Biology subjects

Rojas, A.

Publications and source records attributed to Rojas, A..

30 records · Page 2Linked to original sources

bioRxiv2022

A natural history of networks: Higher-order network modeling for paleobiology research

Paleobiologists are increasingly employing network-based methods to analyze the complex data retrieved from geohistorical records, including stratigraphic sections, sediments, and fossil collections. However, the lack of a common framework for designing, performing, evaluating, and communicating these studies, leads to issues of reproducibility and communicability. The high-dimensional geohistorical data also raises questions about the limitations of standard network approaches, which assume independent interactions between pairs of components. Higher-order network models better suited for the complex relational structure of the geohistorical data provide an opportunity to overcome these challenges. These models can represent temporal and spatial constraints inherent to the biosedimentary record and describe higher-order interactions, capturing more accurate biogeographical, biostratigraphic, and macroevolutionary patterns. Here we describe how to use the Map Equation framework for designing higher-order network models of geohistorical data, address some practical decisions involved in modeling complex dependencies, and discuss critical methodological and conceptual issues that currently make it difficult to compare results across studies in the growing body of network-based paleobiology research. We illustrate different higher-order network representations and models, including multilayers, hypergraphs, and varying Markov times models, using case studies on gradient analysis, bioregionalization, and macroevolution, and delineate future research directions for current challenges in the emerging field of network paleobiology.

paleontology↗

bioRxiv2021

LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signalling axis contributing to islet survival and antidiabetic actions of the agonist BL001

We have previously described a role of LRH-1/NR5A2 in islet morphogenesis during postnatal development and reported that the treatment with BL001, an agonist of LRH-1/NR5A2, protects islets against-stress induced apoptosis and reverts hyperglycemia in 3 mouse models of Type 1 Diabetes Mellitus (T1DM). Islet transcriptome profiling revealed that most differentially expressed genes after BL001 treatment are involved in immunomodulation, among them, the increase in PTGS2/COX2 expression. Herein, we dissected the cellular and molecular branches of the BL001/LRH-1/NR5A2 signalling axis in order to chart the mode of action confering beta cell protection and hyperglycaemia reversion. We found that constitutive LRH-1/NR5A2 ablation within the insulin expression domain (RIP-Cre mouse model) caused a significant beta cell mass reduction characterized by blunted proliferation correlating with animal growth retardation, weight loss and hypoglycemia, leading to lethality before weaning. Using an inducible approach (pdx1PBCreER mouse model), specific deletion of LRH-1/NR5A2 in adult beta cells abolished the anti diabetic effect of BL001 in streptozotocin treated mice, correlating with complete beta-cell mass destruction. Additionally, BL001 induced Ptgs2 expression, was blunted in islets lacking LRH-1/NR5A2. The combined BL001/cytokine treatment did not further stimulate Ptgs2 expression above levels detected with cytokine alone yet secreted PGE2 levels were increased 5-fold. Inactivation of PTGS2 blunted induction of the target and its product PGE2 in islets treated with cytokines alone or with BL001. Importantly, PTGS2 inactivated islets were refractory to the BL001 protective effect under cytokine attack as evidenced by increased Bax expression levels, cytochrome C release and cleaved PARP. The PTGER1 antagonist ONO-8130, but not the PTGER4 antagonist L-161,982, negated BL001-mediated islet survival. Our results establish that the beneficial properties of BL001 against stress-induced cell death are specifically conveyed by LRH-1/NR5A2 activation in beta cells and downstream stimulation of the PTGS2-PGE2/PTGER1 signalling axis.

physiology↗

bioRxiv2021

Prediction and validation of the three-dimensional structure of glucokinase-1 from Phytophthora infestans

According to its primary structure, the [PITG_06016] gene encodes for one of the 7 glucokinases present in Phytophthora infestans (PiGlcK-1), the causal agent of late blight disease. Currently, there are no structural studies of any of its enzymes, being the determination of the three-dimensional (3D) structure of PiGlcK-1 a necessary contribution in the deduction of its functions, its interaction with ligands, and possible regulatory mechanisms. In this work we present the first structural model obtained by in silico tools for PiGlcK-1. For the prediction of this model, different algorithms were used to find the best annealing, refinement, and qualitative evaluation of them. A structural comparison of the predicted model with other structures of crystallized kinase enzymes allowed us to identify the regions of interaction with their classical substrates (glucose and ATP), as well as to identify the amino acid residues involved in the binding of other substrates such as fructose and ADP. In addition, we propose a possible recognition region of PPi, an activator of kinase activity that includes the GXGE motif, conserved in enzymes of the ribokinase (RK) family, which distinguishes this PiGlcK-1 from a classical glucokinase. Accordingly, these findings suggest PPi-binding motif as potential targets for the development of inhibitors of PiGlcK-1 activity.

biochemistry↗

bioRxiv2021

Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome

Short tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS. One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

genomics↗

bioRxiv2020

OCCURRENCE OF THE BRACHIOPOD TICHOSINA IN DEEP-SEA CORAL BOTTOMS OF THE CARIBBEAN SEA AND ITS PALEOENVIRONMENTAL IMPLICATIONS

Despite its importance as the larger component of the modern and Cenozoic brachiopod faunas in the Caribbean region, the ecology and habitat preferences of the terebratulid Tichosina remain poorly understood. We compiled field observations from multiple sites in the Caribbean of Colombia (i.e., San Bernado Bank, Bahia Honda-Guajira, Puerto Escondido, Joint Regime Area Jamaica-Colombia) and data from the R/V Pillsbury program, indicating that Tichosina may have close ecological ties with deep-water corals. In addition, we reviewed literature sources on Cenozoic sediments in the Dominican Republic and found tentative evidence that such ecological ties could have existed since at least the Pliocene. These observations are reminiscent of the Gryphus-anthozoan association observed in the modern Mediterranean continental margin. Understanding to what extent the brachiopod Tichosina is linked to deep-water habitats has implications for the recognition of deep-water macrobenthic communities in the Cenozoic rock record of the Caribbean.

paleontology↗

bioRxiv2020

Genetic diversity of the spinach downy mildew pathogen based on hierarchical sampling

Downy mildew, caused by the obligate oomycete pathogen Peronospora effusa, is the most economically important disease of spinach. In the past 30 years, 14 new races and 13 strains with novel virulence have been identified. However, the mechanism(s) driving the rapid evolution of virulence remains unknown. To understand reproductive strategies potentially driving the emergence of new races in P. effusa, 67 composite isolates (a collection of symptomatic leaves from a single cultivar grown in a defined area) of P. effusa obtained from 13 states between 2010 and 2018 were used to analyze the population genetic diversity hierarchically. Genotypes at 33 SNP loci of 719 lesions from these 67 isolates were determined by targeted sequencing. Diversity was then evaluated among individual lesions within the composite isolates, between isolates, host cultivars, geographic locations, and years of isolates collected. A total of 380 genotypes were identified from 719 individual lesions. Of the 380 genotypes, 350 (92%) were unique while the most common genotype was identified in 110 lesions of 16 isolates collected from 13 cultivars from CA and AZ in 2016. Variation within composite isolates ranged from none (a single genotype among lesions from a composite isolate) to 38 unique genotypes recovered from 39 lesions of a composite isolate. An index of association analysis suggested asexual (clonal) and sexual reproduction play important roles in population structure. Based on discriminant analysis of principal components, four distinct subpopulations were identified. Host cultivar, origin, and time of collection had an effect on population differentiation, and genotypes specific to a certain location or collection period were identified. Some subpopulations were unique to certain areas, and were only detected after 2014-2016. The co-existence of sexual and asexual reproduction strategies may partially explain the rapid emergence and spread of new races and novel strains of P. effusa.

microbiology↗

bioRxiv2020

The proteasomal deubiquitinating enzyme PSMD14 regulates macroautophagy by controlling Golgi-to-ER retrograde transport

Ubiquitination regulates several biological processes. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1,187 genes of the human "ubiquitinome" using Amyloid Precursor Protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel key regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 caused a robust and rapid inhibition of Golgi-to-ER retrograde transport which leads to a potent blockage of macroautophagy by a mechanism associated with the retention of Atg9A and Rab1A at the Golgi apparatus. Because pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and their K-63-Ub chains, act as a crucial regulator factor for macroautophagy by controlling Golgi-to-ER retrograde transport.

cell biology↗

bioRxiv2019

Low-Latitude Origins of the Four Phanerozoic Evolutionary Faunas

The hypothesis of the Great Evolutionary Faunas is a foundational concept of macroevolutionary research postulating that three global mega-assemblages have dominated Phanerozoic oceans following abrupt biotic transitions. Empirical estimates of this large-scale pattern depend on several methodological decisions and are based on approaches unable to capture multiscale dynamics of the underlying Earth-Life System. Combining a multilayer network representation of fossil data with a multilevel clustering that eliminates the subjectivity inherent to distance-based approaches, we demonstrate that Phanerozoic oceans sequentially harbored four global benthic mega-assemblages. Shifts in dominance patterns among these global marine mega-assemblages are abrupt (end-Cambrian 494 Ma; end-Permian 252 Ma) or protracted (mid-Cretaceous 129 Ma), and represent the three major biotic transitions in Earths history. This finding suggests that the mid-Cretaceous radiation of the so-called Modern evolutionary Fauna, concurrent with gradual ecological changes associated with the Mesozoic Marine Revolution, triggered a biotic transition comparably to the transition following the largest extinction event in the Phanerozoic. Overall, our study supports the notion that both long-term ecological changes and major geological events have played crucial roles in shaping mega-assemblages that dominated Phanerozoic oceans.

paleontology↗

bioRxiv2019

Regularities in species niches reveal the World's climatic regions

Although classifications of the Earths climates date back to the ancient Greeks, the climatic regions shaping the distribution of animals remain poorly resolved. Here we present a classification of global climates based on regularities in realised niches of 3657 amphibians, 7204 reptiles, 10684 birds and 4574 mammals. We found 16 main climatic regions that are mostly consistent across groups and previous plant expert-based classifications, confirming the existence of major climatic restrictions for life. The results also suggest that differences among groups likely relate to their particular adaptations and dispersal capabilities. We further show how the integration of species niche classifications with geographical information provides valuable information on potential mechanisms shaping the climatic regions. Our climate classification has applications in several disciplines, including conservation planning and ecological and evolutionary studies.

ecology↗

bioRxiv2019

Genetic Background Dominates Fibrotic Aortic Remodeling During Angiotensin-Induced Hypertension in Mice

Many genetic mutations affect aortic structure and function in mice, but little is known about the influence of background strain. We phenotyped aortas from C57BL/6J and 129SvEv mice before and after continuous infusion of angiotensin II (AngII) for two weeks, which elevated blood pressure similarly in both strains (1.34-fold vs. 1.32-fold, systolic). Excised thoracic aortas were characterized functionally using isobaric vasoactive and cyclic passive stiffness tests whereas immunohistological studies quantified altered medial and adventitial composition as well as the infiltration of pan-inflammatory CD45+ cells. Baseline aortic geometry, composition, and biomechanical properties were similar across strains, consistent with mechanical homeostasis. Yet, aortic remodeling in response to AngII-induced hypertension differed dramatically between strains, with gross maladaptive remodeling in C57BL/6J but not in 129SvEv mice. CD45+ cell density was markedly higher in C57BL/6J than 129SvEv aortas while vasoconstrictive responses to AngII were greater in 129SvEv than C57BL/6J both before and after hypertension; importantly, smooth muscle mediated vasoconstriction reduces pressure-induced wall stress. Bulk RNA sequencing, layer-specific biomechanical modeling, and growth and remodeling simulations support the emergent hypothesis that mechanical stress-mediated immune processes promote maladaptive remodeling while smooth muscle contractile processes reduce wall stress and thereby protect against fibrosis. Differentially expressed mechano-sensitive genes thus play key roles in the distinct hypertensive aortic remodeling in C57BL/6J and 129SvEv mice and must be considered when comparing studies in different background strains, particularly mixed strains that are often used to generate mice with targeted mutations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/727800v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e9f1d9org.highwire.dtl.DTLVardef@104e221org.highwire.dtl.DTLVardef@19a00bforg.highwire.dtl.DTLVardef@1a70cd5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2019

Resting Eyes Closed Beta-Phase High Gamma-Amplitude Coupling Deficits in Children with Attention Deficit Hyperactivity Disorder

ObjectiveAttention-deficit hyperactivity disorder (ADHD) is the neurobehavioral disorder with the largest prevalence rate in childhood. ADHD is generally assessed based on physical examination of the child and interviews, and therefore prone to subjectivity. This fact may lead to a high risk of mis- and over-diagnosis, a problem that can be addressed through the use of objective markers.\n\nMethodsHere we propose to use phase-amplitude coupling as a digital biomarker in ADHD. We investigated the hypothesis that coupling between the phase of slow brain rhythms and the amplitude of fast rhythms is altered in the ADHD population. We tested this hypothesis measuring phase-amplitude coupling (PAC) in the 4 to 200Hz range in electroencephalographic (EEG) signals recorded in the central-frontal area in children during eyes closed resting state.\n\nResultsUsing automatic clustering, we observed statistically significant beta-gamma PAC deficits in the ADHD population in the frontal-left hemisphere.\n\nConclusionsThese findings suggests alterations in the beta-gamma coupling in the ADHD population. We discuss the hypothesis that these alterations may be indicators of working memory and attention deficits.\n\nSignificanceThe study of the coupling between the different brain rhythms can potentially contribute to the understanding and clinical diagnosis of ADHD.

neuroscience↗

bioRxiv2017

Evolutionary footprints reveal insights into plant microRNA biogenesis

MicroRNAs (miRNAs) are endogenous small RNAs that recognize target sequences by base complementarity. They are processed from longer precursors that harbor a fold-back structure. Plant miRNA precursors are quite variable in size and shape, and are recognized by the processing machinery in different ways. However, ancient miRNAs and their binding sites in target genes are conserved during evolution. Here, we designed a strategy to systematically analyze MIRNAs from different species generating a graphical representation of the conservation of the primary sequence and secondary structure. We found that plant MIRNAs have evolutionary footprints that go beyond the small RNA sequence itself, yet, their location along the precursor depends on the specific MIRNA. We show that these conserved regions correspond to structural determinants recognized during the biogenesis of plant miRNAs. Furthermore, we found that the members of the miR166 family have unusual conservation patterns and demonstrated that the recognition of these precursors in vivo differs from other known miRNAs. Our results describe a link between the evolutionary conservation of plant MIRNAs and the mechanisms underlying the biogenesis of these small RNAs, and show that the MIRNA pattern of conservation can be used to infer the mode of miRNA biogenesis.

plant biology↗