Biology subjects

Pena, J.

Publications and source records attributed to Pena, J..

18 recordsLinked to original sources

bioRxiv2026

Hypertension is related to a slower radiotracer removal from lateral ventricles

BackgroundImpairment of brain waste removal contributes to Alzheimers disease etiology and progression. Although hypertension is a risk factor for dementia, little is known about how it affects measures of clearance in human brain. MethodsCross-sectional (n=159) and longitudinal (n=94) analysis of the relationship between blood pressure (BP) and brain clearance. The estimate of brain clearance was measured using positron emission tomography (PET) as the rate of radiotracer (MK-6240) efflux from the lateral ventricles in the 10-30-minute window after tracer injection. We also examined cerebral blood flow, PET-derived tau deposition in the medial temporal lobe, cognition and plasma biomarkers of neurodegeneration. At baseline we compared participants with (n=88) and without (n=71) hypertension. For longitudinal analyses we defined two groups based on systolic BP trajectories from baseline to follow-up: as long-term controlled (n=76) or uncontrolled BP (n=18). ResultsAt baseline, subjects with hypertension had lower ventricular clearance than normotensive controls (Cohens d=0.53, p=0.001). Over the course of the observation period (median 1.85 years) subjects in the uncontrolled BP group experienced a steeper reduction in clearance rates ({beta}=-5.88) than subjects in the controlled BP group ({beta}=-0.81, interaction p=0.039). ConclusionsOur study suggests that hypertension impairs brain clearance of fluids.

neuroscience↗

bioRxiv2024

Population-level control of two manganese oxidases expands the niche for bacterial manganese biomineralization

The enzymatic oxidation of aqueous divalent manganese (Mn) is a widespread microbial trait that produces reactive Mn(III, IV) oxide minerals. These biominerals drive carbon, nutrient, and trace metal cycles, thus playing important environmental and ecological roles. However, the regulatory mechanisms and physiological functions of Mn biomineralization are unknown. This challenge arises from the common occurrence of multiple Mn oxidases within the same organism and the use of Mn oxides as indicators of combined gene activity. Through detection of gene activation in individual cells, we discover that expression of mnxG and mcoA, two Mn oxidase-encoding genes in Pseudomonas putida GB-1, is confined to subsets of cells within the population, with each gene showing distinct spatiotemporal patterns that reflect local microenvironments. These coordinated intra-population dynamics control Mn biomineralization and illuminate the strategies used by microbial communities to dictate the extent, location and timing of biogeochemical transformations.

microbiology↗

bioRxiv2023

Advancement in Cellular Topographic and Nanoparticle Capture Imaging by High Resolution Microscopy Incorporating a Freeze-Drying and Gaseous Nitrogen-based Approach

Scanning electron microscopy (SEM) offers an unparalleled view of the membrane topography of mammalian cells by using a conventional osmium (OsO4) and ethanol-based tissue preparation. However, conventional SEM methods limit optimal resolution due to ethanol and lipid interactions and interfere with visualization of fluorescent reporter proteins. Therefore, SEM correlative light and electron microscopy (CLEM) has been hindered by the adverse effects of ethanol and OsO4 on retention of fluorescence signals. To overcome this technological gap in achieving high-resolution SEM and retain fluorescent reporter signals, we developed a freeze-drying method with gaseous nitrogen (FDGN). We demonstrate that FDGN preserves cyto-architecture to allow visualization of detailed membrane topography while retaining fluorescent signals and that FDGN processing can be used in conjunction with a variety of high-resolution imaging systems to enable collection and validation of unique, high-quality data from these approaches. In particular, we show that FDGN coupled with high resolution microscopy provided detailed insight into viral or tumor-derived extracellular vesicle (TEV)-host cell interactions and may aid in designing new approaches to intervene during viral infection or to harness TEVs as therapeutic agents.

cell biology↗

bioRxiv2023

Evolution of environmentally mediated social interactions under isolation by distance

Many social interactions happen indirectly via modifications of the environment, e.g. through the secretion of functional compounds or the depletion of renewable resources. Here, we derive the selection gradient on a quantitative trait affecting dynamical environmental variables that feed back on reproduction and survival in a finite patch-structured population subject to isolation by distance. Our analysis shows that the selection gradient depends on how a focal individual influences the fitness of all future individuals in the population through modifications of the environmental variables they experience, weighted by the neutral relatedness between recipients and the focal. The evolutionarily relevant trait-driven environmental modifications are formalized as the extended phenotypic effects of an individual, quantifying how a trait change in an individual in the present affects the environmental variables in all patches at all future times. When the trait affects reproduction and survival through a payoff function, the selection gradient can be expressed in terms of extended phenotypic effects weighted by scaled-relatedness. We show how to compute extended phenotypic effects, relatedness, and scaled-relatedness using Fourier analysis, which allow us to investigate a broad class of environmentally mediated social interactions in a tractable way. We use our approach to study the evolution of a trait controlling the costly production of some lasting commons (e.g. a common-pool resource or a toxic compound) that can diffuse in space and persist in time. We show that indiscriminate posthumous spite readily evolves in this scenario. More generally whether selection favours environmentally mediated altruism or spite is determined by the spatial correlation between an individuals lineage and the commons originating from its patch. The sign of this correlation depends on interactions between dispersal patterns and the commons renewal dynamics. More broadly, we suggest that selection can favour a wide range of social behaviours when these have carry-over effects in space and time.

evolutionary biology↗

bioRxiv2023

A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer

Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, [~]10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients mutations would improve patients outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.

cancer biology↗

bioRxiv2023

The shirker's dilemma and the prospect of cooperation in large groups

Cooperation usually becomes harder to sustain as groups become larger because incentives to shirk increase with the number of potential contributors to collective action. But is this always the case? Here we study a binary-action cooperative dilemma where a public good is provided as long as not more than a given number of players shirk from a costly cooperative task. We find that at the stable polymorphic equilibrium, which exists when the cost of cooperation is low enough, the probability of cooperating increases with group size and reaches a limit of one when the group size tends to infinity. Nevertheless, increasing the group size may increase or decrease the probability that the public good is provided at such an equilibrium, depending on the cost value. We also prove that the expected payoff to individuals at the stable equilibrium (i.e., their fitness) decreases with group size. For low enough costs of cooperation, both the probability of provision of the public good and the expected payoff converge to positive values in the limit of large group sizes. However, we also find that the basin of attraction of the stable polymorphic equilibrium is a decreasing function of group size and shrinks to zero in the limit of very large groups. Overall, we demonstrate non-trivial comparative statics with respect to group size in an otherwise simple collective action problem.

evolutionary biology↗

bioRxiv2023

Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications. Using publicly available datasets, we identify copy number amplifications in metastatic breast tumor samples and using our organoid-based metastasis assays, and we validate FGFR1 is amplified in collectively migrating organoids. Because the heterogeneity of breast tumors is increasingly becoming relevant to clinical practice, we demonstrate our organoid method captures genetic heterogeneity of individual tumors.

cancer biology↗

bioRxiv2022

Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are still being understood. For example, we currently lack a comprehensive understanding of the mechanisms of neurotoxicity observed in patients receiving T cell therapies, including recent reports of encephalitis caused by human herpesvirus 6 (HHV-6) reactivation1. Here, via petabase-scale viral RNA data mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in human CD4+ T cells in standard in vitro cultures. Using single-cell sequencing, we identify a rare population of HHV-6 super-expressors (~1 in 300-10,000 cells) that possess high viral transcriptional activity in chimeric antigen receptor (CAR) T cell culture before spreading to infect other cells in vitro. Through the analysis of single-cell sequencing data from patients receiving cell therapy products that are FDA-approved2 or used in clinical studies3,4, we identify the presence of CAR+, HHV-6 super-expressor T cells in vivo. Together, our study implicates cell therapy products as a source of lytic HHV-6 reported in clinical trials1,5-7 and has broad implications for the design, production, and monitoring of cell therapies.

immunology↗

bioRxiv2022

Interferon regulatory factor 3 upregulates the Treg recruitment factor CCL22 in response to double-stranded DNA in cancer cells

Cancer immunotherapy holds great promise for the treatment of solid tumors, but its effectiveness is hindered by the recruitment of regulatory T cells (Tregs), which inhibit anti-tumor immune responses. We report here that cytosolic dsDNA, a characteristic of many cancer cells, upregulates expression of the Treg-recruitment chemokine CCL22 in multiple types of malignant epithelial cells. We also identified that interferon regulatory factor 3 (IRF3) is a key regulator of CCL22 in response to dsDNA. Both IRF3 and NF-{kappa}B are activated downstream of the stimulator of interferon genes (STING), a primary effector protein responding to multiple cytosolic dsDNA sensors. IRF3 activation by STING triggers robust expression of type I interferons, which can boost anti-tumor immune responses. Thus, STING agonists have been used clinically to activate IRF3 during immunotherapy. However, STING activation in some cases is reported to paradoxically foster a pro-tumor, immunosuppressive environment. Our finding that IRF3 regulates CCL22 in response to dsDNA suggests a possible mechanism contributing to STING-mediated immunosuppression. In addition, we found that cultured cancer cells appear able to evolve mechanisms to co-opt nucleic acid sensing pathways to upregulate CCL22, suggesting that these pathways may contribute to acquired immune evasion in tumors with increased cytosolic dsDNA.

cancer biology↗

bioRxiv2020

Eusociality through conflict dissolution via maternal reproductive specialization

Eusociality, where largely unreproductive offspring help their mothers reproduce, is a major form of social organization. An increasingly documented feature of eusociality is that mothers induce their offspring to help by means of hormones, pheromones, or behavioral displays, with evidence often indicating that offspring help voluntarily. The co-occurrence of maternal influence and offspring voluntary help may be explained by what we call the converted helping hypothesis, whereby maternally manipulated helping subsequently becomes voluntary. Such hypothesis requires that parent-offspring conflict is eventually dissolved--for instance, if the benefit of helping increases sufficiently over evolutionary time. We show that help provided by maternally manipulated offspring can enable the mother to sufficiently increase her fertility to transform parent-offspring conflict into parent-offspring agreement. This conflict-dissolution mechanism requires that helpers alleviate maternal life-history trade-offs, and results in reproductive division of labor, high queen fertility, and honest queen signaling suppressing worker reproduction--thus exceptionally recovering diverse features of eusociality. As such trade-off alleviation seemingly holds widely across eusocial taxa, this mechanism offers a potentially general explanation for the origin of eusociality, the prevalence of maternal influence, and the offsprings willingness to help. Overall, our results explain how a major evolutionary transition can happen from ancestral conflict.

evolutionary biology↗

bioRxiv2020

Dividing labour in social microorganisms: coordinated or random specialisation?

In bacteria and other microorganisms, the cells within a population often show extreme phenotypic variation. Different species use different mechanisms to determine how distinct phenotypes are allocated between individuals, including coordinated, random, and genetic determination. However, it is not clear if this diversity in mechanisms is adaptive--arising because different mechanisms are favoured in different environments--or is merely the result of non-adaptive artifacts of evolution. We use theoretical models to analyse the relative advantages of the two dominant mechanisms to divide labour between reproductives and helpers in microorganisms. We show that coordinated specialisation is more likely to evolve over random specialisation in well-mixed groups when: (i) social groups are small; (ii) helping is more "essential"; and (iii) there is a low metabolic cost to coordination. We find analogous results when we allow for spatial structure with a more detailed model of cellular filaments. More generally, this work shows how diversity in the mechanisms to produce phenotypic heterogeneity could have arisen as adaptations to different environments.

evolutionary biology↗

bioRxiv2019

The value of non-motor features and genetic variants of Parkinson's disease for clustering Lewy body diseases

IntroductionThe use of non-motor Parkinsons disease (PD) features and genetic PD variants for clustering analyses may refine the phenotypic classification of idiopathic Lewy body (LB) diseases. MethodsOne-hundred participants [n=7 E46K-SNCA (n=5 symptomatic and n=2 asymptomatic), n=4 PARK2, n=3 LRRK2, n=8 dementia with Lewy bodies (DLB), n=48 idiopathic PD (iPD), n=30 healthy controls (HC)] underwent a comprehensive evaluation of non-motor and motor PD features. Non-motor features were used to perform a hierarchical clustering analysis with patients and HC using a Scikit-learn toolkit. ResultsClustering analysis suggested three clusters of subjects including Cluster 1 or "Normal-to-mild": young iPD (< 60 years) classified together with most HC and the variable LB burden genetic PD variants (PARK2 and LRRK2) characterized by having normal-to-mild cognitive disabilities and mild-to-moderate motor disability with few axial symptoms; Cluster 2 or "Mild-to-moderate": old iPD patients (>60 years) classified together with the lowest symptomatic E46K-SNCA, PARK2 carriers and HCs, characterizing by having mild-to-moderate cognitive and motor disabilities with few axial symptoms; and Cluster 3 or "Severe": old iPD (>60 years) classified together with all DLB and the most symptomatic E46K-SNCA carriers, characterized by having severe pattern-specific cognitive disabilities (visual attention, perception, processing speed, memory and executive functions) and severe motor PD manifestations with marked axial symptoms. ConclusionsOur study supports the potential value of incorporating genetic PD variants in data-driven iPD classification algorithms and the usefulness of non-motor PD features, especially visual cognition abnormalities, to facilitate the identification of aggressive LB diseases.

neuroscience↗

bioRxiv2018

The Olson conjecture for discrete public goods

We consider how group size affects the private provision of a public good with non-refundable binary contributions. A fixed amount of the good is provided if and only if the number of contributors reaches an exogenous threshold. The threshold, the group size, and the identical, non-refundable cost of contributing to the public good are common knowledge. Our focus is on the case in which the threshold is larger than one, so that teamwork is required to produce the public good. We show that both expected payoffs and the probability that the public good is obtained in the best symmetric equilibrium are decreasing in group size. We also characterize the limit outcome when group size converges to infinity and provide precise conditions under which the expected number of contributors is decreasing or increasing in group size for sufficiently large groups. JEL classificationC72, D71, H41.

evolutionary biology↗

bioRxiv2018

The evolution of egg trading in simultaneous hermaphrodites

Egg trading, whereby simultaneous hermaphrodites exchange each others eggs for fertilization, constitutes one of the few rigorously documented and most widely cited examples of direct reciprocity among unrelated individuals. Yet how egg trading may initially invade a population of non-trading simultaneous hermaphrodites is still unresolved. Here, we address this question with an analytical model that considers mate encounter rates and costs of egg production in a population that may include traders (who provide eggs for fertilization only if their partners also have eggs to reciprocate), providers (who provide eggs regardless of whether their partners have eggs to reciprocate), and withholders (\"cheaters\" who only mate in the male role and just use their eggs to elicit egg release from traders). Our results indicate that a combination of inter-mediate mate encounter rates, sufficiently high costs of egg production, and a sufficiently high probability that traders detect withholders (in which case eggs are not provided) is conducive to the evolution of egg trading. Under these conditions traders can invade--and resist invasion from--providers and withholders alike. The prediction that egg trading evolves only under these specific conditions is consistent with the rare occurrence of this mating system among simultaneous hermaphrodites.

evolutionary biology↗

bioRxiv2018

Group size effects in social evolution

How the size of social groups affects the evolution of cooperative behaviors is a classic question in evolutionary biology. Here we investigate group size effects in the evolutionary dynamics of games in which individuals choose whether to cooperate or defect and payoffs do not depend directly on the size of the group. We find that increasing the group size decreases the proportion of cooperators at both stable and unstable rest points of the replicator dynamics. This implies that larger group sizes can have negative effects (by reducing the amount of cooperation at stable polymorphisms) and positive effects (by enlarging the basin of attraction of more cooperative outcomes) on the evolution of cooperation. These two effects can be simultaneously present in games whose evolutionary dynamics feature both stable and unstable rest points, such as public goods games with participation thresholds. Our theory recovers and generalizes previous results and is applicable to a broad variety of social interactions that have been studied in the literature.

evolutionary biology↗

bioRxiv2018

Anticipated ITD statistics built-in human sound localization

A neural code adapted to the statistical structure of sensory cues may optimize perception. We investigated whether interaural time difference (ITD) statistics inherent in natural acoustic scenes are parameters determining spatial discriminability. The natural ITD rate of change across azimuth (ITDrc) and ITD variability over time (ITDv) were combined in a Fisher information statistic for assessing the amount of azimuthal information conveyed by this sensory cue. We hypothesized that natural ITD statistics drive the neural code for ITD and thus influence spatial perception. Human spatial discriminability and spatial novelty detection of sounds with invariant statistics correlated with natural ITD statistics. The lack of natural statistics in the stimuli suggests that this correlation results from natural statistics driving the neural code. Additionally, the density distribution of ITD tuning matching natural statistics is consistent with classic models of ITD coding and can explain the ITD tuning distribution observed in the mammalian brainstem. Impact statementHuman brain has incorporated natural statistics of spatial cues to the neural code supporting perception of sound location. Major subject areaNeuroscience; Research organismHuman;

neuroscience↗

bioRxiv2017

Fragmentation Modes And The Evolution Of Life Cycles

Reproduction is a defining feature of living systems. To reproduce, aggregates of biological units (e.g., multicellular organisms or colonial bacteria) must fragment into smaller parts. Fragmentation modes in nature range from binary fission in bacteria to collective-level fragmentation and the production of unicellular propagules in multicellular organisms. Despite this apparent ubiquity, the adaptive significance of fragmentation modes has received little attention. Here, we develop a model in which groups arise from the division of single cells that do not separate but stay together until the moment of group fragmentation. We allow for all possible fragmentation patterns and calculate the population growth rate of each associated life cycle. Fragmentation modes that maximise growth rate comprise a restrictive set of patterns that include production of unicellular propagules and division into two similar size groups. Life cycles marked by single-cell bottlenecks maximise population growth rate under a wide range of conditions. This surprising result offers a new evolutionary explanation for the widespread occurrence of this mode of reproduction. All in all, our model provides a framework for exploring the adaptive significance of fragmentation modes and their associated life cycles.\n\nAuthor SummaryMode of reproduction is a defining trait of all organisms, including colonial bacteria and multicellular organisms. To produce offspring, aggregates must fragment by splitting into two or more groups. The particular way that a given group fragments defines the life cycle of the organism. For instance, insect colonies can reproduce by splitting or by producing individuals that found new colonies. Similarly, some colonial bacteria propagate by fission or by releasing single cells, while others split in highly sophisticated ways; in multicellular organisms reproduction typically proceeds via a single cell bottleneck phase. The space of possibilities for fragmentation is so vast that an exhaustive analysis seems daunting. Focusing on fragmentation modes of a simple kind we parametrise all possible modes of group fragmentation and identify those modes leading to the fastest population growth rate. Two kinds of life cycle dominate: one involving division into two equal size groups, and the other involving production of a unicellular propagule. The prevalence of these life cycles in nature is consistent with our null model and suggests that benefits accruing from population growth rate alone may have shaped the evolution of fragmentation mode.

evolutionary biology↗

bioRxiv2016

Antisocial rewarding in structured populations

Cooperation in collective action dilemmas usually breaks down in the absence of additional incentive mechanisms. This tragedy can be escaped if cooperators have the possibility to invest in reward funds that are shared exclusively among cooperators(prosocial rewarding). Yet, the presence of defectors who do not contribute to the public good but do reward themselves(antisocial rewarding) deters cooperation in the absence of additional countermeasures. A recent simulation study suggests that spatial structure is sufficient to prevent antisocial rewarding from deterring cooperation. Here we reinvestigate this issue assuming mixed strategies and weak selection on a game-theoretic model of social interactions, which we also validate using individual-based simulations. We show that increasing reward funds facilitates the maintenance of prosocial rewarding but prevents its evolution from rare, and that spatial structure can sometimes select against the evolution of prosocial rewarding. Our results suggest that, even in spatially structured populations, additional mechanisms are required to prevent antisocial rewarding from deterring cooperation in public goods dilemmas.

evolutionary biology↗