Biology subjects

Duran, J.

Publications and source records attributed to Duran, J..

14 recordsLinked to original sources

bioRxiv2026

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

ADGRD1 (GPR133) is an orphan adhesion G protein-coupled receptor (aGPCR) that primarily signals through Gs to regulate intracellular cAMP levels and is increasingly recognized for its roles across multiple tissues, including the central nervous system. Its conserved expression in neural tissues, the presence of splice variants in the fetal brain, and its structural similarity to other aGPCRs all suggest that it might play important roles in the organization of neural circuits. Recent studies have identified a wide range of extracellular, membrane- associated, and intracellular interacting partners, highlighting the receptors ability to integrate diverse signals. In this study, we explored the consequences of Adgrd1 deficiency in mice using behavioral, electrophysiological, and transcriptomic approaches. Adgrd1-null mice showed reduced nest-building behavior and decreased exploratory drive, while motor coordination and recognition memory remained largely intact. Electrophysiological recordings indicated a trend toward impaired long-term potentiation. These mice also exhibit increased susceptibility to kainate-induced excitotoxicity. RNA-seq analysis revealed coordinated changes in genes associated with inhibitory signaling, extracellular matrix organization, and cytoskeletal regulation, pointing to a shift toward reduced synaptic stabilization and increased hippocampal vulnerability. Altogether, these results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.

neuroscience↗

bioRxiv2025

Aging Leads to Altered Physiological Reactivity in Response to Repeated Social Separation Stress in a Nonhuman Primate Model

Social relationships are critical for maintaining physical health and psychological wellbeing. Since nearly 1 in 4 adults aged 65 years or older are socially isolated, there is a strong need to understand how repeated social stress negatively impacts health outcomes. Using a nonhuman primate model of social aging (i.e., marmosets), we examined whether individuals transitioning into old age ("peri-geri") or individuals who were already geriatric ("very-geri") showed differences in measures of hypothalamic-pituitary axis (HPA) activity, markers of metabolic and immune function, and reunion social behavior in response to repeated social separation challenges (SSC). We found female marmosets, especially peri-geri females, had higher HPA reactivity and better HPA recovery than male marmosets, but this difference diminished in older, very-geri marmosets. HPA activity was correlated with multiple outcomes including locomotive behavior and grooming, changes in blood glucose levels, and neutrophil counts. Moreover, marmosets who approached their partner more and were groomed less during reunions had higher cortisol levels the following day. Interestingly, we found two distinct HPA profiles among our marmosets with half showing strong HPA responses (reactors) and the other half showing little or no HPA response (non-reactors). Non-reactors had less weight gain/more weight loss; elevated levels of calcium, phosphorus, and white blood cells; and received less grooming and social contact time during reunion. Overall, old-aged marmosets who show attenuated HPA responses may have different vulnerabilities to negative health and behavioral outcomes during social stress, and male marmosets appear more likely to present with this HPA non-reactor phenotype earlier in aging.

physiology↗

bioRxiv2025

Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage

Lysosomes are essential for cell survival but are highly susceptible to diverse physical and pathological stressors. Thus, the ability to initiate an acute damage response and promote recovery after stressor resolution is critical for maintaining cellular homeostasis and viability. Although recent studies have advanced our understanding of acute responses to lysosomal injury, the molecular mechanisms governing the recovery stage and distinguishing it from the acute phase remain poorly defined. Here, we delineate a key difference between these two stages in translational regulation and uncover lysosomal recovery from acute damage as a novel trigger for processing body (PB) formation. PBs are membraneless biomolecular condensates involved in RNA metabolism and translational reprogramming. We provide the first evidence that PBs are critical for lysosomal quality control and cell survival during recovery. Mechanistically, PBs are induced selectively during the recovery phase, but not during the acute damage response, through interactions with stress granules (SGs), distinct membraneless biomolecular condensates formed upon acute injury to stabilize damaged lysosomal membranes for repair. Functional analyses reveal that PBs promote lysosomal quality control by collaborating with SG-mediated membrane stabilization, while independently recruiting released cathepsins, thereby collectively supporting cell survival. Together, these findings establish PBs as central effectors of the lysosomal recovery program and underscore the broader relevance of biomolecular condensates in cellular responses to lysosomal damage and related disease processes.

cell biology↗

bioRxiv2025

CAMK2D causes heart failure in RBM20 cardiomyopathy

Although heart disease can arise from different etiologies, current treatment is not tailored to the different underlying causes but is rather a one-size-fits-all approach. Importantly, not all patients benefit from this treatment regimen, which means the number needed to treat is very high. Moreover, this makes clinical trials large and costly, limiting clinical translation. Thus, there is a high medical need to develop a first etiology-specific therapy. Mutations in RBM20, a splicing factor that targets multiple pivotal cardiac genes including TTN and CAMK2D, cause a clinically aggressive form of dilated cardiomyopathy (DCM) with a high risk of malignant ventricular arrhythmias. Here, we hypothesized that CAMK2D is the heart disease-causing target of RBM20. We crossed Camk2d- to Rbm20-deficient mice and found that double knockout (DKO) mice were protected from heart failure and sudden cardiac death. Phosphorylation of multiple CAMK2D targets was increased in Rbm20-deficient mouse hearts, which was reverted in DKO hearts, confirming that CAMK2D is not only misspliced but also overactivated. AAV9-mediated re-expression of single CAMK2D splice variants in DKO mice reintroduced cardiac dysfunction irrespective of the splice variant, unmasking that overactivation rather than missplicing underlies the detrimental phenotype. To test whether heart failure could pharmacologically be reversed, we treated heterozygous Rbm20-R636Q knock-in (KI) mice with hesperadin, a potent CAMK2 inhibitor, which rescued both cardiac function and ventricular geometry. These data demonstrate that overactivation of CAMK2D underlies heart failure in RBM20 cardiomyopathy. Pharmacological inhibition of CAMK2D could therefore become the first cause-directed DCM therapy.

molecular biology↗

bioRxiv2024

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

Lysosomal damage poses a significant threat to cell survival. Our previous work has reported that lysosomal damage induces stress granule (SG) formation. However, the importance of SG formation in determining cell fate and the precise mechanisms through which lysosomal damage triggers SG formation remains unclear. Here, we show that SG formation is initiated via a novel calcium-dependent pathway and plays a protective role in promoting cell survival in response to lysosomal damage. Mechanistically, we demonstrate that during lysosomal damage, ALIX, a calcium-activated protein, transduces lysosomal damage signals by sensing calcium leakage to induce SG formation by controlling the phosphorylation of eIF2. ALIX modulates eIF2 phosphorylation by regulating the association between PKR and its activator PACT, with galectin-3 exerting a negative effect on this process. We also found this regulatory event of SG formation occur on damaged lysosomes. Collectively, these investigations reveal novel insights into the precise regulation of SG formation triggered by lysosomal damage, and shed light on the interaction between damaged lysosomes and SGs. Importantly, SG formation is significant for promoting cell survival in the physiological context of lysosomal damage inflicted by SARS-CoV-2 ORF3a, adenovirus infection, Malaria hemozoin, proteopathic tau as well as environmental hazard silica.

cell biology↗

bioRxiv2023

Recent land use and land cover pressures on Iberian peatlands

Iberian peatlands have been severely affected by land use and land cover (LULC) changes. Despite these pressures, some peatlands persist in the region, although their susceptibility to LULC change remains poorly understood. This study presents the most detailed and extensive distribution data for Iberian peatlands to date and analyzes the dynamics and drivers of LULC in Iberian peatlands and their surrounding areas. We compiled peatland records from various sources and used Corine Land Cover Change layers to determine LULC shifts for 1990, 2000, 2006, 2012, and 2018. Environmental and socioeconomic variables were used to create Boosted Regression Tree models explaining spatial variations in the mean percentage of changed area. Analysis of 270 peatland locations in the Iberian Peninsula revealed that forests and seminatural areas constituted over 80% of the peatlands surroundings. Agricultural areas expanded the most, except between 2006 and 2012 when the artificial areas showed more gains. While most areas experienced an average change of 0%-9.51% of the total area, between 1990 and 2018, lowland peatlands (littoral and sublittoral) suffered more intense changes (9.51% to 38.43%). Our models showed that only elevation and agricultural area density were relevant predictors of spatial distribution changes. Upland Iberian peatlands showed lower susceptibility to LULC changes, while lowland peatlands underwent remarkable transformations. This study substantially expands previous knowledge about the distribution and conservation needs of these ecosystems in the Iberian Peninsula, especially those in littoral and sublittoral lowlands.

ecology↗

bioRxiv2023

The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

physiology↗

bioRxiv2022

DISRUPTED CEREBRAL PERI-MICROVASCULAR GLYCOGEN PROMOTES CAPILLARY CONSTRICTIONS AND AGGRAVATES ISCHEMIA IN MICE

Ischemic stroke results in sudden blood flow cessation, thus, unmet energy requirements. Although the clotted artery can be recanalized and blood flow is restored, brain perfusion may not be fully attained due to microvascular constrictions. Under glucose deprived and hypoxic conditions, glucose derived from the glycogen stored around peri-microvascular astrocyte end-feet may serve as an emergency fuel to meet the metabolic demand during acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, we administered glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) intracerebroventricularly. Transgenic mice in which glycogen synthase-1 expression was selectively knocked out in central nervous system (GYS1Nestin-KO) were also used. Both approaches caused microvascular constrictions mediated by CD13-positive pericyte contractions. When mice with disrupted glycogen utilization were subjected to MCA ischemia, pericyte-mediated microvascular constrictions and the infarct volumes were further increased compared to untreated controls or wild type littermates. Perimicrovascular glycogen depletions were highly correlated with microvascular constrictions as shown by Periodic acid Schiff (PAS) staining and immunolabeling with anti-glycogen antibodies. Imaging of regional cortical blood flow changes during ischemia disclosed severely compromised blood flow dynamics in mice with disrupted glycogen metabolism. In conclusion, disrupting glycogen utilization causes ischemic-like microvascular constrictions under non-ischemic circumstances and increases susceptibility to brain ischemia. Understanding the role of glycogen at neurogliovascular level in brain may provide novel insight to the pathophysiology of ischemic stroke and therapeutic opportunities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/505172v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1a4972borg.highwire.dtl.DTLVardef@c09847org.highwire.dtl.DTLVardef@4d961forg.highwire.dtl.DTLVardef@1bae0de_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

The global distribution and environmental drivers of the soil antibiotic resistome

BackgroundLittle is known about the global distribution and environmental drivers of key microbial functional traits such as antibiotic resistance genes (ARGs). Soils are one of Earths largest reservoirs of ARGs, which are integral for soil microbial competition, and have potential implications for plant and human health. Yet, their diversity and global patterns remain poorly described. Here, we analyzed 285 ARGs in soils from 1012 sites across all continents, and created the first global atlas with the distributions of topsoil ARGs. ResultsWe show that ARGs peaked in high latitude cold and boreal forests. Climatic seasonality and mobile genetic elements, associated with the transmission of antibiotic resistance, were also key drivers of their global distribution. Dominant ARGs were mainly related to multidrug resistance genes and efflux pump machineries. We further pinpointed the global hotspots of the diversity and proportions of soil ARGs. ConclusionsTogether, our work provides the foundation for a better understanding of the ecology and global distribution of the environmental soil antibiotic resistome.

ecology↗

bioRxiv2022

Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I

Oocytes form before birth and remain viable for several decades before fertilisation. Although poor oocyte quality accounts for the majority of female fertility problems, little is known about how oocytes maintain cellular fitness, nor why they eventually decline with age. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilisation and embryo survival. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here, we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain (ETC) through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced ETC. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report the first physiological cell type without complex I in animals. Our findings clarify why patients suffering from complex I related hereditary mitochondrial diseases do not experience subfertility, in contrast to diseases involving other mitochondrial complexes. Complex I suppression represents an evolutionary-conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.

cell biology↗

bioRxiv2021

Lack of p62 impairs glycogen aggregation and exacerbates pathology in a mouse model of myoclonic epilepsy of Lafora

BackgroundLafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates--the so-called Lafora Bodies (LBs)--in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. MethodsTo study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. ResultsDeletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. ConclusionsThese results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which to reduce the deleterious consequences of its accumulation in the brain.

neuroscience↗

bioRxiv2020

Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19

SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2[->]AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/344002v4_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1d1507aorg.highwire.dtl.DTLVardef@faa17forg.highwire.dtl.DTLVardef@80ceb1org.highwire.dtl.DTLVardef@81d61c_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHuman lung organoids with mixed proximodistal epithelia are created C_LIO_LIProximal airway cells are critical for viral infectivity C_LIO_LIDistal alveolar cells are important for emulating host response C_LIO_LIBoth are required for the overzealous response in severe COVID-19 C_LI IN BRIEFAn integrated stem cell-based disease modeling and computational approach demonstrate how both proximal airway epithelium is critical for SARS-CoV-2 infectivity, but distal differentiation of alveolar pneumocytes is critical for simulating the overzealous host response in fatal COVID-19.

cell biology↗

bioRxiv2020

Lack of astrocytic glycogen alters synaptic plasticity but not seizure susceptibility

Brain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions is related to astrocytic glycogen, in the present study we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

biochemistry↗

bioRxiv2020

GORASPs link Golgi cisternae laterally to stabilize the rims and prevent vesiculation

In vitro experiments have shown GRASP65 (GORASP1) and GRASP55 (GORASP2) proteins function in stacking Golgi cisternae. However, in vivo depletion of GORASPs in metazoans have given equivocal results. We have generated a mouse lacking both GORASPs and find that Golgi cisternae remained stacked. However, the stacks are disconnected laterally from each other and the cisternal cross-sectional diameters are significantly reduced compared to their normal counterparts. These data support earlier findings on the role of GORASPs in linking stacks and we suggest that unlinking of stacks affects dynamic control of COPI budding and vesicle fusion at the rims. The net result is that cisternal cores remain stacked, but cisternal diameter is reduced by rim consumption.

cell biology↗