bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraperitoneal transfer of wild-type bone marrow cells in theCsf1rknockout rat repopulates resident tissue macrophages without contributing to monocytopoiesis
Authors: Sehgal Anuj , Carter-Cusack Dylan , Keshvari Sahar , Patkar Omkar , Huang Stephen , Summers Kim M. , Hume David A. , Irvine Katharine M.
Published: February 2023

Homozygous null mutation of the macrophage colony-stimulating factor receptor (Csf1r) gene in rats leads to the loss of most tissue macrophage populations and has pleiotropic impacts on postnatal growth and organ maturation leading to mortality by 8-12 weeks of age. The phenotype of theCsf1rknockout (Csf1rko) can be reversed by intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning. Here we used aCsf1r-mApple transgenic reporter, which is expressed in neutrophils and B cells as well as monocytes and macrophages, to track the fate of donor-derived cells. Following BMT intoCsf1rrecipients, wild-type mApple+vecells restored IBA1+tissue macrophage populations in every tissue donor-derived cells also completely replaced recipient macrophages in organs such as spleen, lung and liver that were only partly macrophage-deficient in theCsf1rko. However, monocytes, neutrophils and B cells in bone marrow, blood and lymphoid tissues remained of recipient (mApple-ve) origin. An mApple+vecell population expanded in the peritoneal cavity and invaded locally in the mesentery, fat pads, omentum and diaphragm. One week after BMT, distal organs contained foci of mApple+ve, IBA1-veimmature progenitors that appeared to proliferate, migrate and differentiate locally. We conclude that rat bone marrow contains progenitor cells that are able to restore and maintain all tissue macrophage populations in aCsf1rkorat directly without contributing to the bone marrow progenitor or blood monocyte populations.
Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer
Authors: Garioni Michele , Blukacz Lauriane , Nuciforo Sandro , Parmentier Romuald , Roma Luca , Coto-Llerena Mairene , Pueschel Heike , Piscuoglio Salvatore , Vlajnic Tatjana , Stenner Frank , Seifert Hans-Helge , Rentsch Cyrill A. , Bubendorf Lukas , Magnen Clémentine Le
Published: February 2023

Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such asTP53, RB1, andKRAS. High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.
Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication
Authors: Davila-Calderon Jesse , Li Mei-Ling , Penumutchu Srinivasa R. , Haddad Christina , Malcolm Linzy , Hargrove Amanda E. , Brewer Gary , Tolbert Blanton S.
Published: February 2023

Selective pressures on positive-strand RNA viruses provide opportunities to establish target site specificity and mechanisms of action of antivirals. Here, Enterovirus-A71 revertant viruses with resistant mutations in the SLII IRES domain (SLIIresist) were selected at low doses of the antiviral DMA-135. The EV-A71 revertant viruses were resistant to DMA-135 at concentrations that robustly inhibit replication of wild-type virus. EV-A71 IRES structures harboring the suppressor mutations induced efficient expression of reporter Luciferase mRNA in the presence of non-cytotoxic doses of DMA-135 whereas DMA-135 dose-dependently inhibited Luciferase expression from the wild-type IRES element. NMR studies indicate that the resistant mutations change the structure of SLII at the bulge loop binding site of DMA-135 and at part of an extended surface recognized by host RNA-binding protein AUF1. Comparisons of biophysical analysis of complexes formed between AUF1, DMA-135, or either SLII or SLIIresistshow that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLIIresist. Further studies demonstrate that the hnRNP A1 protein retains binding affinity for SLIIresist, illustrating that DMA-135 inhibition and viral resistance do not perturb the SLII-hnRNP A1 arm of the regulatory axis. Taken together, this work demonstrates how viral evolution under selective pressures of small molecules can elucidate RNA binding site specificity, mechanisms of action, and provide additional insights into the viral pathways inhibited by the antiviral DMA-135.
Disease-associated programming of cell memory in glycogen storage disorder type 1a
Authors: Sprecher U , D’Souza J , Mishra K , Muchtar N , Shalev O , Eliassaf A , Morshina A , Canella Miliano A , Mithieux G , Rajas F , Avraham S , Castellani Moses F , Kauffman H , Bergman Y , Garti N , Garti S , Linial M , Anikster Y , Kakhlon O , Weil M
Published: February 2023

Glycogen storage disorder type 1a (GSD1a) is caused by loss-of-function mutations in the catalytic subunit of glucose-6-phosphatase enzyme (G6PC1) in the liver, kidney and intestine exclusively. Here we show the surprising results that while not expressingG6PC1, primary skin fibroblasts isolated from GSD1a patients’ skin biopsies preserve a distinctive disease phenotype irrespective of the different culture conditions under which they grow. This discovery was initially made by phenotypic image-based high content analysis (HCA). Deeper analysis into this disease phenotype, revealed impaired lysosomal and mitochondrial functions in GSD1a cells, which were driven by a transcriptional dysregulation of the NAD+/NADH-Sirt-1-TFEB regulatory axis. This dysregulation impacts the normal balance between mitochondrial biogenesis and mitophagy in the patients’ cells. The distinctive GSD1a fibroblasts phenotype involves elevated H3 histone acetylation, global DNA hypomethylation, differences in the chromatin accessibility and different RNA-seq and metabolomic profiles, all of which suggesting that in some way a distinctive disease cell phenotype is programmed in these cellsin vivoand that this phenotype is maintainedin vitro. Supporting this notion, reversing H3 acetylation in these cells erased the original cellular phenotype in GSD1a cells. Remarkably, GHF201, an established glycogen reducing molecule, which ameliorated GSD1a pathology in a liver-targeted inducibleL.G6pc-knockout mouse model, also reversed impaired cellular functions in GSD1a patients’ fibroblasts. Altogether, this experimental evidence strongly suggests that GSD1a fibroblasts express a strong and reversible disease phenotype without expressing the causalG6PC1gene.
A globalCorynebacterium diphtheriaegenomic framework sheds light on current diphtheria reemergence
Authors: Hennart Melanie , Crestani Chiara , Bridel Sebastien , Armatys Nathalie , Brémont Sylvie , Carmi-Leroy Annick , Landier Annie , Passet Virginie , Fonteneau Laure , Vaux Sophie , Toubiana Julie , Badell Edgar , Brisse Sylvain
Published: February 2023

Background

Diphtheria, caused byCorynebacterium diphtheriae, reemerges in Europe since 2022. Genomic sequencing can inform on transmission routes and genotypes of concern, but currently, no standard approach exists to detect clinically important genomic features and to interpret emergence in the globalC. diphtheriaepopulation framework.

Methods

We developed the bioinformatics pipeline DIPHTOSCAN (available athttps://gitlab.pasteur.fr/BEBP/diphtoscan) to extract from genomes of Corynebacteria of thediphtheriaespecies complex, medically relevant features includingtoxgene presence and disruption. We analyzed 101 humanC. diphtheriaeisolates collected in 2022 in metropolitan and overseas France (France-2022). To define the population background of this emergence, we sequenced 379 additional isolates (mainly from France, 2018-2021) and collated 870 publicly-available genomes.

Results

The France-2022 isolates comprised 45tox-positive (44 toxigenic) isolates, mostly imported, belonging to 10 sublineages (<500 distinct core genes). The global dataset comprised 245 sublineages and 33.9%tox-positive genomes, with DIPHTOSCAN predicting non-toxigenicity in 16.0% of these. 12% of the global isolates, and 43.6% of France-2022 ones, were multidrug resistant. Convergence of toxigenicity with penicillin and erythromycin resistance was observed in 2 isolates from France-2022. Phylogenetic lineages Gravis and Mitis contrasted strikingly in their pathogenicity-associated genes.

Conclusions

This work provides a bioinformatics tool and global population framework to analyzeC. diphtheriaegenomes, revealing important heterogeneities in virulence and resistance features. Emerging genotypes combining toxigenicity and first-line antimicrobial resistance represent novel threats. Genomic epidemiology studies ofC. diphtheriaeshould be intensified globally to improve understanding of reemergence and spatial spread.
A sweeter future: Using protein language models for exploring sweeter brazzein homologs
Authors: Chua Bryan Nicholas , Guo Wei Mei , Wong Han Teng , Ow Dave Siak-Wei , Ho Pooi Leng , Koh Winston , Koay Ann , Wong Fong Tian
Published: February 2023

Reducing sugar intake lowers the risk of obesity and associated metabolic disorders. Currently, this is achieved using artificial non-nutritive sweeteners, where their safety is widely debated and their contributions in various diseases is controversial. Emerging research suggests that these sweeteners may even increase the risk of cancer and cardiovascular problems, and some people experience gastrointestinal issues as a result of using them. A safer alternative to artificial sweeteners could be sweet-tasting proteins, such as brazzein, which do not appear to have any adverse health effects.

In this study, protein language models were explored as a new method for protein design of brazzein. This innovative approach resulted in the identification of unexpected mutations, which opened up new possibilities for engineering thermostable and potentially sweeter versions of brazzein. To facilitate the characterization of the brazzein mutants, a simplified procedure was developed for expressing and analyzing related proteins. This process involved an efficient purification method usingLactococcus lactis(L. lactis), a generally recognized as safe (GRAS) bacterium, as well as taste receptor assays to evaluate sweetness. The study successfully demonstrated the potential of computational design in producing a more heat-resistant and potentially more palatable brazzein variant, V23.
Fusogenic Structural Changes in Arenavirus Glycoproteins are Associated with Viroporin Activity
Authors: Zhang You , York Joanne , Brindley Melinda A. , Nunberg Jack H. , Melikyan Gregory B.
Published: February 2023

Many enveloped viruses enter host cells by fusing with acidic endosomes. The fusion activity of multiple viral envelope glycoproteins does not generally affect viral membrane permeability. However, fusion induced by the Lassa virus (LASV) glycoprotein complex (GPc) is always preceded by an increase in viral membrane permeability and the ensuing acidification of the virion interior. Here, systematic investigation of “leaky” LASV fusion using single pseudoparticle tracking in live cells reveals that the change in membrane barrier function is associated with the fusogenic conformational reorganization of GPc. We show that a small- molecule fusion inhibitor or mutations that impair viral fusion by interfering with GPc refolding into the post-fusion structure prevent the increase in membrane permeability. We find that the increase in virion membrane permeability occurs early during endosomal maturation and is facilitated by virus-cell contact. This increase is observed using diverse arenavirus glycoproteins, whether presented on lentivirus-based pseudoviruses or arenavirus-like particles, and in multiple different cell types. Collectively, these results suggest that conformational changes in GPc triggered by low pH and cell factor binding are responsible for virion membrane permeabilization and acidification of the virion core prior to fusion. We propose that this viroporin-like activity may augment viral fusion and/or post-fusion steps of infection, including ribonucleoprotein release into the cytoplasm.

Authors summary

Fusion of enveloped virus with host cell membranes is mediated by extensive conformational changes in viral glycoproteins, triggered by binding to cognate receptors and/or by exposure to acidic pH in the maturing endosome. We have previously reported that, unlike many other viral glycoproteins, pH-triggered endosomal fusion by the Lassa virus viral glycoprotein complex (GPc) is preceded by a mild permeabilization of the viral membrane. Here, we provide evidence that this activity is associated with early fusogenic changes in the GPc and is markedly enhanced by virus-cell contact. Permeabilization is induced by the glycoproteins of diverse arenaviruses and occurs in multiple target cell types. Based on these observations, we propose that, by analogy to the influenza virus M2 channel, membrane permeabilization and the resultant acidification of the arenavirus interior facilitate viral fusion and/or post-fusion steps of infection.
Co-chaperone-mediated post-translational control of efflux pump induction underlies adaptive β-lactam resistance inCaulobacter crescentus
Authors: Costafrolaz Jordan , Panis Gaël , Casu Bastien , Ardissone Silvia , Degeorges Laurence , Pilhofer Martin , Viollier Patrick H.
Published: February 2023

The acquisition of multi-drug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the non-pathogenic α-proteobacteriumCaulobacter crescentusvia transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (β-lactam) antibiotics. Combining two-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR uses a common operator of the divergenttipRandacrAB-nodTpromoter for adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified compounds that interfere with DNA-binding by TipR or induce its dependent proteolytic turnover. We found that long-term induction of AcrAB-NodT disfigures the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, to boost pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.
Kaempferol suppresses the activation of mast cells by modulating the expression of FcεRI and SHIP1
Authors: Nagata Kazuki , Araumi Sanae , Ando Daisuke , Ando Miki , Ito Naoto , Ikeda Yuki , Takahashi Miki , Noguchi Sakura , Yashiro Takuya , Hachisu Masakazu , Nishiyama Chiharu
Published: February 2023

In the present study, we evaluated the effects of kaempferol on bone marrow-derived mast cells (BMMCs). Kaempferol treatment significantly and dose-dependently inhibited IgE-induced degranulation, and cytokine production of BMMCs under the condition that cell viability was maintained. Kaempferol downregulated the surface expression levels of FcεRI on BMMCs, but the mRNA levels of FcεRIα, β, and γ-chains were not changed by kaempferol treatment. Furthermore, the kaempferol-mediated downregulation of surface FcεRI on BMMCs was still observed in the presence of a protein-synthesis inhibitor. These results suggest that kaempferol reduced the surface FcεRI on BMMCs, independently of transcription and translation. We also found that kaempferol inhibited both LPS- and IL-33-induced IL-6 production from BMMCs, without affecting the expression levels of their receptors, TLR4 and ST2. Although kaempferol treatment increased the protein amount of NRF2, a master transcription factor of antioxidant stress, in BMMCs, inhibition of NRF2 did not alter the suppressive effect of kaempferol on degranulation. Finally, we observed that kaempferol treatment increased the levels of mRNA and protein of a phosphatase SHIP1 in BMMCs. These results indicate that kaempferol inhibited the IgE-induced activation of BMMCs by downregulating FcεRI and upregulating SHIP1, and the SHIP1 increase is involved in the suppression of various signaling-mediated stimulations of BMMCs, such as those associated with TLR4 and ST2.
Assessment of long-term trends in genetic mean and variance after the introduction of genomic selection in layers: a simulation study
Authors: Pocrnic Ivan , Obšteter Jana , Gaynor R. Chris , Wolc Anna , Gorjanc Gregor
Published: February 2023

Nucleus-based breeding programs are characterized by intense selection that results in high genetic gain, which inevitably means reduction of genetic variation in the breeding population. Therefore, genetic variation in such breeding systems is typically managed systematically, for example, by avoiding mating the closest relatives to limit progeny inbreeding. However, intense selection requires maximum effort to make such breeding programs sustainable in the long-term. The objective of this study was to use simulation to evaluate the long-term impact of genomic selection on genetic mean and variance in an intense layer chicken breeding program. We developed a large-scale stochastic simulation of an intense layer chicken breeding program to compare conventional truncation selection to genomic truncation selection optimized with either minimization of progeny inbreeding or full-scale optimal contribution selection. We compared the programs in terms of genetic mean, genic variance, conversion efficiency, rate of inbreeding, effective population size, and accuracy of selection. Our results confirmed that genomic truncation selection has immediate benefits compared to conventional truncation selection in all specified metrics. A simple minimization of progeny inbreeding after genomic truncation selection did not provide any significant improvements. Optimal contribution selection was successful in having better conversion efficiency and effective population size compared to genomic truncation selection, but it must be fine-tuned for balance between loss of genetic variance and genetic gain. In our simulation, we measured this balance using trigonometric penalty degrees between truncation selection and a balanced solution and concluded that the best results were between 45° and 65°. This balance is specific to the breeding program and depends on how much immediate genetic gain a breeding program may risk vs. save for the future. Furthermore, our results show that the persistence of accuracy is better with optimal contribution selection compared to truncation selection. In general, our results show that optimal contribution selection can ensure long-term success in intensive breeding programs using genomic selection.
A purely visual adaptation to motion can differentiate between perceptual timing and interval timing
Authors: Bruno Aurelio , Segala Federico G. , Baker Daniel H.
Published: February 2023

It is unclear whether our brain extracts and processes time information using a single centralized mechanism or through a network of distributed mechanisms, which are specific for modality and time range. Visual adaptation has previously been used to investigate the mechanisms underlying time perception for millisecond intervals. Here, we investigated whether a well-known duration aftereffect induced by motion adaptation in the sub-second range (referred to as ‘perceptual timing’), also occurs in the supra-second range (called ‘interval timing’), which is more accessible to cognitive control. Participants judged the relative duration of two intervals after spatially localized adaptation to drifting motion. Adaptation substantially compressed the apparent duration of a 600 ms stimulus in the adapted location, whereas it had a much weaker effect on a 1200 ms interval. Discrimination thresholds after adaptation improved slightly relative to baseline, implying that the duration effect cannot be ascribed to changes in attention or to noisier estimates. A novel computational model of duration perception can explain these results, and also bidirectional shifts of perceived duration after adaptation reported in other studies. We suggest that we can use adaptation to visual motion as a tool to investigate the mechanisms underlying time perception at different time scales.
Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection
Authors: Liccardo Francesca , Śniegocka Martyna , Tito Claudia , Iaiza Alessia , Ottone Tiziana , Divona Mariadomenica , Travaglini Serena , Mattei Maurizio , Cicconi Rossella , Miglietta Selenia , Familiari Giuseppe , Nottola Stefania Annarita , Petrozza Vincenzo , Tamagnone Luca , Voso Maria Teresa , Masciarelli Silvia , Fazi Francesco
Published: February 2023

Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). It exerts strong cytotoxic activity on FLT3-ITD+AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with bone marrow stromal cells (BMSC). Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML cells and BMSC upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSC. Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML cells and BMSC, involving mechanotransduction and YAP signaling
Homogenic endothelium-independent hematopoiesis ensures the abundance of erythrocytes and macrophages during zebrafish development.
Authors: Elsaid Ramy , Mikdache Aya , Quintero Castillo Keinis , Salloum Yazan , Diabangouaya Patricia , Gros Gwendoline , Feijoo Carmen , Hernandez Pedro Pablo
Published: February 2023

In all organisms studied, from flies to humans, blood cells emerge in several sequential waves and from distinct hematopoietic origins. However, the relative contribution of these ontogenetically distinct hematopoietic waves to embryonic blood lineages and to tissue regeneration during development is yet elusive. Here, using a lineage-specific switch and trace strategy in the zebrafish embryo, we report that the definitive hematopoietic progeny barely contributes to erythrocytes and macrophages during early development. Lineage tracing further show that ontogenetically distinct macrophages exhibit differential recruitment to the site of injury based on the developmental stage of the organism. We further demonstrate that primitive macrophages can solely maintain tissue regeneration during early larval developmental stages after selective ablation of definitive macrophages. Our findings highlight that the sequential emergence of hematopoietic waves in embryos ensures the abundance of blood cells required for tissue homeostasis and integrity during development.
Chronic industrial perturbation and seasonal change induces shift in the bacterial community from gammaproteobacteria to betaproteobacteria at Amlakhadi canal
Authors: Johnson Jenny , Jain Kunal R. , Patel Anand , Parmar Nidhi , Joshi Chaitanya , Madamwar Datta
Published: February 2023

Escalating proportions of industrially contaminated sites are one of the major catastrophes faced at the present time due to the industrial revolution. In the outlook of the obstacles associated with culturing the microbes, the direct metagenomic analysis of various complex niches is rapidly gaining attention. In this study, metagenomic approach using next generation sequencing technologies was applied to exemplify the taxonomic abundance and metabolic potential of the microbial community residing in Amlakhadi canal, Ankleshwar at two different seasons. All the metagenomes revealed a predominance of Proteobacteria phylum. However, difference was observed within class level where Gammaproteobacteria was relatively high in polluted metagenome in Summer while in Monsoon the abundance shifted to Betaproteobacteria. Similarly, significant statistical differences were obtained while comparing the genera amongst contaminated sites whereSerratia, Achromobacter, StenotrophomonasandPseudomonaswere abundant at one season and the dominance changed toThiobacillus, Thauera, Acidovorax, Nitrosomonas, Sulfuricurvum, Novosphingobium, HyphomonasandGeobacterat the next season. Further upon functional characterization, the microbiomes demonstrated diverse survival mechanisms adapted by the inherent microbial community such as degradation of aromatic compounds, heavy metal resistance, oxidative stress responses and multidrug resistance efflux pumps. The results have important implications in understanding and predicting the impacts of human-induced activities on microbial communities inhabiting natural niche and their responses in coping with the fluctuating pollution load.
Compensation to visual impairments and behavioral plasticity in navigating ants
Authors: Schwarz Sebastian , Clement Leo , Haalck Lars , Risse Benjamin , Wystrach Antoine
Published: February 2023

Desert ants are known to rely heavily on vision while venturing for food and returning to the nest. During these foraging trips, ants memorize and recognize their visual surroundings, which enables them to recapitulate individually learnt routes in a fast and effective manner. The compound eyes are crucial for such visual navigation; however, it remains unclear how information from both eyes are integrated and how ants cope with visual impairment. Here we manipulated the ants’ visual system by covering one of the two compound eyes and analyzed their ability to recognize familiar views in various situations. Monocular ants showed an immediate disruption of their ability to recapitulate their familiar route. However, they were able to compensate for the visual impairment in a few hours by restarting a route-learning ontogeny, as naïve ants do. This re-learning process with one eye forms novel memories, without erasing the previous memories acquired with two eyes. Additionally, ants having learnt a route with one eye only are unable to recognize it with two eyes, even though more information is available. Together, this shows that visual memories are encoded and recalled in an egocentric and fundamentally binocular way, where the visual input as a whole must be matched to enable recognition. We show how this kind of visual processing fits with their neural circuitry.

Significance Statement

If humans look at the world with both eyes, they have no problem to then recognize it with one eye only, and vice-versa. Thus, our way of encoding the world is robust to changes of the visual field. Yet ants do so very differently. Views learnt with two eyes can only be recognized with two eyes, and views learnt with one eye can only be recognized with one eyes (the same eye). However, this rigidity is compensated by a remarkable behavioral flexibility. Upon covering one eye, ants – which can no longer recognize their familiar surroundings – will restart a learning process to store these novel visual inputs in a parallel memory and resume their normal foraging activity.
Geometry-preserving Expansion Microscopy microplates enable high fidelity nanoscale distortion mapping
Authors: Seehra Rajpinder S. , Allouis Benjamin H.K. , Sheard Thomas M.D. , Spencer Michael E , Shakespeare Tayla , Cadby Ashley , Jayasinghe Izzy
Published: February 2023

Expansion microscopy (ExM) is a versatile super-resolution microscopy pipeline, leveraging nanoscale biomolecular cross- linking and osmotically driven swelling of hydrogels. In its current implementation, ExM remains a laborious and skill-intensive technique, involving manual handling of the hydrogels that can compromise the integrity of the gel matrix and diminish reproducibility. The lack of protocols to constrain the gel orientation during this process lends to challenges in tracking gel isotropy during or after the swelling. We have developed a bespoke microplate system capable of carrying out the entire ExM workflow within each well. The microplates enablein situimage acquisition and eliminate the need for direct physical handling of the hydrogels. The preservation of the gel geometry and orientation by the design of the microplate wells also enables convenient tracking of gel expansion, pre- and post-ExM image acquisition, and distortion mapping of every cell or region of interest. We demonstrate the utility of this approach with both single-colour and multiplexed ExM of HeLa cells cultured within the microplate wells to reveal nuclear and sub-plasmalemmal regions as distortion-prone structures.
Fast, multiplexable and highly efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9
Authors: Thürkauf Marco , Lin Shuo , Oliveri Filippo , Grimm Dirk , Platt Randall J. , Rüegg Markus A.
Published: February 2023

Molecular screens comparing different disease states to identify candidate genes rely on the availability of fast, reliable and multiplexable systems to interrogate genes of interest. CRISPR/Cas9- based reverse genetics is a promising method to eventually achieve this. However, such methods are sorely lacking for multi-nucleated muscle fibers, since highly efficient nuclei editing is a requisite to robustly inactive candidate genes. Here, we couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery to establish a system for highly effective somatic gene mutation in mice. Using well-characterized genes, we show that local or systemic inactivation of these genes copy the phenotype of traditional gene-knockout mouse models. Thus, this proof-of-principle study establishes a method to unravel the function of individual genes or entire signaling pathways in adult skeletal muscle fibers without the cumbersome requirement of generating knockout mice.
Bovine milk glycoproteins inhibit SARS-CoV-2 and influenza virus co-infection
Authors: Yu Hanjie , Chen Wentian , Shu Jian , Wu Xin , Quan Jia , Cheng Hongwei , Bao Xiaojuan , Wu Di , Wang Xilong , Li Zheng
Published: February 2023

The attachment of S1 subunit of spike (S) protein to angiotensin-converting enzyme 2 (ACE2) is the first and crucial step of SARS-CoV-2 infection. Although S protein and ACE2 are heavily glycosylated, the precise roles of glycans in their interactions are still unclear. Here, we profiled the glycopatterns of S1 subunit of SARS-CoV-2 and ACE2, and found that the galactosylated glycoforms were dominant in both S1 subunit and ACE2. Interestingly, S1 subunit exhibited the property of glycan-binding protein (GBP) and adhered to the ACE2 via binding to the galactosylated glycans on the ACE2. Our earlier findings demonstrated that the sialylated glycoproteins isolated from bovine milk potently inhibit and neutralize viral activity against influenza A virus (IAV). Importantly, we proved further that the galactosylated glycans on isolated glycoproteins bind to the glycan recognition domains of S1 subunit and competitively inhibit binding of S1 subunit to ACE2 and ultimately impede the entry of SARS-CoV-2 pseudovirus into host cells. We provided a potential protein drug that could be multiple simultaneous inhibitor for coronavirus and IAV co-infection.
Modeling temporal and spatial effects on plant reproduction using observational data
Authors: Rodrigues Flávio R.O. , Freitas Cintia G. , Dambros Cristian
Published: February 2023

Background and Aims

The persistence of a plant species at local sites depend on species ability to survive and reproduce under local conditions. Estimating environmental influence on reproduction is difficult because climatic and soil conditions have synergistic effects on flower and fruit production, and estimating these synergistic effects require tracking a large number of marked individuals. Here, we develop a statistical method that allows investigating the environmental influence on reproduction using observational data only (no marking required).

Methods

We surveyed 30 standardized permanent plots on central Amazonia for six herbaceous families of Zingiberales and Poales. The plots were surveyed for twelve consecutive months. Using the newly developed method, we estimated the effect of climatic (temporal) and edaphic (spatial) covariates on flower and fruit production.

Key results

We demonstrate that plant reproduction can be estimated from observational data only when enough temporal and spatial data are available. By using the proposed statistical method, we show that the conversion of flowers into fruits in Amazonian monocots is highest in sandy soils, and the difference in conversion rates between sandy and clayey soils is more pronounced in wetter months.

Conclusions

By comparing the production of flowers and fruits with previously published data on species occurrence, our results suggesting that species distribution is limited primarily by species capacity to produce fruits (e.g. limited pollination) and not by the capacity to produce flowers. Due to the association of fruit production to climatic and edaphic variables, our results point to potential changes in species reproduction and distribution under future climatic regimes.
Accounting for unobserved population dynamics and aging error in close-kin mark-recapture assessments
Authors: Swenson John D. , Brooks Elizabeth N. , Kacev Dovi , Boyd Charlotte , Kinney Michael , Marcy-Quay Benjamin , Sévêque Anthony , Feldheim Kevin , Komoroske Lisa M.
Published: February 2023

Obtaining robust estimates of population abundance is a central challenge hindering the conservation and management of many threatened and exploited species. Close-kin mark-recapture (CKMR) is a genetics-based approach that has strong potential to improve monitoring of data-limited species by enabling estimates of abundance, survival, and other parameters for populations that are challenging to assess. However, CKMR models have received limited sensitivity testing under realistic population dynamics and sampling scenarios, impeding application of the method in population monitoring programs and stock assessments. Here, we use individual-based simulation to examine how unmodeled population dynamics and aging uncertainty affect the accuracy and precision of CKMR parameter estimates under different sampling strategies. We then present adapted models that correct the biases that arise from model misspecification. Our results demonstrate that a simple base-case CKMR model produces robust estimates of population abundance with stable populations that breed annually; however, if a population trend or non-annual breeding dynamics are present, or if year-specific estimates of abundance are desired, a more complex CKMR model must be constructed. In addition, we show that CKMR can generate reliable abundance estimates for adults from a variety of sampling strategies, including juvenile-focused sampling where adults are never directly observed (and aging error is minimal). Finally, we apply a CKMR model that has been adapted for population growth and intermittent breeding to two decades of genetic data from juvenile lemon sharks (Negaprion brevirostris) in Bimini, Bahamas, to demonstrate how application of CKMR to samples drawn solely from juveniles can contribute to monitoring efforts for highly mobile populations. Overall, this study expands our understanding of the biological factors and sampling decisions that cause bias in CKMR models, identifies key areas for future inquiry, and provides recommendations that can aid biologists in planning and implementing an effective CKMR study, particularly for long-lived data-limited species.
The long-term effects of genomic selection: 2. Changes in allele frequencies of causal loci and new mutations
Authors: Wientjes Yvonne C.J. , Bijma Piter , van den Heuvel Joost , Zwaan Bas J. , Vitezica Zulma G. , Calus Mario P.L.
Published: February 2023

Genomic selection has become the dominant tool for genetic improvement in livestock and plants. Therefore, its sustainability is essential for global food production. Selection changes the allelic architecture of traits to create genetic gain. It remains unknown whether the changes in allele architecture are different for genomic selection and whether they depend on the genetic architectures of traits. Here we investigate the allele frequency changes of loci and new causal mutations under fifty generations of phenotypic, pedigree, and genomic selection, for a trait controlled by either additive, additive and dominance, or additive, dominance and epistatic effects. Genomic selection resulted in slightly larger and faster changes in allele frequencies of causal loci than pedigree selection. For each locus, allele frequency change per generation was not only influenced by its statistical additive effect, but also by the linkage phase with other loci and its allele frequency. Selection fixed a large number of loci, and five times more unfavorable alleles became fixed with genomic and pedigree selection than with phenotypic selection. For pedigree selection, this was mainly a result of increased genetic drift, while genetic hitchhiking had a large effect with genomic selection. When epistasis was present, the average allele frequency change was smaller (∼15% lower) and a lower number of loci became fixed for all selection methods. We conclude that for long-term genetic improvement, it is very important to be able to minimize the impact of hitchhiking and to limit the loss of favorable alleles more that current genomic selection methods do.
Europe PMC Annotated Full-text Corpus for Gene/Proteins, Diseases and Organisms
Authors: Yang Xiao , Saha Shyamasree , Venkatesan Aravind , Tirunagari Santosh , Vartak Vid , McEntyre Johanna
Published: February 2023

Named entity recognition (NER) is a widely used text-mining and natural language processing (NLP) sub-task. In recent years, deep learning methods have superseded traditional dictionary, and rule-based NER approaches. A high-quality dataset is essential to take full advantage of the recent deep learning advancements. While several gold standard corpora for biomedical entities in abstracts exist, only a few are based on full-text research articles. The Europe PMC literature database routinely annotates Gene/Proteins, Diseases and Organisms entities; to transition this pipeline from a dictionary-based to a machine learning-based approach, we have developed a human-annotated full-text corpus for these entities comprising 300 full-text open access research articles. Over 72,000 mentions of biomedical concepts have been identified within approximately 114,000 sentences. This article describes the corpus and details how to access and reuse this open community resource.
Dynamic Changes in Macrophage Polarization during the Resolution Phase of Periodontal Disease
Authors: Uttamani Juhi R. , Kulkarni Varun , Valverde Araceli , Naqvi Raza Ali , Nares Salvador , Naqvi Afsar R.
Published: February 2023

Periodontal inflammation is largely governed by infiltration of myeloid cells, in particular macrophages. Polarization of Mφ within the gingival tissues is a well-controlled axis and has considerable consequences for how Mφ participate in inflammatory and resolution (tissue repair) phases. We hypothesize that periodontal therapy may instigate a pro-resolution environment favoring M2 Mφ polarization and contribute towards resolution of inflammation post-therapy. We aimed to evaluate the markers of macrophage polarization before and after periodontal therapy. Gingival biopsies were excised from human subjects with generalized severe periodontitis, undergoing routine non-surgical therapy. A second set of biopsies were excised after 4-6 weeks to assess the impact of therapeutic resolution at the molecular level. As controls, gingival biopsies were excised from periodontally healthy subjects, undergoing crown lengthening. Total RNA was isolated from gingival biopsies to evaluate pro- and anti-inflammatory markers associated with macrophage polarization by RT-qPCR. Mean periodontal probing depths, CAL and BOP reduced significantly after therapy and corroborated with the reduced levels of periopathic bacterial transcripts after therapy. Compared to heathy and treated biopsies, higher load of Aa and Pg transcripts were observed in disease. Lower expression of M1Mφ markers (TNF-α, STAT1) were observed after therapy as compared to diseased samples. Conversely, M2Mφ markers (STAT6, IL-10) were highly expressed in post-therapy as opposed to pre-therapy, which correlated with clinical improvement. These findings corroborated with murine ligature-induced periodontitis and resolution model, comparing the respective murine Mφ polarization markers (M1 Mφ:cox2,iNOS2and M2 Mφ:tgm2andarg1). Our findings suggest that imbalance in M1 and M2 polarized macrophages by assessment of their markers can provide relevant clinical information on the successful response of periodontal therapy and can be used to target non-responders with exaggerated immune responses.
Synthesis, crystal structure and properties of bis(isoselenocyanato-κN)tetrakis(4-methoxypyridine-κN)cobalt(II)
Authors: Näther Christian , Jess Inke
Published: February 2023

Reaction of CoCl2·6H2O with KNCSe and 4-methoxypyridine in water led to the formation of the title compound, [Co(NCSe)2(C6H7NO)4] or Co(NCSe)2(4-methoxypyridine)2, which was characterized by single-crystal X-ray diffraction. Its asymmetric unit consists of one crystallographically independent Co cation, two selenocyanate anions and four 4-methoxypyridine coligands in general positions. In the crystal structure, the cobalt cations are sixfold coordinated by two terminal N-bonded selenocyanate anions and four 4-methoxypyridine coligands within a slightly distorted octahedral coordination. Between the complexes, weak C—H...Se interactions are found. IR spectroscopic investigations revealed that the CN stretching vibration of the anionic ligands is observed at 2068 cm−1, which is in agreement with the presence of only terminally coordinated selenocyanate anions. PXRD measurements prove that a pure compound was obtained. Differential thermoanalysis coupled to thermogravimetry (DTA-TG) at different heating rates shows that the TG curves are poorly resolved. PXRD measurements of the residue obtained by a TG measurement prove that an amorphous compound was obtained.
1,4-Phenylene diallyl bis(carbonate)
Authors: López-Velázquez Delia , Núñez-Méndez Irma , Bernès Sylvain , Martínez-de la Luz Isabel , Pérez-Cruz María Ana
Published: February 2023

The title molecule, C14H14O6, is based on a benzene core di-substituted by allyl carbonate groups in the para positions. The molecule is placed on an inversion centre, and the substituents are twisted with respect to the central benzene ring plane. The crystal structure does not include significant intermolecular interactions other than weak C—H...O contacts between CH groups in the benzene ring and carbonate O atoms.
Multiple mating rescues offspring sex ratio but not productivity in a haplodiploid exposed to developmental heat stress
Authors: Costa Sofia G. , Magalhães Sara , Rodrigues Leonor R.
Published: February 2023

Reproduction is generally more sensitive to high temperatures than survival and arguably a better predictor of the response of populations to climate change than survival estimates. Still, how temperature simultaneously impacts male and female reproductive success, the mating system and the operational sex ratio remains an open question.

Here, we addressed how a sublethal high temperature affects the reproductive system of the haplodiploid spider mite Tetranychus urticae. Males and females maintained at 25 or 36°C during development were paired and the fertility of both sexes, their mating and remating eagerness, and the paternity of the offspring of females with different mating histories were measured.

Female and male fertility decreased at 36°C compared to 25°C, resulting in lower offspring production and a more male‐biased sex ratio, respectively, because of haplodiploidy. However, when either heat‐stressed females or females that mated with heat‐stressed males remated, there was a shift in paternity share, with more than one male contributing to the offspring. This was accompanied by reduced mating eagerness in pairs with partially sterile males and increased remating eagerness in pairs in which at least one sex was partially sterile in the first mating.

The observed temperature‐induced changes in female remating eagerness and sperm use allowed restoring the offspring sex ratio, by increasing the proportion of fertilized offspring, but did not lead to the recovery of offspring number.

The temperature‐induced changes in the mating behaviour and mating system should alter the interactions within and between the sexes, and with it the strength of sexual selection and sexual conflict in this species. Whether such changes are sufficient to prevent population extinction, despite the inability to recover offspring number, remains an open question.

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