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Alvarez, N.

Publications and source records attributed to Alvarez, N..

15 recordsLinked to original sources

Cryptic diversification proceeds despite historical and contemporary hybridization in Patagonian ants

Understanding how independently evolving lineages arise despite ongoing gene flow remains a central question in evolutionary biology. Although genomic studies increasingly suggest that hybridization can accompany diversification, empirical evidence from ecologically dominant insect groups remains limited. Here, we present the first population-scale phylogenomic analysis of Patagonian ants, sampling Dorymyrmex across approximately 450,000 km2. Using genome-wide SNPs, coalescent phylogenetics, phylogenetic networks, demographic modelling, species delimitation, and genome scans, we reconstruct the evolutionary history of this widespread genus. We discovered extensive cryptic diversity with strong genomic differentiation and detected both recent and historical hybridization, demonstrating that substantial genomic divergence accumulated despite recurrent gene flow events. Genome scans further identify candidate loci associated with adaptation to Patagonias contrasting environments, suggesting that ecological divergence contributed to lineage diversification. Our results show that cryptic diversification can proceed despite recurrent gene flow, supporting hybridization as an integral component of the diversification process. More broadly, this study illustrates how genome-scale data can reveal hidden biodiversity and the evolutionary processes shaping it in ecologically important but genomically understudied taxa.

evolutionary biology↗

Immune Cell Dysfunction of SARS-CoV-2: Mathematical Modeling of the Within-Host Immune Dynamics

The COVID-19 pandemic has spurred extensive research into viral transmission and control, yet the mechanisms of the human immune response to SARS-CoV-2 remain incompletely understood, particularly the role of natural killer (NK) cells and cytokine regulation in disease severity. Mathematical modeling provides a powerful approach to bridge this gap by linking viral dynamics with immune interactions. In this work, we develop a mechanistic within-host model, formulated in a system of coupled ordinary and delayed differential equations, to investigate the contributions of NK cell activity, interferon signaling, and pro-inflammatory cytokines to viral clearance and disease outcome. Model parameters are estimated from experimental data, and computational simulations are used to explore how dysregulated NK responses and cytokine feedback loops may drive divergent clinical outcomes. Local sensitivity analysis identifies the most influential parameters shaping host-pathogen dynamics, highlighting potential control points for intervention. In addition, knockdown simulations are performed to mimic potential therapeutic interventions, allowing us to evaluate their advantages and limitations in silico. These findings provide mechanistic insights into COVID-19 immune dynamics and offer a foundation for guiding the design of future treatment strategies. HighlightsO_LIWe develop a within-host mathematical model of the SARS-CoV-2 immune response. C_LIO_LIThe model incorporates key cytokines and immune cells including Natural Killer cells. C_LIO_LINumerical simulations reproduce cytokine storms and NK cell dysfunction in severe disease. C_LIO_LISensitivity analysis identifies parameter impact and potential therapeutic interventions. C_LI

immunology↗

The role of peripheral regions in shaping the phylogeography of the Bear s ear complex across the Alps

AimPeripheral regions of the Alps are often overlooked in molecular studies, yet they may play a major role in shaping the current distribution of species and genetic lineages. LocationEurope TaxonAngiosperms (Primulaceae: Primula) MethodsBy focusing on the bears ear (Primula auricula) complex as model species, we used genetic inferences for population genetic structure and performed genetic reconstructions, species delimitations and divergence time estimates in order to get a detailed view of its molecular evolution and current genetic structuring across the Alps sensu lato. ResultsThe Lombardian Alps and the southern eastern Alps are genetically distinct in the vicinity of the Adige valley. The northern and western Alps and their peripheries constitute a third clade and are separated by the siliceous central Alps. Within the latter, an additional cluster made of singular populations from the Devoluy and Vercors regions is retrieved, likely reflecting a strong founder effect rather than an ancient divergence. Main conclusionsThe biogeographic history P. auricula sensu lato pinpoints the importance of the peripheral regions in a phylogeographic context. Populations from northern peripheral regions exhibit long-lasting isolation and in situ survival during glaciations, followed by recolonization into the central Alpine massif.

genetics↗

Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice

Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries. Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased ROS production. Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline. In briefReproductive aging is associated with changes in alternative splicing patterns in the mouse ovary. Our study identifies alterations in exon usage that may have altered protein function and important roles in ovarian physiology as well as in reproductive aging.

cell biology↗

Conservation strategy insights for three protected Phengaris butterflies combining genetic and landscape analyses

Biodiversity loss is accelerating globally, with insects among the most affected taxa. Wetlands, crucial ecosystems providing essential services, have experienced significant decline due to agricultural intensification and habitat destruction. These changes threaten species that rely on wetland habitats, such as the Phengaris butterflies, which exhibit complex ecological dependencies on specific host plants and ant species. Their populations are structured into metapopulations, where connectivity between habitat patches plays a crucial role in species persistence. This study focuses on population genomics and landscape analysis of three Phengaris species (P. alcon, P. nausithous, P. teleius) in the Bugey Mountain Massif, France, with the aim of developing a conservation strategy. Using ddRAD sequencing, we analyzed genetic diversity, population structure, and gene flow across multiple localities, revealing distinct population clusters with varying degrees of connectivity. Despite some populations exhibiting high genetic diversity levels, others demonstrate low heterozygosity and signs of genetic isolation, emphasizing conservation concerns. Migration estimates and resistance mapping further identified key dispersal corridors and isolated patches requiring targeted interventions. Our findings support metapopulation conservation strategies that prioritize maintaining connectivity, enhancing degraded patches, and identifying new potential habitats. By combining genomic and landscape data, we propose an evidence-based approach to conservation planning, facilitating adaptive management for Phengaris species. This study provides a practical framework for habitat restoration and corridor management in fragmented ecosystems, ensuring long-term species resilience in rapidly changing landscapes.

evolutionary biology↗

Role of the NHE1 exchanger in the antitumor effects of copper(II) complexes and phenanthroline derivatives

Three copper(II) complexes containing 1,10-phenanthroline ([CuCl2(phen)]{middle dot}4H2O,1), neocuproine ([CuCl2(neo)]{middle dot}4H2O, 2) and tetramethyl-phenanthroline ([CuCl2(tmp)]{middle dot}4H2O, 3) as the primary ligand and another three copper(II) complexes with the L-Ala-Phe dipeptide as an auxiliary ligand: [Cu(L-Ala-Phe)(phen)]{middle dot}4H2O (4), [Cu(L-Ala-Phe)(neo)]{middle dot}4H2O (5) and [Cu(L-Ala-Phe)(tmp)]{middle dot}4H2O (6), inhibited cell viability in breast cancer MCF-7 cell line, both in the monolayer and spheroid cell culture models. The pair with tetramethyl-phenanthroline displayed a better selectivity index than cisPt and non-cytotoxicity-related ROS induction and apoptosis in the monolayer breast cancer model. Cell proliferation was affected by all compounds in a concentration-dependent manner, with a more substantial effect on the tetramethyl-phenanthroline complexes. Cell viability on multicellular spheroids showed a concentration-dependent reduction from 1 M, with IC50 that were half the one for cisplatin. All copper complexes, except for 1 showed DNA damage, demonstrated by the comet assay at a concentration below the IC50. The role of NHE1 has been linked to many types of cancers. Our study revealed that all compounds inhibited NHE1 activity in MCF-7 cells. However, only complexes containing the dipeptide auxiliary ligand could extend their effect on cell migration (Wound Healing Assay) and MMP-9 activity studied by zimography. Wester Blot analysis showed that expressions of MMP-2, MMP-9, and NHE1 were affected when MCF7 cells were treated with the six compounds as well. Overall, our results reveal an antitumor effect of all copper(II) complexes studied in breast cancer cells and a fundamental role of NHE1 in cell migration.

cancer biology↗

In Vivo Antiviral Efficacy of LCTG-002, a Pooled, Purified Human Milk Secretory IgA product, Against SARS-CoV-2 in a Murine Model of COVID-19

Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosal compartments including the respiratory tract, with the secretory form of IgA (sIgA) being dominant and uniquely stable in these environments. sIgA is naturally found in human milk, which could be considered a global resource for this biologic, justifying the development of human milk sIgA as a dedicated airway therapeutic for respiratory infections such as SARS-CoV-2. In the present study, methods were therefore developed to efficiently extract human milk sIgA from donors who were either immunologically naive to SARS-CoV-2 (pooled as a control IgA) or had recovered from a PCR-confirmed SARS-CoV-2 infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA Abs in their milk (pooled together to make LCTG-002). Mass spectrometry determined that proteins with a relative abundance of 1.0% or greater were all associated with sIgA. None of the proteins exhibited statistically significant differences between batches. Western blot demonstrated all batches consisted predominantly of sIgA. Compared to control IgA, LCTG-002 demonstrated significantly higher binding to Spike, and was also capable of blocking the Spike - ACE2 interaction in vitro with 6.3x greater potency compared to control IgA (58% inhibition at [~]240ug/mL). LCTG-002 was then tested in vivo for its capacity to reduce viral burden in the lungs of K18+hACE2 transgenic mice inoculated with SARS-CoV-2. LCTG-002 was demonstrated to significantly reduce SARS-CoV-2 titers in the lungs compared to control IgA when administered at either 250ug/day or 1 mg/day, as measured by TCID50, plaque forming units (PFU), and qRT-PCR, with a maximum reduction of 4.9 logs. This innovative study demonstrates that LCTG-002 is highly pure, efficacious, and well tolerated in vivo, supporting further development of milk-derived, polyclonal sIgA therapeutics against SARS-CoV-2 and other mucosal infections.

immunology↗

The identity of Argyria lacteella (Fabricius, 1794) (Lepidoptera, Pyraloidea, Crambinae), synonyms, and related species using morphology and DNA capture in type specimens

Recent developments in museomics enable genetic information to be recovered from previously unusable collection specimens and thus to answer complex taxonomic questions. Here we apply museomics to a taxonomic problem involving several species of Argyria Hubner (Pyraloidea, Crambinae), with previously unrecognized morphological variation. By analysing the DNA barcode (COI-5P) in numerous specimens, we aimed to reconstruct phylogenetic relationships between species, to provide better evidence for synonymies, and to circumscribe their geographical distribution. Using an innovative DNA hybridization capture protocol, we partially recovered the DNA barcode of the lectotype of Argyria lacteella (Fabricius, 1794) for comparison with the 229 DNA barcode sequences of Argyria specimens available in the Barcode of Life Datasystems, and this firmly establishes the identity of the species. The same protocol was used for the following type specimens: the Argyria abronalis (Walker, 1859) holotype, thus confirming the synonymy of this name with A. lacteella, the holotype of A. lusella (Zeller, 1863), rev. syn., the holotype of A. multifacta Dyar, 1914, syn. n., newly synonymized with A. lacteella, and a specimen of Argyria diplomochalis Dyar, 1913, collected in 1992. A complementary sampling composed of nine specimens of A. lacteella, A. diplomochalis, A. centrifugens Dyar, 1914 and A. gonogramma Dyar, 1915, from North to South America, were integrated using classical COI amplification and Sanger sequencing. Argyria gonogramma Dyar, described from Bermuda, is the name to be applied to the more widespread North American species formerly identified as A. lacteella. Following morphological study of its holotype, Argyria vestalis Butler, 1878, syn. n. is also synonymized with A. lacteella. The name A. pusillalis Hubner, 1818, is considered a nomen dubium associated with A. gonogramma. The adult morphology is diagnosed and illustrated, and distributions are plotted for A. lacteella, A. diplomochalis, A. centrifugens, and A. gonogramma based on slightly more than 800 specimens. For the first time, DNA barcode sequences are provided for the Antillean A. diplomochalis. Our work highlights the efficiency of the DNA hybrid capture enrichment method to retrieve DNA barcodes from 18th and 19th century type specimens in order to solve taxonomic issues in Lepidoptera.

zoology↗

Effect of reduced graphene oxide (rGO) compaction degree and concentration on rGO-polymer composites printability and cell interactions

Graphene derivatives combined with polymers have attracted enormous attention for bone tissue engineering applications. Among others, reduced graphene oxide (rGO) is one of the preferred graphene-based fillers for the preparation of composites via melt compounding, and their further processing into 3D scaffolds, due to its established large-scale production method, thermal stability, and electrical conductivity. In this study, rGO (low bulk density 10g/L) was compacted by densification using a solvent (either acetone or water) prior to melt compounding, to simplify its handling and dosing into a twin-screw extrusion system. The effects of rGO bulk density (medium and high), densification solvent, and rGO concentration (3, 10 and 15% in weight) on rGO dispersion within the composite, electrical conductivity, printability and cell-material interactions were studied. High bulk density rGO (90 g/L) occupied a low volume fraction within polymer composites, offering poor electrical properties but a reproducible printability up to 15 wt% rGO. On the other hand, the volume fraction within the composites of medium bulk density rGO (50 g/L) was higher for a given concentration, enhancing rGO particle interactions and leading to enhanced electrical conductivity, but compromising the printability window. For a given bulk density (50 g/L), rGO densified in water was more compacted and offered poorer dispersability within the polymer than rGO densified in acetone, and resulted in scaffolds with poor layer bonding or even lack of printability at high rGO percentages. A balance in printability and electrical properties was obtained for composites with medium bulk density rGO densified in acetone. Here, increasing rGO concentration led to more hydrophilic composites with a noticeable increase in protein adsorption. Moreover, scaffolds prepared with such composites presented antimicrobial properties even at low rGO contents (3 wt%). In addition, the viability and proliferation of human mesenchymal stromal cells (hMSCs) was maintained on scaffolds with up to 15% rGO and with enhanced osteogenic differentiation on 3% rGO scaffolds.

bioengineering↗

Codon composition in human oocytes reveals age-associated defects in mRNA decay

Oocytes from women of advanced reproductive age have lower developmental potential, yet the underlying mechanisms of this phenomena are incompletely understood. Oocyte maturation is dependent upon translational control of stored maternal mRNA that were synthesized during oocyte growth. We observed that GC content of mRNA was negatively associated with half-life in oocytes from reproductively young women (< 30 years), contrastingly directly with oocytes from reproductively aged women ([&ge;] 40 years) where mRNA half-lives were positively associated with GC nucleotide content. Additionally, we observed that mRNA half-lives were negatively associated with protein abundance in young oocytes, while GC content was positively associated with protein abundance in aged oocytes. Examination of codon composition during the GV-to-MII transition revealed that codons that facilitate rapid translation promoted mRNA stability and are considered optimal, while codons that slow translation destabilized mRNA, and are considered non-optimal. GC-containing codons were more optimal in reproductive aging, and also correlated positively with protein abundance. This study indicates that reproductive aging coincides with the stabilization of a subset of mRNA that have the potential to be over-translated during oocyte maturation, this is likely to lead to observed decreases in oocyte quality in older women. Because oocyte mRNA decay is translationally linked, this suggests that maternal aging causes defects in translation, which results in reduced translational efficiency and the retention of maternal mRNA that are normally degraded in oocytes from young women. In the case of oocytes, defects in translation can alter the RNA decay pathways and result in incorrect maternal mRNA dosage, which may negatively impact embryonic development.

developmental biology↗

Within-species floral odor variation is maintained by spatial and temporal heterogeneity in pollinator communities

Floral odor is a complex trait that mediates many biotic interactions, including pollination. While high intraspecific floral odor variation appears to be common, the ecological and evolutionary drivers of this variation are often unclear. Here, we investigated the influence of spatially and temporally heterogeneous pollinator communities on floral odor variation in Arum maculatum (Araceae). Through Europe-wide field surveys, we identified high floral odor diversity and shifts in the dominant pollinator species within several A. maculatum populations compared to pollinator data from the same sites ten years ago. Using common-garden experiments, we further confirmed that inflorescences from native and foreign pollinator backgrounds were equally efficient at attracting local pollinators. The substantial within-population floral odor variation we observed may therefore be advantageous when facing temporally heterogeneous pollinator communities. We propose spatio-temporal heterogeneity in pollinators as one potential mechanism maintaining diverse floral odor bouquets in angiosperms.

ecology↗

The Role of DOT1L Methyltransferase Activity in Fetal Hematopoiesis

Early mammalian erythropoiesis requires the DOT1L methyltransferase. We demonstrated that loss of DOT1L in mutant mice resulted in lethal anemia during midgestation. The molecular mechanisms by which DOT1L regulates embryonic erythropoiesis have not yet been elucidated. In this study, a methyltransferase mutant mouse line (Dot1L-MM) was generated to determine whether the methyltransferase activity of DOT1L is essential for erythropoiesis. Dot1L-MM mice displayed embryonic lethality between embryonic days 10.5 and 13.5, similar to Dot1lL knockout (Dot1L-KO) mice. However, when examined at E10.5, unlike the Dot1L-KO, Dot1L-MM embryos did not exhibit evidence of anemia. In ex vivo hematopoietic differentiation cultures, Dot1L-KO and Dot1L-MM yolk sac (YS) cells both formed reduced numbers of myeloid, and mixed hematopoietic colonies. Erythroid colonies were able to be formed in numbers equal to wildtype embryos. Extensively self-renewing erythroblast (ESRE) cultures were established using YS cells from E10.5 embryos. Dot1L-KO and Dot1L-MM cells expanded significantly less than wild-type cells and exhibited increased cell death. Strikingly, Dot1L-KO and Dot1L-MM cells of YS origin exhibited profound genomic instability, implicating DOT1L methyltransferase activity in maintenance of the genome as well as viability of hematopoietic progenitors. Our results indicate that the methyltransferase activity of DOT1L plays an important role early murine hematopoiesis.

developmental biology↗

3D additive manufactured composite scaffolds with antibiotic-loaded lamellar fillers for bone infection prevention and tissue regeneration

Bone infections following open bone fracture or implant surgery remain a challenge in the orthopedics field. In order to avoid high doses of systemic drug administration, optimized local antibiotic release from scaffolds is required. 3D additive manufactured (AM) scaffolds made with biodegradable polymers are ideal to support bone healing in non-union scenarios and can be given antimicrobial properties by the incorporation of antibiotics. In this study, ciprofloxacin and gentamicin intercalated in the interlamellar spaces of magnesium aluminum layered double hydroxides (MgAl) and -zirconium phosphates (ZrP), respectively, are dispersed within a thermoplastic polymer by melt compounding and subsequently processed via high temperature melt extrusion AM ([~]190 {degrees}C) into 3D scaffolds. The inorganic fillers enable a sustained antibiotics release through the polymer matrix, controlled by antibiotics counterions exchange or pH conditions. Importantly, both antibiotics retain their functionality after the manufacturing process at high temperatures, as verified by their activity against both Gram + and Gram - bacterial strains. Moreover, scaffolds loaded with filler-antibiotic do not impair human mesenchymal stromal cells osteogenic differentiation, allowing matrix mineralization and the expression of relevant osteogenic markers. Overall, these results suggest the possibility of fabricating dual functionality 3D scaffolds via high temperature melt extrusion for bone regeneration and infection prevention.

bioengineering↗

Genomic signatures accompanying the dietary shift to phytophagy in polyphagous beetles

BackgroundThe diversity and evolutionary success of beetles (Coleoptera) are proposed to be related to the diversity of plants on which they feed. Indeed the largest beetle suborder, Polyphaga, mostly includes plant-eaters among its ~315,000 species. In particular, plants defend themselves with a diversity of specialized toxic chemicals. These may impose selective pressures that drive genomic diversification and speciation in phytophagous beetles. However, evidence of changes in beetle gene repertoires driven by such interactions remains largely anecdotal and without explicit hypothesis testing.\n\nResultsTo address this, we explored the genomic consequences of beetle-plant trophic interactions by performing comparative gene family analyses across 18 species representing the two most species-rich beetle suborders. We contrasted the gene contents of species from the mostly plant-eating suborder Polyphaga with those of the mainly predatory Adephaga. We found gene repertoire evolution to be more dynamic, with significantly more adaptive lineage-specific expansions, in the more speciose Polyphaga. Testing the specific hypothesis of adaptation to plant-feeding, we identified families of enzymes putatively involved in beetle-plant interactions that underwent adaptive expansions in Polyphaga. There was especially strong support for the selection hypothesis on large gene families for glutathione S-transferase and carboxylesterase detoxification enzymes.\n\nConclusionsOur explicit modeling of the evolution of gene repertoires across 18 species identifies adaptive lineage-specific gene family expansions that accompany the dietary shift towards plants in beetles. These genomic signatures support the popular hypothesis of a key role for interactions with plant chemical defenses, and for plant-feeding in general, in driving beetle diversification.

evolutionary biology↗

DiscoSnp-RAD: de novo detection of small variants for population genomics

We present an original method to de novo call variants for Restriction site associated DNA Sequencing (RAD-Seq). RAD-Seq is a technique characterized by the sequencing of specific loci along the genome, that is widely employed in the field of evolutionary biology since it allows to exploit variants (mainly SNPs) information from entire populations at a reduced cost. Common RAD dedicated tools, as STACKS or IPyRAD, are based on all-versus-all read comparisons, which require consequent time and computing resources. Based on the variant caller DiscoSnp, initially designed for shotgun sequencing, DiscoSnp-RAD avoids this pitfall as variants are detected by exploring the De Bruijn Graph built from all the read datasets. We tested the implementation on RAD data from 259 specimens of Chiastocheta flies, morphologically assigned to 7 species. All individuals were successfully assigned to their species using both STRUCTURE and Maximum Likelihood phylogenetic reconstruction. Moreover, identified variants succeeded to reveal a within species structuration and the existence of two populations linked to their geographic distributions. Furthermore, our results show that DiscoSnp-RAD is at least one order of magnitude faster than state-of-the-art tools. The overall results show that DiscoSnp-RAD is suitable to identify variants from RAD data, and stands out from other tools due to his completely different principle, making it significantly faster, in particular on large datasets.\n\nLicenseGNU Affero general public license\n\nAvailabilityhttps://github.com/GATB/DiscoSnp\n\nContactjeremy.gauthier@inria.fr

bioinformatics↗