bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding growers’ choice of disease management options can promote suboptimal social outcomes
Authors: Murray-Watson Rachel E. , Cunniffe Nik J.
Published: September 2022

1

Previous models of growers’ decision-making during epidemics have unrealistically limited disease management choices to just two options. Here, we expand previous game-theoretic models of grower decision-making to include three control options: crop that is either tolerant, resistant, or susceptible to disease. Using Tomato Yellow Leaf Curl Virus (TYLCV) as a case study, we investigate how growers can be incentivised to use different control options to achieve socially-optimal outcomes. To do this, we consider the efforts of a “social planner” who moderates the price of crops. We find that subsidising tolerant crop costs the social planner more in subsidies, as its use encourages selfishness and widespread adoption. Subsidising resistant crop, however, provides widespread benefits by reducing the prevalence of disease across the community of growers, including those that do not control, reducing the number of subsidies required from the social planner. We then use Gini coefficients to measure equitability of each subsidisation scheme. This study highlights how grower behaviour can be altered using crop subsidies to promote socially-optimal outcomes during epidemics.
Immune dynamics at single cell protein level after delta/omicron infection in COVID-19 vaccinated convalescent individuals
Authors: Bajaj Rimpi , Yang Zhiqi , Hammer Vincent , Pöschel Simone , Bieber Kristin , Salker Madhuri S , Casadei Nicolas , Ossowski Stephan , Riess Olaf , Singh Yogesh
Published: September 2022

Both COVID-19 mRNA or recombinant Adenovirus vector (rAdVV) based vaccines have shown a great efficacy in generating humoral and cellular immune responses. Two doses of the COVID-19 vaccines generate enough antibodies and generate spike-specific T cell responses. However, after 6-8 months there is a decline in antibody production and T cell responses. Due to the rise of new SARS-CoV-2 variants of concern, a third or even fourth dose of vaccine was recommended for the elderly, immune comprised and frontline medical health care workers. However, despite additional booster doses given, those who were infected with either delta or omicron (during December 2021 – March 2022) had symptoms of illness. By what means these COVID-19 vaccines provide immunity against the SARS-CoV-2 virus at the molecular level is not explored extensively yet and, it is an emerging research field as to how the SARS-CoV-2 virus is able to evade the host immunity. Most of the infected people had mild symptoms whilst some were asymptomatic. Many of the people had developed nucleocapsid antibodies against the SARS-CoV-2 delta/omicron variants confirming a humoral immune response against viral infection. Furthermore, cellular analysis shows that post-vaccinated recovered COVID-19 individuals have significantly reduced NK cells and increased T naïve CD4+, TEM CD8+ and B cells. This decrease in cellular immunity corresponds to individuals who recovered from alpha variants infection and had mild symptoms. Our results highlight that booster doses clearly reduce the severity of infection against delta/omicron infection. Furthermore, our cellular and humoral immune system is trained by vaccines and ready to deal with breakthrough infections in the future.
Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization
Authors: Wang Qian , Li Zhiteng , Ho Jerren , Guo Yicheng , Yeh Andre Yanchen , Liu Michael , Wang Maple , Yu Jian , Sheng Zizhang , Huang Yaoxing , Liu Lihong , Ho David D.
Published: September 2022

SARS-CoV-2 Omicron subvariants BA.4.6, BA.4.7, and BA.5.9 have recently emerged, and BA.4.6 appears to be expanding even in the presence of BA.5 that is globally dominant. Compared to BA.5, these new subvariants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion. We compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance. We also performed VSV-based pseudovirus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs). Compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera. Moreover, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of tixagevimab and cilgavimab completely lost neutralizing activity against these three subvariants. The loss of activity of tixagevimab and cilgavimab against BA.4.6 leaves us with bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2. As the virus continues to evolve, our arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.
The Schema Method: Using Quantified Learning to Innovate, Augment, Assess and Analyze Learning in Medicine
Authors: Sebin Deepu , Doda Vishwin , Balami Skanthvelan
Published: September 2022

Introduction

The predominant method of learning Medicine at its core has remained unchanged for decades. This stagnancy creates a need for making learning more effective, insightful, and quantified. ‘Schema’ achieves this through e-learning, active feedback, and quantified learning by granulating the medical curriculum into specific subtopics selected based on the crucial knowledge that a competent medical learner must possess, hereafter referred to as ‘yield.’ This particular study aims to analyze medical students’ multidimensional competency in solving clinical scenario-based MCQs pertaining to vertically integrated topics derived from the ‘Schema.’

Methods

A retrospective study was conducted by analyzing the user data of a leading e-learning platform for medical students. For the purposes of this study, twenty such “high-yield” Schema topics were shortlisted as being the most crucial knowledge areas. Students’ performance in solving a fixed set of SOC-MCQs of these Schema topics was used to gauge their competence. Performance variation over five years (2018-2022) was also analyzed to study the changing patterns in topic-specific performance.

Results

A total of 20 Schema topics were shortlisted, consisting of 128 MCQs. The number of participants solving each Single Option Correct Multiple Choice Question (SOC-MCQ) ranged from 60,080 to 2,06,672. A significant improvement in the Net Delta was observed in 9 topics. Performance in other topics showed either no significant change or a significant downtrend.

Conclusion

A significant performance uptrend (ND = 128%) was observed in Anaphylaxis, Basic Lifesaving Skills, ST-Elevated Myocardial Infarction, Glasgow Coma Scale, and subdural hemorrhage & Syndromic management of Sexually Transmitted Infections, most of which are either acute or emergency conditions. A significant downtrend in performance was seen in Schema topics such as Asthma management, Hypertension management, Diabetic Ketoacidosis, and Subarachnoid hemorrhage pertaining to chronic conditions. Several hypotheses for these findings can be derived, the validities and collective impacts of which can be explored in more in-depth and broader studies in the future.
The establishment ofPopulusxLaccaria bicolorectomycorrhiza requires the inactivation of MYC2 coordinated defense response with a key role for root terpene synthases
Authors: Marqués-Gálvez José Eduardo , Basso Veronica , Kohler Annegret , Barry Kerrie , Keymanesh Keykhosrow , Johnson Jenifer , Singan Vasanth , Grigoriev Igor V. , Vilgalys Rytas , Martin Francis , Veneault-Fourrey Claire
Published: September 2022

The jasmonic acid (JA) signaling pathway plays an important role in the establishment of the ectomycorrhizal symbiosis (ECM) betweenLaccaria bicolorand poplar. We previously showed that theL. bicoloreffector MiSSP7 induces the stabilization of the poplar JAZ6, a JA co-repressor protein that binds toPopulusMYC2.1 and MYC2.2, orthologs of theArabidopsisMYC2 transcription factor (TF), blocking their activity. Here we showed that both TFs play a central role in root colonization byL. bicolormycelium, since their overexpression decreased the formation of the Hartig net, the hyphal network involved in symbiotic nutrient exchanges. By combining RNA sequencing and DNA Affinity Purification sequencing (DAP-seq) analysis, we identified a core set of JA-responsive genes directly activated by poplar MYC2.1 and MYC2.2, that need to be bypassed by the fungi to colonize root apoplastic spaces. These genes encode for other TFs, receptor-like kinases and many defense-related proteins, including terpene synthases (TPS). Monoterpenes produced by some of these TPS impactL. bicolorgrowth and ECM formation, suggesting a role for poplar root monoterpenes as negative regulators ofin plantafungal growth and ECM symbiosis.

Significance statement

The ectomycorrhizal symbiosis is a predominant mutualistic plant-fungus interaction occurring in forests, sustaining tree health. Ectomycorrhizal fungi colonize the root intercellularly establishing the symbiotic interface required for bidirectional nutrients exchanges, the Hartig net. During root colonization, the fungusL. bicolorproduces the effector protein MiSSP7 that binds to the jasmonate co-receptor PtJAZ6, maintaining the repression of MYC2-targeted genes. Here we showed that defensive genes are major targets of MYC2, suggesting that their strict control is required to allow fungal colonization, with special emphasis on the host root monoterpene synthesis. Future research will focus on how root terpene defenses mediate belowground mutualistic interactions and how they can be manipulated to engineer plants with enhanced disease resistance but stable mutualistic interactions.
Viral infection impacts the 3D subcellular structure of the abundant marine diatomGuinardia delicatula
Authors: Walde Marie , Camplong Cyprien , de Vargas Colomban , Baudoux Anne-Claire , Simon Nathalie
Published: September 2022

Viruses are key players in marine ecosystems where they infect abundant marine microbes. RNA viruses are emerging as key members of the marine virosphere. They have recently been identified as a potential source of mortality in diatoms, a group of microalgae that accounts for roughly 40% of the primary production in the ocean. Despite their likely importance, their impacts on host populations and ecosystems remain difficult to assess.

In this study, we introduce an innovative tool approach that combines automated 3D confocal microscopy with quantitative image analysis and physiological measurements to expand our understanding of viral infection. We followed different stages of infection of the bloom-forming diatomGuinardia delicatulaby the RNA virus GdelRNAV-04 until the complete lysis of the host. From 20h after infection, we observed quantifiable changes in subcellular host morphology and biomass. Our microscopy monitoring also showed that viral infection ofG. delicatulainduced the formation of auxospores as a probable defense strategy against viruses. Our method enables the detection of discriminative morphological features on the subcellular scale and at high throughput for comparing populations, making it a promising approach for the detection quantification of viral infections in the field in the future.
Redefining normal breast cell populations using long noncoding RNAs
Authors: Bitar Mainá , Rivera Isela Sarahi , Pimentel de Almeida Isabela , Shi Wei , Ferguson Kaltin , Beesley Jonathan , Lakhani Sunil R , Edwards Stacey L , French Juliet D
Published: September 2022

Single-cell RNAseq has allowed unprecedented insight into gene expression across different cell populations in normal tissue and disease states. However, almost all studies rely on annotated gene sets to capture gene expression levels and sequencing reads that do not align to known genes are discarded. Here, we discover thousands of long noncoding RNAs (lncRNAs) expressed in human mammary epithelial cells and analyze their expression in individual cells of the normal breast. We show that lncRNA expression alone can discriminate between luminal and basal cell types and define subpopulations of both compartments. Clustering cells based on lncRNA expression identified additional basal subpopulations, compared to clustering based on annotated gene expression, suggesting that lncRNAs can provide an additional layer of information to better distinguish breast cell subpopulations. In contrast, these breast-specific lncRNAs poorly distinguish brain cell populations, highlighting the need to annotate tissue-specific lncRNAs prior to expression analyses. We also identified a panel of 100 breast lncRNAs that could discern breast cancer subtypes better than protein-coding markers. Overall, our results suggest that lncRNAs are an unexplored resource for new biomarker and therapeutic target discovery in the normal breast and breast cancer subtypes.
Rapid and accurate discrimination of Mycobacterium abscessus subspecies based on matrix-assisted laser desorption ionization-time of flight spectrum and machine learning algorithms
Authors: Wang Hsin-Yao , Kuo Chi-Heng , Chung Chia-Ru , Lin Ting-Wei , Yu Jia-Ruei , Lu Jang-Jih , Wu Ting-Shu
Published: September 2022

Background

Mycobacterium abscessus complex (MABC) has been reported to cause considerable complicated infections. Subspecies identification of MABC is crucial for adequate treatment due to different antimicrobial resistance property amid the subspecies. However, long incubation days is needed for the traditional antibiotic susceptibility testing (AST) method. Effective antibiotics administration often delayed considerably and caused unfavorable outcomes. Thus, we proposed a novel and accurate method to identify subspecies and its potential antibiotics resistance, to guide clinical treatment within hours.

Methods

Subspecies of the MABC isolates were determined by secA1, rpoB, and hsp65. AST was tested by using microdilution method, as well as sequencing of erm(41) and rrl genes. MALDI-TOF mass spectrometry (MS) spectra were analyzed. The informative peaks on MS spectra were detected by random forest (RF) importance. Machine learning (ML) algorithms were used to build models for classifying MABC subspecies based on MALDI-TOF spectrum. The models were developed and validated by nested five-fold cross-validation to avoid over-fitting.

Results

In total, 102 MABC isolates (52 subspecies abscessus and 50 subspecies massiliense) were analyzed. Top informative peaks including m/z 6715, 4739, 2805, etc. were identified. RF model attained AUROC of 0.9166 (95% CI: 0.9072-0.9196) and outperformed other algorithms in discriminating subspecies abscessus from massiliense.

Conclusion

We developed a MALDI-TOF based ML model for rapid and accurate MABC subspecies identification. The novel diagnostic tool would guide a more accurate and timely MABC subspecies-specific treatment.
ETV7 reduces inflammatory responses in breast cancer cells by repressing TNFR1/NF-κB axis
Authors: Meškytė Erna Marija , Pezzè Laura , Forcato Mattia , Bocci Irene Adelaide , Bisio Alessandra , Bicciato Silvio , Baltriukienė Daiva , Ciribilli Y.
Published: September 2022

The transcription factor ETV7 is an oncoprotein that is up-regulated in all breast cancer (BC) types. We have recently demonstrated that ETV7 promoted breast cancer progression by increasing cancer cell proliferation and stemness and was also involved in the development of chemo- and radio-resistance. However, the roles of ETV7 in breast cancer inflammation have yet to be studied. Gene ontology analysis previously performed on BC cells stably over-expressing ETV7 demonstrated that ETV7 was involved in the suppression of innate immune and inflammatory responses. To better decipher the involvement of ETV7 in these signaling pathways, in this study, we identified TNFRSF1A, encoding for the main receptor of TNF-α, TNFR1, as one of the genes down-regulated by ETV7. We demonstrated that ETV7 directly binds to the intron I of this gene, and we showed that the ETV7-mediated down-regulation of TNFRSF1A reduced the activation of NF-κB signaling. Furthermore, in this study, we unveiled a potential crosstalk between ETV7 and STAT3, another master regulator of inflammation. While it is known that STAT3 directly up-regulates the expression of TNFRSF1A, here we demonstrated that ETV7 reduces the ability of STAT3 to bind to the TNFRSF1A gene via a competitive mechanism, leading to the repression of its transcription. These results suggest that ETV7 can reduce the inflammatory responses in breast cancer through the down-regulation of TNFRSF1A.
Investigating the risk of cardiac fibrosis due to heat-not-burn cigarettes through human cardiac stromal cells
Authors: Picchio Vittorio , Pagano Francesca , Carnevale Roberto , D’Amico Alessandra , Cozzolino Claudia , Floris Erica , Bordin Antonella , Schirone Leonardo , Saade Wael , Miraldi Fabio , De Falco Elena , Sciarretta Sebastiano , Peruzzi Mariangela , Biondi-Zoccai Giuseppe , Frati Giacomo , Chimenti Isotta
Published: September 2022

Background

The use of alternative smoking devices, such as heat-not-burn cigarettes (HNBC), is increasing on a global scale, and their impact on health is still uncertain.

Objective

To investigate the effects of circulating molecules in HNBC chronic smokers on the fibrotic specification and paracrine function of cardiac stromal cells (CSCs).

Methods

Resident CSCs were isolated from the atrial tissue of patients with cardiovascular diseases, and exposed to the serum of 60 young healthy subjects, stratified in exclusive HNBC smokers, traditional combustion cigarette (TCC) smokers, or non-smokers (NS) as reference.

Results

CSCs treated with TCC serum displayed impaired 3D growth and migration, as well as increased expression and/or release of pro-inflammatory and pro-fibrotic cytokines. Cells cultured with HNBC serum showed increased mRNA levels of pro-fibrotic genes, and reduced expression of the gap junction protein CX43. Nonetheless, both TCC and HNBC sera reduced the release of angiogenic and protective factors from CSCs. In fact, their paracrine support to tube-formation by endothelial cells and to preserved cell viability of cardiomyocytes in culture was significantly impaired. Treatment with the sera of both types of smokers also increased the expression of NOX isoforms and the release of H2O2by CSCs.

Conclusion

The circulating molecules in the serum of chronic HNBC smokers induce fibrotic specification in CSCs. They also reduce the beneficial paracrine effects of stromal cells on endothelial cells and cardiomyocytes, albeit to a reduced extent for some features. These results point to a potential risk for atrial fibrosis development triggered by chronic HNBC use.

CONDENSED ABSTRACT

The use of alternative smoking devices, such as heat-not-burn cigarettes (HNBC), is increasing on a global scale, and their impact on health is still uncertain. We isolated human stromal cells from the atrial tissue of patients with cardiovascular diseases, and exposed them to the serum of young healthy subjects, that are exclusive HNBC smokers. Results showed significant alterations in the phenotype of CSCs exposed to HNBC serum, suggesting a specification towards fibrosis, reduced support to parenchymal cells, and increased oxidative stress production. Data point to a potential risk for atrial fibrosis development triggered by chronic HNBC use.
GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice
Authors: Takaoka Minoru , Tadross John A. , Al-Hadithi Ali , Villena-Gutiérrez Rocío , Tromp Jasper , Absar Shazia , Au Marcus , Harrison James , Coll Anthony P. , Marciniak Stefan J. , Rimmington Debra , Oliver Eduardo , Ibáñez Borja , Voors Adriaan A. , O’Rahilly Stephen , Mallat Ziad , Goodall Jane C.
Published: September 2022

Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
Long-term retention of antigens in germinal centres is controlled by the spatial organisation of the follicular dendritic cell network
Authors: Martinez-Riano Ana , Wang Shenshen , Boeing Stefan , Minoughan Sophie , Casal Antonio , Spillane Katelyn M , Ludewig Burkhard , Tolar Pavel
Published: September 2022

Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC B cells are immune complexes (ICs) displayed on follicular dendritic cells (FDCs). Here we show that FDC spatial organization regulates antigen dynamics in the GC. We show the existence of two light zone (LZ) FDC populations, which differ in the duration of antigen retention. While the entire light zone (LZ) FDC network captures ICs initially, only the central cells of the network function as a long-term antigen reservoir, where different antigens arriving from subsequent immunizations co-localize. Mechanistically, central FDCs constitutively express subtly higher CR2 membrane densities than peripheral FDCs, which strongly increases the IC retention half-life. Even though repeated immunizations gradually saturate central FDCs, B cell responses remain efficient because new antigens partially displace old ones. These results reveal the principles shaping antigen display on FDCs during the GC reaction.
A double-spiral maze and hi-resolution tracking pipeline to study dispersal by groups of minute insects
Authors: Cointe M. , Burte V. , Perez G. , Mailleret L. , Calcagno V.
Published: September 2022

Minute insects such as parasitic micro-wasps have high basic and applied importance, for their widespread use as biocontrol agents. Their dispersal is a phenotype of particular interest. Classically, it is evaluated using field releases, but those are time consuming, costly, and their results highly variable, preventing high-throughput and repeatability. Alternatively, dispersal can be studied using small-scale assays, but those neglect important higher-scale processes. Consequently, proper evaluation of dispersal is often complicated or lacking in academic studies and biocontrol breeding programs. Here we introduce a new method, the double-spiral maze, that allows the study of spatial propagation at relevant scales (several hours and meters), retaining high throughput and experimental power. The method records the location of every individual at every time, enabling accurate precise estimates of diffusion coefficients or other dispersal metrics. We describe this affordable, scalable, and easy-to-implement method, and illustrate its application with a species of agricultural interest.
Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine
Authors: Lu Changrui , Zhang Yuntao , Liu Xiaohu , Hou Fujun , Cai Rujie , Yu Zhibin , Liu Fei , Yang Guohuan , Ding Jun , Xu Jiang , Hua Xianwu , Pan Xinping , Liu Lianxiao , Lin Kang , Wang Zejun , Li Xinguo , Lu Jia , Zhang Qiu , Li Yuwei , Hu Chunxia , Fan Huifeng , Liu Xiaoke , Wang Hui , Jia Rui , Xu Fangjingwei , Wang Xuewei , Huang Hongwei , Zhao Ronghua , Li Jing , Cheng Hang , Jia William , Yang Xiaoming
Published: September 2022

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naïve animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccine’s targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by “recall” and “reshape” the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine– primed populations.
Real time visualisation of conjugation reveals the molecular strategy evolved by the conjugative F plasmid to ensure the sequential production of plasmid factors during establishment in the new host cell
Authors: Couturier Agathe , Virolle Chloé , Goldlust Kelly , Berne-Dedieu Annick , Reuter Audrey , Nolivos Sophie , Yamaichi Yoshiharu , Bigot Sarah , Lesterlin Christian
Published: September 2022

DNA conjugation is a contact-dependent horizontal gene transfer mechanism responsible for disseminating drug resistance among bacterial species. Conjugation remains poorly characterised at the cellular scale, particularly regarding the reactions occurring after the plasmid enters the new host cell. Here, we use live-cell microscopy to visualise the intracellular dynamics of conjugation in real time. We reveal that the transfer of the plasmid in single-stranded DNA (ssDNA) form followed by its conversion into double-stranded DNA (dsDNA) are fast and efficient processes that occur with specific timing and subcellular localisation. Notably, the ss-to-dsDNA conversion is the critical step that governs the timing of plasmid-encoded protein production. The leading region that first enters the recipient cell carries single-stranded promoters that allow the early and transient synthesis of leading proteins immediately upon entry of the ssDNA plasmid. The subsequent ss-to-dsDNA conversion turns off leading gene expression and licences the expression of the other plasmid genes under the control of conventional double-stranded promoters. This elegant molecular strategy evolved by the conjugative plasmid allows for the timely production of factors sequentially involved in establishing, maintaining and disseminating the plasmid.
Extending protein interaction networks using proteoforms and small molecules
Authors: Hernández Sánchez Luis Francisco , Burger Bram , Castro Campos Rodrigo Alexander , Johansson Stefan , Njølstad Pål Rasmus , Barsnes Harald , Vaudel Marc
Published: September 2022

Biological network analysis is used to interpret modern high-throughput biomedical data sets in terms of biological functions and pathways. However, the results greatly depend on the topological characteristics of the underlying network, commonly composed of nodes representing genes or proteins that are connected by edges when interacting. In this study, we build biological networks accounting for small molecules, protein isoforms and post-translational modifications. We highlight how these change the global structure of the network and how the connectedness of pathway-based networks is altered. Our findings highlight the importance of carefully crafting the networks for network analysis to better represent the reality of biological systems.
Comparative abundance and diversity of populations of thePseudomonas syringaeand Soft RotPectobacteriaceaespecies complexes throughout the Durance River catchment from its French Alps sources to its delta
Authors: Morris C.E. , Lacroix C. , Chandeysson C. , Guilbaud C. , Monteil C. , Piry S. , Newall E. Rochelle , Fiorini S. , Van Gijsegem F. , Barny M.A. , Berge O.
Published: September 2022

Rivers, creeks, streams are integrators of biological, chemical and physical processes occurring in a catchment linking land cover from the headwaters to the outlet. The dynamics of human and animal pathogens in catchments have been widely studied in a large variety of contexts allowing the optimization of disease risk reduction. In parallel, there is an emerging awareness that crop pathogens might also be disseminated via surface waters especially when they are used for irrigation. However, there are no studies on the extent to which potential plant pathogens are present – nor about their dynamics - along the full course of a catchment. Here we have compared the seasonal dynamics of populations of thePseudomonas syringae(Psy) and the Soft RotPectobacteriaceae(SRP) species complexes along a 270 km stretch of the Durance River from the upstream alpine reaches to the downstream agricultural production areas at the confluence with the Rhone River at Avignon. Among 168 samples collected at 21 sites in fall, winter, spring and summer of 2016 and 2017, Psy strains were detected at all sampling sites and in 156 of the samples at population densities up to 105bacteria L−1. In contrast, SRP strains were detected in 98 of the samples, mostly from the southern part of the river, at population densities that did not exceed 3 × 104bacteria L−1. Among the biological and chemical parameters that were characterized at each sampling site, temperature was the only factor that explained a significant amount of the variability in population size for both species complexes. Psy densities decreased with increasing temperature whereas SRP densities increased with increasing temperature. River-borne populations of SRP were composed mainly ofPectobacterium versatileandP. aquaticumthat have little known epidemiological importance. Only a few strains ofPectobacteriumandDickeyaspecies reputed for their epidemiological impact were observed. In contrast, Psy populations at all sites were dominated by a genetic lineage of phylogroup 2 known from other studies for its broad host range and its geographic and habitat ubiquity. Our observations suggest that surveillance of river water for SRP could be leveraged to signal diagnostic and management reactions to avoid disease outbreaks. In contrast, the constant presence of Psy throughout the catchment in absence of regular and widespread disease outbreaks due to this group of bacteria suggests that surveillance should focus on future changes in land use, river water conditions and agronomic practices that could destabilize the mechanisms currently holding Psy outbreaks in check.
Initial niche condition determines the aging speed and regenerative activity of quiescent cells
Authors: Liu Qi , Sheng Nan , Zhang Zhiwen , He Chenjun , Zhao Yao , Sun Haoyuan , Chen Jianguo , Yang Xiaojing , Tang Chao
Published: September 2022

Quiescent cell ages with decline in both the survivability and regenerative activity. While most cellular quiescence/ageing research have focused on the survivability and from the population level, the question how the regenerative activity change with the quiescence time (i.e., chronological age) has rarely been addressed quantitatively. In this work, we systematically measured both features in ageing quiescent fission yeast cells at single cell level. We found that the regenerative activity declines linearly before survivability decline and the cellular chronological ageing speed is predetermined by the initial niche condition. Moreover, this linear ageing behavior is robust under various niche conditions and follows a common ageing trajectory in terms of gene expression. Furthermore, initial calorie restriction was found to improve not only the survivability but also the later regenerative activity. Our results reveal a continuous diverse spectrum of quiescence depth and ageing plasticity.
Inferring local molecular dynamics from the global actin network structure: a case study of 2D synthetic branching actin networks
Authors: Rostami Minghao W. , Bannish Brittany E. , Gasior Kelsey , Pinals Rebecca L. , Copos Calina , Dawes Adriana T.
Published: September 2022

Cells rely on their cytoskeleton for key processes including division and directed motility. Actin filaments are a primary constituent of the cytoskeleton. Although actin filaments can create a variety of network architectures linked to distinct cell functions, the microscale molecular interactions that give rise to these macroscale structures are not well understood. In this work, we investigate the microscale mechanisms that produce different branched actin network structures using an iterative classification approach. First, we employ a simple yet comprehensive agent-based model that produces synthetic actin networks with precise control over the microscale dynamics. Then we apply machine learning techniques to classify actin networks based on measurable network density and geometry, identifying key mechanistic processes that lead to particular branched actin network architectures. Extensive computational experiments reveal that the most accurate method uses a combination of supervised learning based on network density and unsupervised learning based on network symmetry. This framework can potentially serve as a powerful tool to discover the molecular interactions that produce the wide variety of actin network configurations associated with normal development as well as pathological conditions such as cancer.
Flexible communication between cell assemblies and ‘reader’ neurons
Authors: Pompili Marco N. , Todorova Ralitsa , Boucly Céline J. , Leroux Eulalie M. , Wiener Sidney I. , Zugaro Michaël
Published: September 2022

Cell assemblies are considered fundamental units of brain activity, underlying diverse functions ranging from perception to memory and decision-making. Cell assemblies have generally been studied in relation to specific stimuli or actions, but this approach does not readily extend to more abstract constructs. An alternative approach is to assess cell assemblies without making reference to external variables, and instead focus on internal brain processes — by defining assemblies by their endogenous ability to effectively elicit specific responses in downstream (‘reader’) neurons. However, this compelling idea currently lacks experimental support. Here, we provide evidence for assembly–reader communication. Reader activation was genuinely collective, functionally selective, yet flexible, implementing both pattern separation and completion. These processes occurred at the time scale of membrane integration, synaptic plasticity and gamma oscillations. Finally, assembly–reader couplings were selectively modified upon associative learning, indicating that they were plastic and could become bound to behaviorally relevant variables. These results support cell assemblies as an endogenous mechanism for brain function.
Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers
Authors: Savary Clara , Huchedé Paul , Luciana Léa , Tourbez Arthur , Deligne Clémence , Picard Cécile , Diot Thomas , Coquet Claire , Meynard Nina , Grand Marion Le , Tonon Laurie , Gadot Nicolas , Degletagne Cyril , Léon Sophie , Attignon Valéry , Bomane Alexandra , Rochet Isabelle , Müller Kevin , Mournetas Virginie , Bergeron Christophe , Rinaudo Paul , Dutour Aurélie , Cordier-Bussat Martine , Dijoud Frédérique , Corradini Nadège , Maucort-Boulch Delphine , Pasquier Eddy , Blay Jean-Yves , Castets Marie , Broutier Laura
Published: September 2022

Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS.

Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of their preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data.
Heritability enrichment in context-specific regulatory networks improves phenotype-relevant tissue identification
Authors: Feng Zhanying , Duren Zhana , Xin Jingxue , Yuan Qiuyue , He Yaoxi , Su Bing , Wong Wing Hung , Wang Yong
Published: September 2022

Systems genetics holds the promise to decipher complex traits by interpreting their associated SNPs through gene regulatory networks derived from comprehensive multi-omics data of cell types, tissues, and organs. Here, we propose SpecVar to integrate paired chromatin accessibility and gene expression data into context-specific regulatory network atlas and regulatory categories, conduct heritability enrichment analysis with GWAS summary statistics, identify relevant tissues, and depict shared heritability and regulations by relevance correlation. Our method improves power upon existing approaches by associating SNPs with context-specific regulatory elements to assess heritability enrichments and by explicitly prioritizing gene regulations underlying relevant tissues. Experiments on GWAS of six phenotypes show that SpecVar can improve heritability enrichment, accurately detect relevant tissues, and reveal causal regulations. Furthermore, SpecVar correlates the relevance patterns for pairs of phenotypes and better reveals shared heritability and regulations of phenotypes than existing methods. Studying GWAS of 206 phenotypes in UK-Biobank demonstrates that SpecVar leverages the context-specific regulatory network atlas to prioritize phenotypes’ relevant tissues and shared heritability for biological and therapeutic insights. SpecVar provides a powerful way to interpret SNPs via context-specific regulatory networks and is available at https://github.com/AMSSwanglab/SpecVar.
Coordinated and distinct LD-transpeptidase-independent roles of peptidoglycan carboxypeptidases DacC and DacA in stress adaptation and cell shape maintenance
Authors: Choi Umji , Park Si Hyoung , Lee Han Byeol , Lee Chang-Ro
Published: September 2022

Peptidoglycan (PG) is an essential bacterial architecture pivotal for shape maintenance and adaptation to osmotic stress. Although PG synthesis and modification are tightly regulated under harsh environmental stresses, few related mechanisms have been investigated. In this study, we aimed to investigate the coordinated and distinct roles of the PG carboxypeptidases DacC and DacA, in adaptation to alkaline and salt stresses and shape maintenance in Escherichia coli. We found that DacC is an alkaline PG carboxypeptidase, whose enzyme activity and protein stability are significantly enhanced under alkaline stress. Both DacC and DacA were required for bacterial growth under alkaline stress, whereas only DacA was required for the adaptation to salt stress. Under normal growth conditions, only DacA was necessary for cell shape maintenance, while under alkaline stress conditions, both DacA and DacC were necessary for cell shape maintenance, but their roles were distinct. Notably, all these roles of DacC and DacA were independent of LD-transpeptidases, which are necessary for the formation of PG 3-3 crosslinks and covalent bonds between PG and the outer membrane lipoprotein Lpp. Instead, DacC and DacA interacted with penicillin-binding proteins (PBPs), DD-transpeptidases, mostly in a C-terminal domain-dependent manner, and these interactions were necessary for most of their roles. Collectively, our results demonstrate the coordinated and distinct novel roles of PG carboxypeptidases in stress adaptation and shape maintenance and provide novel insights into the cellular functions of PG carboxypeptidases associated with PBPs.
Comparing the signaling and transcriptome profiling landscapes of human iPSC-derived and primary rat neonatal cardiomyocytes
Authors: Bourque Kyla , Jones-Tabah Jace , Pétrin Darlaine , Martin Ryan D. , Hébert Terence E.
Published: September 2022

The inaccessibility of human cardiomyocytes significantly hindered years of cardiovascular research efforts. Post-mortem tissue or biopsies from diseased patients, which remain scarcely available, rendered it possible to study end-stage heart disease yet the inclusion of healthy human cardiac materials for basic science research was beyond reach. To overcome these limitations, non-human cell sources were used as proxies to study heart function and associated diseases. Rodent models became increasingly acceptable surrogates to model the human heart either in vivo or through in vitro cultures. More recently, due to concerns regarding animal to human translation, including cross-species differences, the use of human inducible stem cell derived cardiomyocytes presented a renewed opportunity. We think it necessary to conduct a comparative study, assessing cellular signalling through cardiac G protein-coupled receptors and bulk transcriptomics of traditional rat neonatal cardiomyocytes and human iPSC-CMs. Genetically-encoded biosensors were used to interrogate nuclear protein kinase A (PKA) and extracellular signal-regulated kinase 1/ 2 (ERK1/2) in rat and human-derived cardiomyocyte populations. To increase data granularity, a single-cell analytical approach was conducted for an in-depth examination of existing differences between both in vitro cardiomyocyte models. Using automated high content microscopy, our analyses of nuclear PKA and ERK1/2 signaling revealed distinct response clusters in rat and human CMs. In line with this, bulk RNA-seq demonstrated key differences regarding the expression patterns of GPCRs, G proteins and effectors. Overall, our study demonstrates that human stem cell derived models of the cardiomyocyte do provide significant advantages and should be taken advantage of.
Omicron-induced interferon signalling prevents influenza A virus infection
Authors: Bojkova Denisa , Bechtel Marco , Rothenburger Tamara , Kandler Joshua D. , Hayes Lauren , Olmer Ruth , Ulrich Martin , Jonigk Danny , Ciesek Sandra , Wass Mark N. , Michaelis Martin , Cinatl Jindrich
Published: September 2022

Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show that BA.1 and BA.5 but not Delta induce an antiviral state in air-liquid interface (ALI) cultures of primary human bronchial epithelial (HBE) cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active type I (α/β) and III (λ) interferons and protected cells from super-infection with influenza A viruses. Notably, abortive Omicron infection of monocytes was sufficient to protect monocytes from influenza A virus infection. Interestingly, while influenza-like illnesses surged during the Delta wave in England, their spread rapidly declined upon the emergence of Omicron. Mechanistically, Omicron-induced interferon signalling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knock-out prevented it. The JAK/ STAT inhibitor baricitinib inhibited the Omicron-mediated antiviral response, suggesting it is caused by MDA5-mediated interferon production, which activates interferon receptors that then trigger JAK/ STAT signalling. In conclusion, our study 1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, 2) shows that Omicron infection protects cells from influenza A virus super-infection, and 3) indicates that BA.1 and BA.5 induce comparable antiviral states.
A novel cancer-associated cassette exon in TLN1 alters Talin 1 mechanosensitivity
Authors: Gallego-Paez Lina M. , Edwards William J.S. , Guo Yanyu , Chanduri Manasa , Koorman Thijs , Lee Chieh-Yu , Grexa Nina , Derksen Patrick W. B. , Yan Jie , Schwartz Martin A. , Mauer Jan , Goult Benjamin T.
Published: September 2022

Talin 1 is the core mechanosensitive adapter protein linking integrins to the cytoskeleton. The TLN1 gene is comprised of 57 exons that encode the 2541 amino acid TLN1 protein. TLN1 was previously considered to be expressed as a single isoform. However, through differential pre-mRNA splicing analysis, we discovered a cancer-enriched, non-annotated 51-nucleotide exon in TLN1 between exons 17 and 18, which we refer to as exon 17b. TLN1 is comprised of an N-terminal FERM domain, linked to 13 force-dependent switch domains, R1-R13. Inclusion of exon 17b results in an in-frame insertion of 17 amino acids immediately after Gln665 in the region between R1-R2 which lowers the force required to open the R1-R2 switches potentially altering downstream mechanotransduction. Biochemical analysis of this isoform revealed enhanced vinculin binding, and cells expressing this variant show altered adhesion dynamics. Finally, we show that the TGF-β/SMAD3 signaling pathway regulates this isoform switch. Future studies will need to consider the balance of these two TLN1 isoforms.
Evaluation of noninvasive biospecimens for transcriptome studies
Authors: Martorella Molly , Kasela Silva , Garcia-Flores Renee , Gokden Alper , Castel Stephane E. , Lappalainen Tuuli
Published: September 2022

Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are limited to investigating cell types found in blood. Noninvasive tissues may improve disease-relevant discovery by enabling more complex longitudinal study designs, by capturing different and potentially more applicable cell types, and by increasing sample sizes due to reduced collection costs and possible higher enrollment from vulnerable populations. Here, we develop methods for sampling noninvasive biospecimens, investigate their performance across commercial and in-house library preparations, characterize their biology, and assess the feasibility of using noninvasive tissues in a multitude of transcriptomic applications. We collected buccal swabs, hair follicles, saliva, and urine cell pellets from 19 individuals over three to four timepoints, for a total of 300 unique biological samples, which we then prepared with replicates across three library preparations, for a final tally of 472 transcriptomes. Of the four tissues we studied, we found hair follicles and urine cell pellets to be most promising due to the consistency of sample quality, the cell types and expression profiles we observed, and their performance in disease-relevant applications. This is the first study to thoroughly delineate biological and technical features of noninvasive samples and demonstrate their use in a wide array of transcriptomic and clinical analyses. We anticipate future use of these biospecimens will facilitate discovery and development of clinical applications.