is recognised by the genePm4, previously shown to confer resistance to specific races ofBlumeria graminisf.sp.tritici, the cause of powdery mildew of wheat. We show thatPm4alleles differ in their recognition of differentAVR-Rmg8alleles, and some confer resistance only in seedling leaves but not spikes making it important to select for those alleles that function in both tissues. This study has identified a gene recognising an important virulence factor present in wheat blast isolates in Bangladesh and Zambia and represents an important first step towards developing durably resistant wheat cultivars for these regions.
Chronic Intermittent Hypoxia reveals role of the Postinspiratory Complex in the mediation of normal swallow production
Authors: Huff Alyssa , Karlen-Amarante Marlusa , Oliveira Luiz Marcelo , Ramirez Jan Marino
Published: September 2023

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurologic and systemic comorbidities including dysphagia, or disordered swallow, and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently we showed the Postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger Complex, to regulate proper swallow-breathing coordination (Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly disrupts swallow behavior via triggering variable swallow motor patterns. This suggests, glutamatergic-cholinergic neurons in PiCo are not only critical for the regulation of swallow-breathing coordination, but also play an important role in the modulation of swallow motor patterning. Our study also suggests that swallow disruption, as seen in OSA, involves central nervous mechanisms interfering with swallow motor patterning and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia, both in OSA and other breathing and neurological disorders.
Non-destructive, whole-plant phenotyping reveals dynamic changes in water use efficiency, photosynthesis, and rhizosphere acidification of sorghum accessions under osmotic stress
Authors: Ginzburg Daniel N. , Cox Jack A. , Rhee Seung Y.
Published: September 2023

Noninvasive phenotyping can quantify dynamic plant growth processes at higher temporal resolution than destructive phenotyping and can reveal phenomena that would be missed by end-point analysis alone. Additionally, whole-plant phenotyping can identify growth conditions that are optimal for both above- and below-ground tissues. However, noninvasive, whole-plant phenotyping approaches available today are generally expensive, complex, and non-modular. We developed a low-cost and versatile approach to non-invasively measure whole-plant physiology over time by growing plants in isolated hydroponic chambers. We demonstrate the versatility of our approach by measuring whole-plant biomass accumulation, water use, and water use efficiency every two days on unstressed and osmotically-stressed sorghum accessions. We identified relationships between root zone acidification and photosynthetic efficiency on whole-plant water use efficiency over time. Our system can be implemented using cheap, basic components, requires no specific technical expertise, and is suitable for any non-aquatic vascular plant species.
FAM210B is dispensable for erythroid differentiation in adult mice
Authors: Perfetto Mark , Rondelli Catherine M. , Gillis Samantha , Stratman Amber N. , Yien Yvette Y.
Published: September 2023

Iron plays a central role in cellular redox processes, but its ability to adopt multiple oxidation states also enables it to catalyze deleterious reactions. The requirement for iron in erythropoiesis has necessitated the evolution of mechanisms with which to handle the iron required for hemoglobinization. FAM210B was identified as a regulator of mitochondrial iron import and heme synthesis in erythroid cell culture and zebrafish models. In this manuscript, we demonstrate that while FAM210B is required for erythroid differentiation and heme synthesis under standard cell culture conditions, holotransferrin supplementation was sufficient to chemically complement the iron-deficient phenotype. As the biology of FAM210B is complex and context specific, and whole-organism studies on FAM210 proteins have been limited, we sought to unravel the role of FAM210B in erythropoiesis using knockout mice. We were surprised to discover thatFam210b-/-mice were viable and the adults did not have erythropoietic defects in the bone marrow. In contrast to studies inC. elegans, Fam210b-/-mice were also fertile. There were some modest phenotypes, such as a slight increase in lymphocytes and white cell count inFam210b-/-females, as well as an increase in body weight inFam210b-/-males. However, our findings suggest that FAM210B may play a more important role in cellular iron homeostasis under iron deficient conditions. Here, we will discuss the cell culture conditions used in iron metabolism studies that can account for the disparate finding on FAM210B function. Moving forward, resolving these discrepancies will be important in identifying novel iron homeostasis genes.
Pre-piRNA trimming safeguards piRNAs against erroneous targeting by RNA-dependent RNA Polymerase
Authors: Pastore Benjamin , Hertz Hannah L. , Tang Wen
Published: September 2023

In animal germ lines, The Piwi/piRNA pathway plays a crucial role in safeguarding genome integrity and promoting fertility. Following transcription from discrete genomic loci, piRNA precursors undergo nucleolytic processing at both 5’ and 3’ ends. The ribonuclease PARN-1 and its orthologs mediate piRNA 3’ trimming in worms, insects and mammals. Yet, the significance of this evolutionarily conserved processing step is not well understood. EmployingC. elegansas a model organism, our recent work has demonstrated that 3’ trimming protects piRNAs against non-templated nucleotide additions and degradation. In this study, we present an unexpected finding thatC. elegansdeficient for PARN-1 accumulate a heretofore uncharacterized RNA species termed anti-piRNAs, which are antisense to piRNAs. These anti-piRNAs associate with Piwi proteins and display the propensity for a length of 17-19 nucleotides and 5’ guanine and adenine residues. We show that untrimmed pre-piRNAs inparn-1mutants are modified by the terminal nucleotidyltransferase RDE-3 and erroneously targeted by the RNA-dependent RNA polymerase EGO-1, thereby giving rise to anti-piRNAs. Taken together, our work identifies a previously unknown class of small RNAs upon loss ofparn-1and provides mechanistic insight to activities of RDE-3, EGO-1 and Piwi proteins.
The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle
Authors: Joshi Aniket S. , da Silva Meiricris Tomaz , Roy Anirban , Koike Tatiana E. , Wu Mingfu , Castillo Micah B. , Gunaratne Preethi H. , Liu Yu , Iwawaki Takao , Kumar Ashok
Published: September 2023

Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. Inositol requiring enzyme 1 alpha (IRE1α) is one of the arms of the unfolded protein response (UPR) that regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in adult muscle stem cells (i.e. satellite cells) of mice impairs skeletal muscle regeneration primarily through inhibiting myoblast fusion step. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits fusion of cultured myoblasts during myogenesis. Genome-wide transcriptome analysis revealed that knockdown of IRE1α or XBP1 deregulates the gene expression of molecules involved in the regulation of myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including Myomaker (Mymk) during myogenic differentiation. Our study demonstrates that spliced XBP1 (sXBP1) transcription factor binds to the promoter region ofMymkgene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Finally, our results show that inducible deletion ofIRE1α in satellite cells inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation in the gene expression of profusion molecules.

Significance Statement

Myoblast fusion is an essential step for regeneration and post-natal growth of skeletal muscle. We demonstrate that the activation of the IRE1α/XBP1 arm of the unfolded protein response induces myoblast fusion through augmenting the gene expression of multiple profusion molecules, including myomaker. This study has identified a novel signaling axis that link ER stress-induced non-myogenic signaling pathway to myoblast fusion. Augmenting the activity of IRE1α/XBP1 pathway could be a potential therapeutic strategy for various muscle degenerative diseases.
Expansion of highly interferon-responsive T cells in early-onset Alzheimer’s disease
Authors: Sirkis Daniel W. , Solsberg Caroline Warly , Johnson Taylor P. , Bonham Luke W. , Oddi Alexis P. , Geier Ethan G. , Miller Bruce L. , Rabinovici Gil D. , Yokoyama Jennifer S.
Published: September 2023

INTRODUCTION

Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer’s disease (EOAD).

METHODS

We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls.

RESULTS

We analyzed ~182,000 PBMCs by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhiT cells in EOAD. We isolated CD4 T cells from additional EOAD cases and confirmed increased expression of ISAGhimarker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes.

DISCUSSION

ISAGhiT cells, apparently primed for antiviral activity, are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.
Conditional Chemoconnectomics (cCCTomics): Conditional Targeting of Chemical Transmission Efficiently
Authors: Mao Renbo , Yu Jianjun , Deng Bowen , Dai Xihuimin , Du Yuyao , Du Sujie , Zhang Wenxia , Rao Yi
Published: September 2023

Dissection of neural circuitry underlying behaviors is a central theme in neurobiology. We have previously proposed the concept of chemoconnectome (CCT) to cover the entire chemical transmission between neurons and target cells in an organize and created tools for studying it (CCTomics) by targeting all genes related to the CCT in Drosophila. Here we have created lines targeting the CCT in conditional manners after modifying GFP RNA interference, Flp-out and CRISPR/Cas9 technologies. All three strategies are validated to be highly effective with the best using chromatin-peptide fused Cas9 variants and scaffold optimized sgRNAs. As a proof of principle, we conduct a comprehensive intersection analysis of CCT genes expression profiles in the clock neurons, uncovering 43 CCT genes present in clock neurons. Specific elimination of each from clock neurons revealed that loss of the neuropeptide CNMa in two posterior dorsal clock neurons (DN1ps) or its receptor (CNMaR) caused advanced morning activity, indicating a suppressive role of CNMa-CNMaR on morning anticipation, opposite to the promoting role of PDF-PDFR on morning anticipation. These results demonstrate the effectiveness of conditional CCTomics and its tools created by us here and establish an antagonistic relationship between CNMa-CNMaR and PDF-PDFR signaling in regulating morning anticipation.
The shape and volume of air, kernels and cracks, in a nutshell
Authors: Amézquita Erik J. , Quigley Michelle Y. , Brown Patrick , Munch Elizabeth , Chitwood Daniel H.
Published: September 2023

Walnuts are the second most produced and consumed tree nut, with over 2.6 million metric tons produced in the 2022-23 harvest cycle alone. The United States is the second largest producer, accounting for 25% of the total global supply. Nonetheless, producers face an ever-growing demand in a more uncertain climate landscape, which requires effective and efficient walnut selection and breeding of new cultivars with increased kernel content and easy-to-open shells. Past and current efforts select for these traits using hand-held calipers and eye-based evaluations. Yet there is plenty of morphology that meets the eye but goes unmeasured, such as the volume of inner air or the convexity of the kernel. Here, we study the shape of walnut fruits based on X-ray CT (Computed Tomography) 3D reconstructions. We compute 49 different morphological phenotypes for 1264 individuals comprising 149 accessions. These phenotypes are complemented by traits of breeding interest such as ease of kernel removal and kernel weight. Through allometric relationships —relative growth of one tissue to another—, we identify possible biophysical constraints at play during development. We explore multiple correlations between all morphological and commercial traits, and identify which morphological traits can explain the most variability of commercial traits. We show that using only volume and thickness-based traits, especially inner air content, we can successfully encode several of the commercial traits.

Core Ideas

X-ray Computed Tomography (CT) imaging is used to compute a broad array of morpho-logical phenotypes in walnuts.

These morphological traits suggest biophysical constraints at play during walnut development.

Relative inner air, shell, and packing tissue volumes are significantly correlated to the rest of shape phenotypes.

These volumes produce the best prediction models for traits of commercial interest such as shell strength.

Inexpensive phenotyping platforms that focus solely on volume measurement would enable better walnut breeding.
Reach, adoption, and implementation strategies of a telehealth falls prevention program: perspectives from francophone communities across Canada
Authors: O’Neil Jennifer , Dionne Nathalie , Marchand Sylvie , Cardinal Dominique , Handrigan Grant , Savard Jacinthe
Published: September 2023

Introduction

A fall may impact a person’s physical, emotional, and psychological well-being. Fall prevention programs are being implemented to reduce these negative outcomes. However, linguistic barriers in health services may reduce access to such prevention programs. A telehealth fall prevention program was designed to increase access to such programs in French for Francophone minority communities in Canada. This capacity building project aimed to support community partners to deliver this telehealth program and document strategies used to reach, adopt, and implement the program within various Francophone and Acadian Minority Communities.

Methods

A sequential explanatory mixed methodology was used to document reach, adoption and implementation strategies and describe lived experiences of program facilitators and organization representatives. Reach, adoption, and implementation were documented and analyzed descriptively while lived experiences were analyzed using content analysis following the Consortium Framework Implementation Research.

Results

Twelve organization representatives or program facilitators from eight organizations operating in four different provinces participated in the study. Three themes emerged from the qualitative data on reach and adoption: external context, internal context, and capacity building. Four themes were identified as barriers and facilitators to implementation: level of preparation and time management, interpersonal relations and telepresence, exercise facilitation and safety, and technological problem-solving.

Conclusion

Using tailored reach and adoption strategies such as prioritizing provinces with higher proportions of needs and training local community program facilitators may lead to successful implementation of a new telehealth fall prevention program. Results from this study could potentially inform other primary prevention programs or telehealth program implementation.
Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir based antiretroviral therapy
Authors: Dorward Jienchi , Govender Katya , Moodley Pravikrishnen , Lessells Richard , Samsunder Natasha , Sookrajh Yukteshwar , Fanshawe Thomas R. , Turner Philip J. , Butler Christopher C. , Drain Paul K. , Hayward Gail N. , Garrett Nigel
Published: September 2023

Objective

We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia.

Design

Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART).

Methods

We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia ≥ 1000 copies/mL using logistic regression models. In exploratory analyses, we used receiver operating curves to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia.

Results

Among 124 participants, 68 (54.8%) were women, median age was 39 years (interquartile range [IQR] 34-45) and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV (1000 ng/mL increase, odds ratio [OR] 0.97 95%CI 0.94-0.99, p=0.005) and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95%CI 0.67-0.86, p<0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV p=0.072, DBS TFV-DP p=0.003). Nagelkerke Pseudo-R2for the DBS TFV-DP models was higher than for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥ 1000 copies/ml.

Conclusions

Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir.
Sex-specific socioeconomic inequalities in trajectories of anthropometry, blood pressure and blood-based biomarkers from birth to 18 years: a prospective cohort study
Authors: O’Neill Kate N , Ahmed Minhal , O’Keeffe Linda M
Published: September 2023

Background

Evidence on when socioeconomic inequalities in conventional cardiometabolic risk factors emerge and how these change over time is sparse but important in identifying pathways leading to socioeconomic inequalities in cardiovascular disease (CVD). We examine socioeconomic inequalities in trajectories of cardiometabolic risk factors across childhood and adolescence.

Methods

Data were from offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC), born in 1991/1992. Socioeconomic position (SEP) was measured using maternal education from questionnaires administered to mothers at 32-weeks’ gestation. Cardiometabolic risk factors were measured from birth/mid-childhood to age 18 years (y) and included fat and lean mass (9y–18y), systolic and diastolic blood pressure (SBP, DBP), pulse rate and glucose (7y-18y), high-density lipoprotein cholesterol (HDL-c), non-HDL-c and triglycerides (birth-18y). We examined the sex-specific associations between SEP and trajectories of risk factors using linear spline multilevel models.

Results

Among 6,517-8,952 participants with 11,948-42,607 repeated measures, socioeconomic inequalities in fat mass were evident at age 9y and persisted throughout adolescence, with graded associations across levels of SEP among females only. By 18y, fat mass was 12.32% (95% Confidence Interval (CI):6.96,17.68) lower among females and 7.94% (95% CI:1.91,13.97) lower among males with the highest SEP compared to the lowest. Socioeconomic inequalities in SBP and DBP trajectories were evident at 7y, narrowed in early adolescence and re-emerged between ages 16y-18y, particularly among females. Socioeconomic inequalities in lipid trajectories emerged, among females only, between birth and 9y in non-HDL-c, 7y and 18y in HDL-c and 9y and 18y in triglycerides while inequalities in glucose emerged among males only between ages 15y-18y.

Conclusion

Prevention targeting the early life course may be beneficial for reducing socioeconomic inequalities in CVD especially among females who have greater socioeconomic inequalities in cardiometabolic risk factors than males at the end of adolescence.
Smartphone Apps for Cannabis Cessation: Quality Assessment and Content Analysis
Authors: Seth Siddharth , Kushwaha Sumedha , Prashad Reshma , Chaiton Michael
Published: September 2023

Background

The rising rates of cannabis use, cannabis-related problems, and hospitalization rates related to cannabis usage warrant further research into better treatment methods and interventions.

Purpose

This study aims to identify the quality of free cannabis cessation applications available on both the Apple App Store and the Google Play Store and analyse their features, content, and adherence to evidence-based practices.

Methods

A systematic search was conducted in April 2023 using a variety of keywords. The applications were deemed eligible if they were free, in English, available on both the Apple App Store and the Google Play Store and were related to cannabis cessation. Each application was used for at least one month and were rated on the Mobile App Rating Scale by two users. There was excellent agreement determined between the two reviewers (≤2 points on all categories).

Results

A total of 4 applications were included in the overall quality and content analysis. The mean total quality scores of applications were determined to be 3.36 out of 5 indicating a poor to acceptable quality of applications. It was determined that there was a very limited number of available applications for users and those that were available were not of high quality with few applications incorporating evidence-based practices.

Conclusions

There are a very limited number of cannabis cessation applications available, and the currently available products have poor to acceptable quality.
Macrophage-expressed Neuropilin 2 promotes plaque formation in ApoE knockout mice and is essential for pro-inflammatory macrophage polarisation and gene expression
Authors: Fernando-Sayers Jacob , Harman Jennifer L. , Gage Matthew C. , Zachary Ian C. , Pellet-Many Caroline
Published: September 2023

Aims

Atherosclerosis is a chronic inflammatory disease causing the narrowing of arteries, leading to ischaemic heart disease. It is characterised by the subendothelial retention, and modification, of lipoproteins by macrophages, highly plastic cells which undergo polarisation to a pro-inflammatory phenotype in response to cytokines and other environmental stimuli.

Neuropilin-2 (NRP2) is a cell-surface co-receptor with essential roles in angiogenesis and axonal guidance, that is also expressed by macrophages. However, the role of NRP2 in macrophage function in the development of atherosclerosis has not been studied.

Methods and results

The role of NRP2 in modulating macrophage polarisation and signalling was assessed using functional assays and transcriptome analysis in macrophages obtained from mice with macrophage-specific deletion ofNrp2(Nrp2-KOMac,EYFP). These mice were further crossed with pro-atherogenic Apolipoprotein E-deficient mice to produceNrp2-KOMac,Apoe-/-,EYFPmice, which were fed a high-fat diet (HFD) for 16 weeks. Plaque formation and composition were characterised using chemical and immuno-staining.

NRP2 was significantly upregulated upon differentiation of bone marrow progenitors into bone marrow derived macrophages (BMDM), and further upregulated by pro-inflammatory polarisation. Transcriptome analysis revealed that inflammatory signalling pathway genes, and genes regulating monocyte chemotaxis, were downregulated inNrp2-KOMac,EYFPBMDMs. HFD-induced plaque development was significantly reduced inNrp2-KOMac,Apoe-/-,EYFPmice. Additionally, plaques from those mice displayed features consistent with increased plaque stability, including reduced necrotic core area, plaque lipid content and increased cap thickness.

Conclusions

Macrophage-derived NRP2 is proatherogenic, likely resulting from its ability to positively regulate pro-inflammatory pathways and macrophage migration. Targeting NRP2 expressed on the surface of macrophages could therefore offer a novel therapeutic approach for reducing the disease burden associated with atherosclerosis.
Proteome profiling of brain vessels in a mouse model of cerebrovascular pathology
Authors: Haqqani Arsalan S. , Mianoor Zainab , Star Alexandra T. , Detcheverry Flavie , Stanimirovic Danica B. , Hamel Edith , Badhwar AmanPreet
Published: September 2023

A cerebrovascular pathology that involves altered protein levels or signaling of the transforming growth factor beta (TGFβ) family has been associated with various forms of dementia, including Alzheimer disease (AD) and vascular cognitive impairment and dementia (VCID). Transgenic mice overexpressing TGFβ1 in the brain (TGF mice) recap VCID-associated cerebrovascular pathology and develop cognitive deficits in old age or when submitted to comorbid cardiovascular risk-factors for dementia. Here, we characterized the cerebrovascular proteome of TGF mice using mass-spectrometry (MS) based quantitative proteomics. Cerebral arteries were surgically removed from 6-month-old-TGF and wild-type mice, proteins extracted and analyzed by gel-free nanoLC-MS/MS. We identified 3,602 proteins in brain vessels, with 20 demonstrating robust altered levels in TGF mice. For total and/or differentially-expressed proteins (p≤0.01, ≥2-fold change), using multiple databases, we performed protein characterization, and identified proteins demonstrating RNA-transcripts in both mouse and human cerebrovascular cells, and known to be present in human-extracellular-vesicles (EVs). Dysregulated proteins point to perturbed brain vessel vasomotricity, remodeling, and inflammation. Given that blood-isolated EVs are novel, attractive and a minimally invasive biomarker discovery platform for the age-related dementias, several proteins identified in this study can potentially serve as VCID markers in humans.
Avoidance, confusion or solitude? Modelling how noise pollution affects whale migration
Authors: Johnston Stuart T. , Painter Kevin J.
Published: September 2023

Many baleen whales are renowned for their acoustic communication. Under pristine conditions, this communication can plausibly occur across hundreds of kilometres. Frequent vocalisations may allow a dispersed migrating group to maintain contact, and therefore benefit from improved navigation via the “wis-dom of the crowd.” Human activities have considerably inflated ocean noise levels. Here we develop a data-driven mathematical model to investigate how ambient noise levels may inhibit whale migration. Mathematical models allow us to simul-taneously simulate collective whale migration behaviour, auditory cue detection, and noise propagation. Rising ambient noise levels are hypothesised to influence navigation through three mechanisms: (i) diminished communication space; (ii) reduced ability to hear external sound cues and; (iii) triggering noise avoidance behaviour. Comparing pristine and current soundscapes, we observe navigation impairment that ranges from mild (increased journey time) to extreme (failed navigation). Notably, the three mechanisms induce qualitatively different impacts on migration behaviour. We demonstrate the model’s potential predictive power, exploring the extent to which migration may be altered under future shipping and construction scenarios.
Cytoplasmic fluidization triggers breaking spore dormancy in fission yeast
Authors: Sakai Keiichiro , Kondo Yohei , Goto Yuhei , Aoki Kazuhiro
Published: September 2023

The cytoplasm is a complex, crowded environment that influences myriad cellular processes including protein folding and metabolic reactions. Recent studies have suggested that changes in the biophysical properties of the cytoplasm play a key role in cellular homeostasis and adaptation. However, it still remains unclear how cells control their cytoplasmic properties in response to environmental cues. Here, we used fission yeast spores as a model system of dormant cells to elucidate the mechanisms underlying regulation of the cytoplasmic properties. By tracking fluorescent tracer particles, we found that particle mobility decreased in spores compared to vegetative cells, and rapidly increased at the onset of dormancy breaking upon glucose addition. This cytoplasmic fluidization depended on glucose sensing via the cAMP-PKA pathway. PKA activation led to trehalose degradation through trehalase Ntp1, thereby increasing particle mobility as the amount of trehalose decreased. In contrast, the rapid cytoplasmic fluidization did not requirede novoprotein synthesis, cytoskeletal dynamics, or cell volume increase. Furthermore, the measurement of diffusion coefficients with tracer particles of different sizes suggests that the spore cytoplasm impedes the movement of larger protein complexes (40–150 nm) such as ribosomes, while allowing free diffusion of smaller molecules (∼3 nm) such as second messengers and signaling proteins. Our experiments have thus uncovered a series of signaling events that enable cells to quickly fluidize the cytoplasm at the onset of dormancy breaking.

Significance statement

Cellular processes are influenced by the biophysical properties of the cytoplasm such as crowding and viscoelasticity. Although it has been suggested that cells tune the cytoplasmic properties in response to environmental changes, the molecular mechanisms remain unclear. Here, we used the dormant fission yeast spores and uncovered signaling pathways that facilitate cytoplasmic fluidization during dormancy breaking. Furthermore, we tracked the mobility of intracellular tracer particles, and found that the spore cytoplasm impedes the mobility of larger protein complexes, while allowing free diffusion of smaller molecules. These results suggest that small signaling proteins can diffuse relatively freely in the spore cytoplasm and have the ability to transmit dormancy breaking signals, while the motion of large complexes, such as ribosomes, is restricted.
Mapping the task-general and task-specific neural correlates of speech production: meta-analysis and fMRI direct comparisons of category fluency and picture naming
Authors: Humphreys Gina F. , Ralph Matthew A. Lambon
Published: September 2023

Improving our understanding of the neural network engaged by different forms of speech production is a crucial step for both cognitive and clinical neuroscience. We achieved this aim by exploring two of the most commonly utilised speech production paradigms in research and the clinic, which have been rarely, if ever, compared directly: picture naming and category fluency. This goal was achieved in this two study investigation through a full ALE meta-analysis as well as a targeted fMRI study. Harnessing the similarities and differences between the two tasks offers a powerful methodology to delineate the core systems recruited for speech production, as well as revealing task-specific processes. The results showed that both tasks engaged a bilateral fronto-temporal speech production network, including executive and motor frontal areas, as well as semantic representational regions in the ATL, bilaterally. In addition, it was found that the extent of relative frontal lateralisation was task-dependent with the more executively-demanding category fluency task showing augmented left hemisphere activation. The results have implications for neurocomputational speech production models and the clinical assessment of speech production impairments.

Open access: For the purpose of open access, the UKRI-funded authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.
53BP1 interacts with the RNA primer from Okazaki fragments to support their processing during unperturbed DNA replication
Authors: Leriche Melissa , Bonnet Clara , Jana Jagannath , Chhetri Gita , Mennour Sabrina , Martineau Sylvain , Pennaneach Vincent , Busso Didier , Veaute Xavier , Bertrand Pascale , Lambert Sarah , Somyajit Kumar , Uguen Patricia , Vagner Stéphan
Published: September 2023

RNA-binding proteins are found at replication forks, but their direct interaction with DNA-embedded RNA species that inevitably shape physiological DNA replication remains unexplored. Here we report that 53BP1, involved in the DNA damage and replication stress response, is an RNA-binding protein that directly interacts with Okazaki fragments, in the absence of any external stress. The bulk chromatin association of 53BP1 shows dramatic dependence on PRIM1, which synthesizes the RNA primer of Okazaki fragments. The direct recruitment of 53BP1 to nascent DNA shows susceptibility toin situribonuclease A treatment. Conversely, depletion of FEN1, which results in the accumulation of uncleaved RNA primers, leads to an upregulation of 53BP1 levels at the replication forks, suggesting that RNA primers contribute to the recruitment of 53BP1 at the lagging DNA strand. 53BP1 depletion induces an accumulation of S phase poly(ADP-ribose), which constitutes a sensor of unligated Okazaki fragments. Collectively, our data indicate that 53BP1, distinct from its canonical mode of chromatin-binding, is anchored at the replication fork through its RNA-binding activity, highlighting the role of an RNA-protein interaction at DNA replication forks.
Transcriptional reactivation of the tRNASer/tRNATyrgene cluster inArabidopsis thalianaroot tip (V2)
Authors: Hummel Guillaume , Kumari Priyanka , Hua Chenlei , Wang Long , Mai Yan-Xia , Wang Nan , Shala Negjmedin , Kaya Emir Can , Molinier Jean , Wang Jia-Wei , Liu Chang
Published: September 2023

Plants retain a repetitious tRNA gene content in their nuclear genome. How important are these individuals, how exactly plants orchestrate their usage, and for what purposes, is poorly understood.Arabidopsis thalianachromosome 1 holds a cluster of tandemly repeated serine– and tyrosine-decoding tRNA genes (SYY cluster). They intersect with constitutive heterochromatin and are silenced in most parts of the plant. Yet, the natural conditions leading to their transcription remain unknown. Here, we resolve the tissular expression pattern of this cluster along seedling establishment. We show that the root cap columella and few adjacent lateral root cap cells are the main sources of SYY cluster tRNAs. The transcriptional reactivation of the SYY cluster occurs in these tissues although elevated DNA methylation levels. Furthermore, we evidence that these cells are able to accumulate high levels of a transgenic glycoprotein rich in serine, tyrosine, and proline, and that the CRISPR/Cas9 deletion of the SYY cluster alters the phenomenon. Altogether, our work sheds light on pioneering evidence of a developmental and cell-specific expression program for a plant tRNA gene. We provide new perspectives on the role of peculiar tRNA genes in conferring a potential for the high synthesis of glycoproteins in protective tissues of the meristem.
Dairy practices select for thermostable endolysins in phages
Authors: Oechslin Frank , Zhu Xiaojun , Morency Carlee , Somerville Vincent , Shi Rong , Moineau Sylvain
Published: September 2023

Endolysins are phage lytic enzymes that degrade the bacterial cell wall to release phage progeny. We found that the diversity of endolysins is unsuspectedly low and dominated by a single structural type in distinct phages that infectStreptococcus thermophilus. Through X-ray crystallography, we discovered that this type of endolysin contains a highly conserved calcium-binding motif in its cell wall binding domain. Inactivation of the motif in the purified endolysin or in the phage genome revealed its key role in stabilizing the enzyme under conditions that mimic the cheesemaking process, including at elevated temperatures. Fermented dairy products such as yogurt and cheeses are incubated or cooked at higher temperatures and require the addition of thermophilic lactic acid bacteria such asS. thermophilusto drive milk fermentation. It appears that dairy practices have influenced the genetic signatures of streptococcal phages by selecting for thermostable endolysins, which in turn have limited their diversity.
RlmQ: A Newly Discovered rRNA Modification Enzyme Bridging RNA Modification and Virulence Traits inStaphylococcus aureus
Authors: Bahena-Ceron Roberto , Teixeira Chloe , Jaramillo Ponce Jose R , Wolff Philippe , Couzon Florence , François Pauline , Klaholz Bruno , Vandenesch François , Romby Pascale , Moreau Karen , Marzi Stefano
Published: September 2023

rRNA modifications play crucial roles in fine-tuning the delicate balance between translation speed and accuracy, yet the underlying mechanisms remain elusive. Comparative analysis of the ribosomal RNA modifications in taxonomically distant bacteria could help define their general as well as species-specific roles. In this study, we identified a new methyltransferase, RlmQ, inStaphylococcus aureusresponsible for the Gram-positive specific m7G2601, which is not modified inE. coli(G2574). We also demonstrate the absence of methylation on C1989, equivalent toE. coliC1962, which is methylated at position 5 by the Gram-negative specific RlmI methyltransferase, a paralogue of RlmQ. Both modifications (S. aureusm7G2601 andE. colim5C1962) are situated within the same tRNA accommodation corridor, hinting at a potential shared function in translation. Inactivation ofS. aureus rlmQcauses the loss of methylation at G2601 and significantly impacts growth, cytotoxicity, and biofilm formation. These findings unravel the intricate connections between rRNA modifications, translation, and virulence in pathogenic Gram-positive bacteria.
Transient states during the annealing of mismatched and bulged oligonucleotides
Authors: Todisco Marco , Ding Dian , Szostak Jack W.
Published: September 2023

Oligonucleotide hybridization is crucial in various biological, prebiotic and nanotechnological processes, including gene regulation, non-enzymatic primer extension and DNA nanodevice assembly. Although extensive research has focused on the thermodynamics and kinetics of nucleic acid hybridization, the behavior of complex mixtures and the outcome of competition for target binding remain less well understood. In this study, we investigate the impact of mismatches and bulges in a 12bp DNA or RNA duplex on its association (kon) and dissociation (koff) kinetics. We find that such defects have relatively small effects on the association kinetics, while the dissociation kinetics vary in a position-dependent manner by up to 6 orders of magnitude. Building upon this observation, we explored a competition scenario involving multiple oligonucleotides, and observed a transient low specificity of probe hybridization to fully vs. partially complementary targets in solution. We characterize these long-lived metastable states and their evolution toward equilibrium, and show that sufficiently long-lived mis-paired duplexes can serve as substrates for prebiotically relevant chemical copying reactions. Our results suggest that transient low accuracy states may spontaneously emerge within all complex nucleic acid systems comprising a large enough number of competing strands, with potential repercussions for gene regulation in the realm of modern biology and the prebiotic preservation of genetic information.