Biology subjects

Lopez, J. M.

Publications and source records attributed to Lopez, J. M..

11 recordsLinked to original sources

bioRxiv2026

A distributed pallial circuit links sensory and bodily representations to aversive motivational value in the goldfish dorsomedial pallium

Understanding how neural circuits transform sensory and bodily signals into motivational states and adaptive behavior is a central problem in neuroscience. In teleost fish, the dorsomedial telencephalon (Dm) is a key pallial region implicated in both sensory processing and aversive behavior, yet whether these functions arise from a functionally uniform region or from interactions among specialized pallial domains has remained unknown. Here we show that the teleost dorsomedial telencephalon exhibits a previously unrecognized functional organization in which distinct but interconnected pallial domains perform complementary computations that progressively transform multimodal sensory and bodily representations into aversive motivational value and adaptive behavioral control. Wide-field voltage-sensitive dye imaging revealed that tactile, auditory, and gustatory stimuli evoke spatially organized, modality-specific activity exclusively within the caudal subdivision of Dm (Dmc), whereas the rostral subdivision (Dmr) showed little or no sensory responsiveness. In contrast, focal intracerebral microstimulation demonstrated that activation of Dmr, but not Dmc, is sufficient to generate robust, flexible, and reversible conditioned place avoidance, identifying Dmr as a pallial node causally involved in the assignment of negative motivational value. Anatomical tracing revealed a circuit in which sensory and bodily-related inputs converge onto Dmc, are relayed intrapallially to Dmr, where they are transformed into an aversive motivational signal before being conveyed to hypothalamic and brainstem centers involved in autonomic and behavioral regulation. Immunohistochemical analyses confirmed the pallial identity of both subdivisions and their distinct rostrocaudal organization, while providing no evidence that Dm corresponds to a classical pallial amygdaloid territory. This functional architecture more closely resembles the distributed organization of mammalian corticolimbic networks than either a unitary pallial amygdala or a neocortical sensory hierarchy, suggesting that the transformation of sensory and bodily representations into motivational control may represent a conserved organizational feature of the pallium that emerged early during vertebrate evolution. Short abstract / Significance statementThis study shows that the teleost dorsomedial pallium is organized into complementary functional domains that dissociate multimodal sensory representation from negative motivational processing while forming an interconnected pallial circuit associated with adaptive behavioral control. Our findings reveal a distributed pallial organization resembling mammalian corticolimbic architectures and provide a new framework for understanding the evolution of vertebrate pallial function.

neuroscience↗

bioRxiv2026

The human parasite, Toxoplasma gondii, is paralyzed without two components of the apical polar ring

The phylum Apicomplexa contains [~] 6000 known species of unicellular eukaryotic parasites. A unifying feature among the apicomplexans is the apical complex, which varies in complexity in different lineages, but always contains an annulus (a.k.a. the apical polar ring) into which the minus ends of an array of cortical microtubules are embedded. In Toxoplasma gondii, the apical complex also includes the conoid, which contains several signaling and structural proteins critical for parasite motility. The conoid extends and retracts through the apical polar ring in a calcium-dependent manner. Here we report the identification of several new apical polar ring components, including APR9, which is highly conserved among the apicomplexans and their free-living relative Chromera velia. The loss of APR9 alone has only a moderate impact on the parasite lytic cycle. However, the knockout of both APR9 and KinesinA (another apical polar ring component) paralyzes parasite and drastically impairs invasion, egress and the lytic cycle. The double-knockout displays multiple subcellular abnormalities, including the formation of an apical actin concentration, impaired conoid extension, and significantly reduced secretion of a major adhesin (MIC2) upon stimulation with a calcium ionophore. These findings reveal that the apical polar ring plays a critical role in parasite motility and contributes to multiple subcellular processes.

cell biology↗

bioRxiv2025

The shared genomic history of Middle to Late Holocene Southern Cone populations

The Southern Cone represents the southernmost region of South America to be colonized by humans. Although ancient genomes have been sequenced from southern Patagonia, genomic data from the central Southern Cone remain temporally and spatially sparse. The archaeological record of this region documents major cultural transformations during the Middle and Late Holocene, yet their relationship to demographic processes has long been debated. Here, we present genome-wide data from 52 individuals spanning the past 5,000 years, originating from four regions of the central Southern Cone in present-day Argentina and Uruguay: the central and southern Pampas, Northwest Patagonia, the Parana River Delta and Lower Uruguay River, and the eastern lowlands of Uruguay. Genomic evidence from the Pampas reveals the presence of at least three distinct ancestries during the Middle Holocene. While genetic contacts with southern Patagonian groups were sporadic, we identify the expansion of an ancestry of unknown geographic origin by 4,800 years ago, which increased substantially during the Late Holocene. This same ancestry arrived in Northwest Patagonia by at least 600 years ago, and it co-existed with individuals carrying a southern Andean genetic profile until colonial times. Genetic structure differentiates populations along the Parana River Delta and the Lower Uruguay River by approximately 1,600 years ago. In contrast, individuals from the eastern lowlands of Uruguay show genetic links with Sambaqui-associated populations from the southern coast of Brazil, suggesting the role of human dispersals in connecting tropical lowland cultural traditions. Overall, our work documents the diffusion of genetically distinct groups across all regions studied and provides compelling evidence that large-scale human movements contributed to the remarkable cultural diversity of central Southern Cone populations during the Middle and Late Holocene.

genetics↗

bioRxiv2025

Spatial modeling of Cultural Ecosystem Services from social media data: Systematic review of operability, opportunities, limitations and ways forward

O_LIThis systematic review explores the use of social media data to spatially model Cultural Ecosystem Services (CES), which are non-material benefits provided by ecosystems that support human well-being. Based on a search of 510 scientific articles in Web of Science and Scopus, we carefully selected and analyzed those that focused on spatial modeling of CES using social media data. We aimed to (a) identify the diversity of CES assessed, (b) analyse the social media platforms used as data sources, (c) evaluate the modelling frameworks employed, and (d) summarise the predictor variables included in these models. C_LIO_LIWe found that the most studied CES were those related to physical and psychological experiences (62%; especially recreation) and the main predictor variables were the presence of natural elements (52%), land use and land cover maps, and topographic variables, often weighted by applying distance-based metrics (24%). Twenty-four social media data sources were identified but Flickr was by far the most widely used one (40%). MaxEnt (37%) and Random Forest (16%) were the most commonly used modeling tools. The most commonly used metrics to assess model performance were AUC-ROC, AIC, and R2 values. C_LIO_LIWhile the use of social media offers an opportunity to study CES and provide cost-effective and scalable insights, this article discusses some limitations and considerations raised from the literature review to be taken into account when using this type of data. These include the quality and representativeness of social media data, the importance of a clear definition of CES, a proper labeling of social media data, and an appropriate selection of spatial modeling techniques. C_LIO_LIFuture research should address these limitations and considerations by integrating different data sources and refining methodologies to improve the accuracy and applicability of CES models. This review provides a comprehensive overview of current practices and highlights areas for further investigation in the spatial modeling of CES using social media data. C_LI

ecology↗

bioRxiv2024

The initiation and early development of apical-basal polarity in Toxoplasma gondii

The human parasite Toxoplasma gondii has a distinctive body plan with a well-defined polarity. In the apical complex, the minus ends of the 22 cortical microtubules are anchored to the apical polar ring, a putative microtubule-organizing center. The basal complex caps and constricts the parasite posterior end, and is critical for cytokinesis. How this apical-basal polarity axis is initiated was unknown. Here we examined the development of the apical polar ring and the basal complex in nascent daughters using expansion microscopy. We found that different substructures in the apical polar ring have different sensitivity to stress. In addition, apical-basal differentiation is already established upon nucleation of the cortical microtubule array: arc forms of the apical polar ring and basal complex associate with opposite ends of the microtubules. As the construction of the daughter framework progresses towards the centrioles, the apical and the basal arcs co-develop in striking synchrony ahead of the microtubule array, and close into a ring-form before all the microtubules are nucleated. We also found that two apical polar ring components, APR2 and KinesinA, act synergistically. The removal of each protein individually has modest to no impact on the lytic cycle. However, the loss of both results in abnormalities in the microtubule array and highly reduced plaquing and invasion efficiency.

cell biology↗

bioRxiv2023

The Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses

Latrophilin-1 (Lphn1, a.k.a. CIRL1 and CL1; gene symbol Adgrl1) is an Adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for -latrotoxin. Here we analyzed conditional knockin/knockout mice for Lphn1 that contain an extracellular myc-epitope tag. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but contributes to inhibitory synaptic connections.

neuroscience↗

bioRxiv2022

An apical protein, Pcr2, is required for persistent movement by the human parasite Toxoplasma gondii

The phylum Apicomplexa includes thousands of species of unicellular parasites that cause a wide range of human and animal diseases such as malaria and toxoplasmosis. To infect, the parasite must first initiate active movement to disseminate through tissue and invade into a host cell, and then cease moving once inside. The parasite moves by gliding on a surface, propelled by an internal cortical actomyosin-based motility apparatus. One of the most effective invaders in Apicomplexa is Toxoplasma gondii, which can infect any nucleated cell and any warm-blooded animal. During invasion, the parasite first makes contact with the host cell "head-on" with the apical complex, which features an elaborate cytoskeletal apparatus and associated structures. Here we report the identification and characterization of a new component of the apical complex, Preconoidal region protein 2 (Pcr2). Pcr2 knockout parasites replicate normally, but they are severely diminished in their capacity for host tissue destruction due to significantly impaired invasion and egress, two vital steps in the lytic cycle. When stimulated for calcium-induced egress, Pcr2 knockout parasites become active, and secrete effectors to lyse the host cell. Calcium-induced secretion of the major adhesin, MIC2, also appears to be normal. However, the movement of the Pcr2 knockout parasite is spasmodic, which drastically compromises egress. In addition to faulty motility, the ability of the Pcr2 knockout parasite to assemble the moving junction is impaired. Both defects likely contribute to the poor efficiency of invasion. Interestingly, actomyosin activity, as indicated by the motion of mEmerald tagged actin chromobody, appears to be largely unperturbed by the loss of Pcr2, raising the possibility that Pcr2 may act downstream of or in parallel with the actomyosin machinery.

cell biology↗

bioRxiv2021

A Genetic Screen for Suppressors of Cryptic 5' Splicing in C. elegans Reveals Roles for KIN17 and PRCC in Maintaining Both 5' and 3' Splice Site Identity

Pre-mRNA splicing is an essential step of eukaryotic gene expression carried out by a series of dynamic macromolecular protein/RNA complexes, known collectively and individually as the spliceosome. This series of spliceosomal complexes define, assemble on, and catalyze the removal of introns. Molecular model snapshots of intermediates in the process have been created from cryo-EM data, however, many aspects of the dynamic changes that occur in the spliceosome are not fully understood. Caenorhabditis elegans follow the GU-AG rule of splicing, with almost all introns beginning with 5 GU and ending with 3 AG. These splice sites are identified early in the splicing cycle, but as the cycle progresses and "custody" of the pre-mRNA splice sites is passed from factor to factor as the catalytic site is built, the mechanism by which splice site identity is maintained or re-established through these dynamic changes is unclear. We performed a genetic screen in C. elegans for factors that are capable of changing 5 splice site choice. We report that KIN17 and PRCC are involved in splice site choice, the first functional splicing role proposed for either of these proteins. Previously identified suppressors of cryptic 5 splicing promote distal cryptic GU splice sites, however, mutations in KIN17 and PRCC instead promote usage of an unusual proximal 5 splice site which defines an intron beginning with UU, separated by 1nt from a GU donor. We performed high-throughput mRNA sequencing analysis and found that mutations in PRCC but not KIN17 changed 5 splice sites genome-wide, promoting usage of nearby non-consensus sites. We further found that mutations in KIN17 and PRCC changed dozens of 3 splice sites, promoting non-consensus sites upstream of canonical splice sites. Our work has uncovered both fine and coarse mechanisms by which the spliceosome maintains splice site identity during the complex assembly process. Author SummaryPre-mRNA splicing is an essential step of gene regulation, carried out by an unusual molecular machine, the spliceosome. Unlike other molecular machines, such as ribosomes, that simply assemble and catalyze chemical reactions, "the spliceosome" is a highly-dynamic cycle, carried out by 5 specialized small nuclear RNAs and over 100 proteins, which sequentially join, rearrange, and withdraw from the splicing assembly during each splicing cycle. These assemblies initially choose "splice sites" where the pre-mRNA will be cut, and then undergo multiple rearrangements to finally form the active site which catalyzes the splicing reactions which remove an intron from a pre-mRNA. We are currently in the midst of a "resolution revolution", with ever-clearer cryo-EM snapshots of stalled complexes allowing researchers to visualize moments in time in the splicing cycle. These models are illuminating, but do not always elucidate mechanistic functioning, therefore our lab takes a complementary approach, using the power of genetics in a multicellular animal to gain functional insights into the spliceosome. Using a C .elegans genetic screen, we have found novel functional splicing roles for two proteins, KIN17 and PRCC. Our results suggest that the spliceosome does not just rely on its initial identification of the splice site, but in a later step, re-identifies where to cut. We liken this two-stage identification to using a microscope by first using the coarse focus to find the area of interest, and then using the fine focus to adjust as needed. This work moves us closer to full mechanistic understanding of how the spliceosome chooses where to cut a pre-mRNA message.

molecular biology↗

bioRxiv2020

Targeted millisecond-scale activation of cells using non-invasive Sonogenetics

Ultrasound has been used to non-invasively manipulate neuronal functions in humans and other animals1-4. However, this approach is limited as it has been challenging to target specific cells within the brain or body5-8. Here, we identify human Transient Receptor Potential A1 (hsTRPA1) as a candidate that confers ultrasound sensitivity to mammalian cells. Ultrasound-evoked gating of hsTRPA1 specifically requires its N-terminal tip region and cholesterol interactions; and target cells with an intact actin cytoskeleton, revealing elements of the sonogenetic mechanism. Next, we use calcium imaging and electrophysiology to show that hsTRPA1 potentiates ultrasound-evoked responses in primary neurons. Furthermore, unilateral expression of hsTRPA1 in mouse layer V motor cortical neurons leads to c-fos expression and contralateral limb responses in response to ultrasound delivered through an intact skull. Collectively, we demonstrate that hsTRPA1-based sonogenetics can effectively manipulate neurons within the intact mammalian brain, a method that could be used across species.

neuroscience↗

bioRxiv2018

Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms

Human skeleton undergoes constant remodeling during the whole life. By means of such process, which occurs at a microscopic scale, worn out bone is replaced by new, fully functional one. Multiple bone remodeling events occur simultaneously and independently throughout the body, so the whole skeleton is completely renewed about every ten years.\n\nBone remodeling is performed by groups of cells called Bone Multicellular Units (BMU). BMUs consist of different cell types; some are specialized in destroying old bone, whereas others produce new bone to replace the former. The whole process is tightly regulated so that the amount of new bone produced exactly balances that of old one removed and bone microscopic structure is maintained.\n\nTo date, many regulatory molecules involved in bone remodeling have been identified, but the precise mechanism of BMU operation remains to be fully elucidated. Given the complexity of the signaling pathways already known, the question arises of ascertaining whether such complexity is an inherent requirement of the process, or a consequence of operational redundancy.\n\nIn this work we propose a minimal model of BMU function which involves a small number of signals and accounts for fully functional BMU operation. Our main assumptions are i) at any given time, any cell within a BMU can select only one among a reduced choice of decisions: divide, die, migrate or differentiate, ii) such decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor is coupled to that of a few external mediators. It is shown that efficient BMU operation then unfolds as an emergent property, which results from individual decisions taken by cells in the BMU unit in the absence of any external planning.\n\nAuthor summaryOur skeleton is a living organ that is being renewed throughout our life. This task is accomplished by teams of bone cells termed as Bone Multicellular Units (BMUs) that are recruited when and where needed, to operate at places where bone has lost functionality either for an excess of mechanical stress or because loss of activity. Once assembled, BMU remove old bone and replace it by new one, and disband as soon as their mission has been accomplished. No single bone evades BMU screening, so that the whole human skeleton is completely renewed approximately every ten years.\n\nIt is natural to wonder how such robust and fascinating process is regulated. Many signaling pathways involved in bone remodeling have been identified so far, but whether all of them are necessary for BMU operation remains unclear. In this work we show that just a reduced number of such signals could suffice for that purpose. This suggests that a large degree of redundancy might have been kept in place, perhaps as a consequence of different convergent strategies developed in the course of evolution.

systems biology↗

bioRxiv2018

In vivo CRISPR-Cas gene editing with no detectable genome-wide off-target mutations

CRISPR-Cas genome-editing nucleases hold substantial promise for human therapeutics1-5 but identifying unwanted off-target mutations remains an important requirement for clinical translation6, 7. For ex vivo therapeutic applications, previously published cell-based genome-wide methods provide potentially useful strategies to identify and quantify these off-target mutation sites8-12. However, a well-validated method that can reliably identify off-targets in vivo has not been described to date, leaving the question of whether and how frequently these types of mutations occur. Here we describe Verification of In Vivo Off-targets (VIVO), a highly sensitive, unbiased, and generalizable strategy that we show can robustly identify genome-wide CRISPR-Cas nuclease off-target effects in vivo. To our knowledge, these studies provide the first demonstration that CRISPR-Cas nucleases can induce substantial off-target mutations in vivo, a result we obtained using a deliberately promiscuous guide RNA (gRNA). More importantly, we used VIVO to show that appropriately designed gRNAs can direct efficient in vivo editing without inducing detectable off-target mutations. Our findings provide strong support for and should encourage further development of in vivo genome editing therapeutic strategies.

molecular biology↗