Biology subjects

Gonzalez, A.

Publications and source records attributed to Gonzalez, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Making the Monitoring Framework of the Kunming-Montreal Global Biodiversity Framework fit for purpose.

The Kunming-Montreal Global Biodiversity Framework (GBF) is the most ambitious agreement on biodiversity conservation and sustainable use to date. It calls for a whole-of government and whole-of-society approach to halt and reverse biodiversity loss worldwide. The Monitoring Framework of the GBF lays out how Parties to the Convention on Biological Diversity (CBD) are expected to report their progress. A CBD expert group provided guidance on its implementation, including a gap analysis to identify the strengths and limitations of the indicators in the Monitoring Framework. We present the results of the gap analysis, highlight where more work is needed and provide recommendations on implementing and improving monitoring to allow effective and comprehensive tracking of the GBFs ambition. We find that with the headline and binary indicators, which Parties are required to use, the Monitoring Framework fully covers 19% of the GBFs ambition and partially covers an additional 40%. Including disaggregations of the headline indicators improves coverage to 22% fully and an additional 41% partially. Adding optional (component and complementary) indicators brings full coverage to 29% with an additional 47% partial coverage. No indicators are available for 12% of the GBF. In practice, the coverage of the Monitoring Framework will depend on which indicators (headline and binary as well as component and complementary) and disaggregations are used by countries. Disaggregations are particularly relevant to monitor the cross-cutting considerations defined under section C. Substantial investment is required to collect the necessary data to compute indicators, infer change, and effectively monitor progress. We highlight important next steps to progressively improve the efficacy of the Monitoring Framework.

ecology↗

bioRxiv2024

Partial repair causes permanent defects in papillary structure and function after reversal of urinary obstruction

Urinary obstruction causes injury to the renal papilla and leads to defects in the ability to concentrate urine which predisposes to progressive kidney injury. However, the regenerative capacity of the papilla after reversal of obstruction is poorly understood. To address this, we developed a mouse model of reversible urinary obstruction which is characterized by extensive papillary injury, followed by a robust regeneration response and complete histological recovery over a 3- month period. However, these mice have a pronounced defect in urinary concentrating capacity. We now show that this is due to permanent changes in the composition, organization, and transcriptional signatures of epithelial, endothelial, and interstitial cell lineages in the papilla. There are persistent inflammatory responses that are also seen in patients with renal stone disease but are associated with cell-specific adaptive responses to the increasingly hypoxic environment of the papilla after reversal of obstruction. Taken together, our analysis of a new model of reversible urinary obstruction reveals that partial repair leads to permanent changes in the structure and function of all of the major cellular compartments in the papilla that include both shared and distinct responses to different types of renal papillary injury in humans and mice. SummaryPartial repair after reversal of urinary obstruction leads to permanent changes in structure and function of all major cellular compartments in the renal papilla O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/612436v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1438af5org.highwire.dtl.DTLVardef@157ff60org.highwire.dtl.DTLVardef@3f09c0org.highwire.dtl.DTLVardef@9950b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2024

Metapipeline-DNA: A Comprehensive Germline & Somatic Genomics Nextflow Pipeline

SummaryThe price, quality and throughout of DNA sequencing continue to improve. Algorithmic innovations have allowed inference of a growing range of features from DNA sequencing data, quantifying nuclear, mitochondrial and evolutionary aspects of both germline and somatic genomes. To automate analyses of the full range of genomic characteristics, we created an extensible Nextflow meta-pipeline called metapipeline-DNA. Metapipeline-DNA analyzes targeted and whole-genome sequencing data from raw reads through pre-processing, feature detection by multiple algorithms, quality-control and data- visualization. Each step can be run independently and is supported robust software engineering including automated failure-recovery, robust testing and consistent verifications of inputs, outputs and parameters. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subset and optimize each analysis. Metapipeline-DNA facilitates high-scale, comprehensive analysis of DNA sequencing data. AvailabilityMetapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is available at https://github.com/uclahs-cds/metapipeline-DNA.

bioinformatics↗

bioRxiv2024

Antimicrobial nanolayers of thymol and carvacrol on titanium surfaces: the crucial role of interfacial properties in thymol's superior osteogenic response

"Green nanotechnologies have emerged as environmentally friendly alternatives against microbial multidrug-resistant biofilms. In this study, bactericidal "green" nanolayers (NL) were developed on Ti surfaces using two isomeric phytocompounds, carvacrol (Carv-Ti-NL) and thymol (TOH-Ti-NL). These NLs were fabricated using a one-step immersion treatment method based on a simple and spontaneous self-assembly process. Both NLs revealed strong antimicrobial activity, displaying anti-biofilm and biocidal effects. Notably, TOH-Ti-NL exhibited superior osteogenic performance compared to Carv-Ti-NL, as evidenced by enhanced pre-osteoblast cell attachment and growth, and the production of ALP, collagen type I and Ca2+ deposition. In contrast, fibroblastic cells exhibited reduced attachment on TOH-Ti-NL and enhanced proliferation on Carv-Ti-NL. Considering the biological differential effects, the physicochemical properties of these conformational isomers NLs were studied to elucidate potential differences that could impact on cell response. Although the ATR-FTIR spectra of the NLs were similar and indicated the spontaneous oxidation of Carv and TOH leading to ketonic structures, distinct contributions were observed after the electrooxidation of each NL. Slight differences in hydrophilicity were found for both nanostructures, but higher roughness was found for TOH-Ti-NL. Furthermore, the release curves of Carv and TOH from the NLs revealed distinct profiles over time. Overall, Carv and TOH formed self-assembled layers on Ti able to eradicate Staphylococcus aureus biofilms. Their different physical and chemical characteristics induced distinct responses from eukaryotic cells attached to the NLs. Given these characteristics one might envisage the use of either Carv-Ti-NL or TOH-Ti-NL in order to fine-tune specific chemical physical properties of Ti-based implants. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/610464v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1c288f5org.highwire.dtl.DTLVardef@adc72corg.highwire.dtl.DTLVardef@ef2763org.highwire.dtl.DTLVardef@102d823_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

The minimal number of genes needed to identify a tumor

We demonstrate that the global state of a Gene Regulatory Network [1] may be labeled by a few genes in spite of the fact that there are thousands of genes participating in it. For example, the expression values of only 3 genes are enough to discriminate between a tissue sample coming from a normal lung or a lung adenocarcinoma. We follow a pragmatic procedure, dependent on the sample set, but which is expected to become exact for large enough sets of samples. The proof relies on a scheme for the construction of perfect classification panels of genes [2], inspired by rough set theory [3].

cancer biology↗

bioRxiv2024

Intracellular lipopolysaccharide regulates ER remodeling upon bacterial infection

Selective autophagy of the endoplasmic reticulum (ER), termed ERphagy or reticulophagy, plays a key role in organelle remodeling and cellular homeostasis. However, whether and how ERphagy is regulated during Gram-negative bacteria infection to influence host responses remains unclear. Here, we show that Salmonella enterica serovar Typhimurium releases lipopolysaccharide (LPS) that colocalizes with RETREG1/FAM134B, a reticulon-like ER-resident receptor for ERphagy. Cytosolic delivery of LPS, either during infection or via transfection, markedly increases RETREG1- and LC3B-decorated ER fragments. Mechanistically, affinity-isolation assays demonstrate that LPS directly binds RETREG1 through interactions between lipid A and positively charged residues within its amphipathic helices and C-terminal region. This interaction promotes RETREG1 oligomerization and drives ER membrane fragmentation, a process further amplified by the O-antigen moiety of LPS. The resulting ER fragments accumulate around LC3-positive Salmonella-containing vacuoles, facilitating bacterial clearance. Importantly, both intracellular and extracellular Salmonella exploit outer membrane vesicles (OMVs) to deliver LPS into the host cytosol, triggering RETREG1 activation and ER remodeling. Collectively, our findings reveal a previously unrecognized host response by which LPS of Gram-negative bacteria are sensed by the host ERphagy machinery to promote xenophagy and enhance antibacterial defense.

cell biology↗

bioRxiv2024

Gut microbiome is associated with recurrence-free survival in patients with resected Stage IIIB-D or Stage IV melanoma treated with immune checkpoint inhibitors

The gut microbiome (GMB) has been associated with outcomes of immune checkpoint blockade therapy in melanoma, but there is limited consensus on the specific taxa involved, particularly across different geographic regions. We analyzed pre-treatment stool samples from 674 melanoma patients participating in a phase-III trial of adjuvant nivolumab plus ipilimumab versus nivolumab, across three continents and five regions. Longitudinal analysis revealed that GMB was largely unchanged following treatment, offering promise for lasting GMB-based interventions. In region-specific and cross-region meta-analyses, we identified pre-treatment taxonomic markers associated with recurrence, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium. Recurrence prediction by these markers was best achieved across regions by matching participants on GMB compositional similarity between the intra-regional discovery and external validation sets. AUCs for prediction ranged from 0.83-0.94 (depending on the initial discovery region) for patients closely matched on GMB composition (e.g., JSD [≤]0.11). This evidence indicates that taxonomic markers for prediction of recurrence are generalizable across regions, for individuals of similar GMB composition. HighlightsO_LIOverall gut microbiome (GMB) composition is largely unchanged during ICB treatment. C_LIO_LIGMB composition varies by geographic region C_LIO_LIWe identified gut bacterial markers associated with recurrence in region-specific analyses. C_LIO_LIRegion-identified markers are generalizable if GMB composition is taken into account by matching. C_LI

cancer biology↗

bioRxiv2024

Population estimates of shorebirds on the Atlantic Coast of southern South America generated from large-scale, simultaneous, volunteer-led surveys

Population abundance and trend estimates are crucial to science, management, and conservation. Shorebirds, which are abundant in many coastal habitats and play important roles in coastal ecosystems, are facing some of the most dramatic population declines of any group of birds globally. However, accurate and up-to-date population estimates are lacking for most shorebird species. We thus conducted comprehensive, simultaneous, and community scientist-led surveys of the entire Atlantic Coast of southern South America -- stretching from central Brazil to Tierra del Fuego -- to gather counts of shorebirds that we combined with remote sensing analyses and two-step hurdle models that accounted for presence and abundance. Our objectives were to estimate shorebird densities by habitat, identify high-concentration areas, understand the environmental factors affecting their distributions, and provide population estimates for both Nearctic and Neotropical species. We counted a total of 37,207 shorebirds of 17 species and, from those counts, estimated that nearly 1.1 million shorebirds use the regions coastline. We also found that shorebirds occurred in the highest densities in shallow water wetland habitats and that fewer shorebirds occupied areas that were further away from estuaries. Although not directly comparable, our results suggest the population sizes of the Nearctic species whose nonbreeding ranges are predominantly in southern South America may have declined substantially since previous estimates. At the same time, our study represents the first empirically derived population estimates for Neotropical breeding shorebird species and indicates that they are far more abundant than previously thought. Taken together, our results highlight the power of community scientists to carry out structured protocols at continental scales and generate critical data for a group of at-risk species.

ecology↗

bioRxiv2024

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

Background and PurposeThe mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin (RAP), a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that RAP may also have agonist activity on TRPM8. Experimental approachUsing calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized RAP effects on TRPM8. We also examined the effects of RAP on tearing in mice. Key ResultsMicromolar concentrations of RAP activate rat and mouse TRPM8 directly and potentiate cold-evoked responses. These effects were also observed in human TRPM8. In cultured mouse DRG neurons, RAP evoked an increase in intracellular calcium almost exclusively in cold-sensitive neurons. Responses were drastically blunted in Trpm8 KO mice or by TRPM8 antagonists. Cutaneous cold thermoreceptor endings were also activated by RAP. Topical application of RAP to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism. Conclusion and implicationsThese results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant RAP. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, RAP could be used as an experimental tool in the clinic to explore cold thermoreceptors. Bullet point summaryWHAT IS ALREADY KNOWN O_LITRPM8 is a polymodal channel involved in cold detection, thermoregulation, tearing and cold pain C_LIO_LITacrolimus, a macrolide immunosupressor, is an agonist of cold-activated TRPM8 channels C_LI WHAT THIS STUDY ADDS O_LIThe macrolide rapamycin also activates directly TRPM8 channels in mouse sensory neurons and human TRPM8 C_LIO_LIRapamycin stimulates tearing in mice in a TRPM8-dependent manner CLINICAL SIGNIFICANCE C_LIO_LIRapamycin, an FDA-approved drug, shows agonist activity on TRPM8 channels C_LIO_LIBeneficial effects of rapamycin and other macrolides on inflammatory ocular disorders may involve TRPM8 activation C_LI

neuroscience↗

bioRxiv2024

Current limitations in predicting mRNA translation with deep learning models

BackgroundThe design of nucleotide sequences with defined properties is long-standing problem in bioengineering. An important application is protein expression, be it in the context of research or the production of mRNA vaccines. The rate of protein synthesis depends on the 5 untranslated region (5UTR) of the mRNAs, and recently, deep learning models were proposed to predict the translation output of mRNAs from the 5UTR sequence. At the same time, large data sets of endogenous and reporter mRNA translation have become available. ResultsIn this study we use complementary data obtained in two different cell types to assess the accuracy and generality of currently available models of translation. We find that while performing well on the data sets on which they were trained, deep learning models do not generalize well to other data sets, in particular of endogenous mRNAs, which differ in many properties from reporter constructs. ConclusionsThese differences limit the ability of deep learning models to uncover mechanisms of translation control and to predict the impact of genetic variation. We suggest directions that combine high-throughput measurements and machine learning to unravel mechanisms of translation control and improve construct design.

bioinformatics↗

bioRxiv2023

Deregulation cascades in carcinogenesis

BackgroundThe construction of realistic gene regulatory networks is currently hindered by the complex, often redundant, combinatorial and multi-layered nature of gene interdependencies, the limited availability of functional annotations, and the intrinsic shortcomings of co-expression-based approaches. Here, we introduce Gene Deregulation Networks (GDNs), a new structure in which linked genes indicate that an expression deregulation in one is likely to propagate to the other. GDNs are inferred directly from gene expression data using a probabilistic theory of causation, without requiring prior functional annotation or other domain knowledge. MethodsUsing highly specific tissue markers--N-genes specifically expressed in normal tissues and T-genes specifically expressed in tumors--we construct separate GDNs for normal and tumor tissues. Data are obtained from TCGA RNA-Seq profiles of bulk tumor and normal tissue samples across multiple cancer localizations. GDN links are preliminarily identified via a statistical test of causal sufficiency between gene expression deregulation events, and then reassessed as spurious or redundant using additional causal criteria. A simple scheme based on the GDNs is implemented in order to describe the evolution dynamics. ResultsThe T-GDN in prostate adenocarcinoma comprises 6138 genes and 102362 directed edges (0.27% of possible connections). Genes with low expression deregulation frequency (< 0.2) exhibit high out-degrees, indicating high deregulation potential, while high-frequency genes (> 0.4) show high in-degrees, suggesting they are convergence points of deregulation cascades. EPHA10 (frequency 0.74, in-degree 182) and ENSG00000275479 (out-degree 209) represent these extremes. The N-GDN contains 1097 genes and 4984 edges, featuring compressed nodes reflecting the multi-step nature of somatic evolution. Analysis of tumor samples reveals that early-stage tumors rely primarily on spontaneous gene activations, while advanced tumors exhibit extensive cascade-driven deregulation. Preliminary simulations show qualitative agreement with experiments on gene knockdown in tumor cellular lines. ConclusionsGDNs provide a robust framework to understand cancer progression through deregulation cascades. The separation into N and T networks, connected by NT-genes, i.e. genes common to both networks, offers a systematic basis for modeling carcinogenesis and the possible outcomes of therapeutic interventions.

systems biology↗

bioRxiv2023

Rapid evaluation of habitat connectivity change to safeguard multispecies persistence in human-transformed landscapes

Protecting habitat connectivity in fragmented landscapes is essential for safeguarding biodiversity and natures contributions to people. Following the Post-2020 Kunming-Montreal Global Biodiversity Framework (KM-GBF) of the Convention on Biological Diversity (CBD) there is a clear science-policy need to assess habitat connectivity and track its change over time to inform conservation planning. In response to this need we describe an analytical, multi-indicator and multispecies approach for the rapid assessment of habitat connectivity at fine spatial grain and at the extent of an entire ecoregion. Out of 69 connectivity indicators we found through a literature review, we identified a key-set of nine indicators that align with the Essential Biodiversity Variables framework and that are suitable to guide rapid action for connectivity and conservation targets in the KM-GBF. Using these selected indicators, we mapped and evaluated connectivity change from 2011 to 2021 across the ecoregion of the St-Lawrence Lowlands in Quebec ([~]30,000 km2) for seven ecoprofile species representing regional forest habitat needs. For the majority of these ecoprofile species, trends over the last decade indicate a decline in effective connected area and metapopulation carrying capacity, mainly via a division of large contiguous habitat into smaller fragments, whereas total habitat area largely remained unchanged. These results highlight that trends in habitat area and connectivity are not necessarily correlated and the urgent need to conserve and restore connectivity in the St-Lawrence Lowlands, in order to meet regional targets under the KM-GBF. Our general approach enables a comprehensive evaluation of connectivity for regional spatial planning for biodiversity. We develop an R-tool to support this analysis and that can be extended to other conservation planning efforts for connectivity.

ecology↗

bioRxiv2023

A bird's eye view to the homeostatic, Alzheimer and Glioblastoma attractors

Available data for white matter of the brain allows to locate the normal (homeostatic), Glioblastoma and Alzheimers disease attractors in gene expression space and to identify paths related to transitions like carcinogenesis or Alzheimers disease onset. A predefined path for aging is also apparent, which is consistent with the hypothesis of programmatic aging. In addition, reasonable assumptions about the relative strengths of attractors allow to draw a schematic landscape of fitness: a Wrights diagram. These simple diagrams reproduce known relations between aging, Glioblastoma and Alzheimers disease, and rise interesting questions like the possible connection between programmatic aging and Glioblastoma in this tissue. We anticipate that similar multiple diagrams in other tissues could be useful in the understanding of the biology of apparently unrelated diseases or disorders, and in the discovery of unexpected clues for their treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/568350v3_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@1e2ba82org.highwire.dtl.DTLVardef@42c55dorg.highwire.dtl.DTLVardef@1ab84cforg.highwire.dtl.DTLVardef@19c32e4_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefAging, carcinogenesis and Alzheimers disease onset in white matter of the brain are shown as paths or directions in gene-expression space, a simple view that allows the analysis of their mutual relations and to rise interesting questions such as whether programmatic aging could be related to avoiding the Glioblastoma. HighlightsO_LINormal homeostatic, Glioblastoma and Alzheimers disease attractors are apparent in gene-expression space C_LIO_LIThe relative disposition of paths for carcinogenesis and Alzheimers disease onset reproduce known relations between these diseases C_LIO_LIThe observed corridor for aging is consistent with programmatic aging C_LIO_LIAvoiding the fall into the huge basin of the Glioblastoma could be the subject of selection pressure C_LIO_LIAged normal samples could be captured by the weak Alzheimers disease attractor C_LI

biophysics↗

bioRxiv2023

Neglected consequences of spatio-temporal heterogeneity and dispersal: Metapopulations, the inflationary effect, and real-world consequences for public health

The metapopulation perspective is an important conceptual framework in ecology and evolutionary ecology. Metapopulations are spatially distributed populations linked by dispersal. Both metapopulation models and their community and ecosystem level analogues, metacommunity and meta-ecosystem models, tend to be more stable regionally than locally and display enhanced abundance because of the interplay of spatiotemporal heterogeneity and dispersal (an effect that has been called the "inflationary effect"). We highlight the essential role of spatiotemporal heterogeneity in metapopulation biology, sketch empirical demonstrations of the inflationary effect, and provide a mechanistic interpretation of how the inflationary effect arises and impacts population growth and abundance. We illustrate the effect with examples from the spread of infectious disease. Namely, failure to recognize the full possible effects of spatiotemporal heterogeneity likely enhanced the spread of COVID-19, a failure based on lack of understanding of emergent population processes at large scales which may hamper control and eradication of other infectious diseases. We finish by noting how the effects of spatiotemporal heterogeneity have implicitly played roles in the history of ecology, ranging across subdisciplines as diverse as natural enemy-victim dynamics, species coexistence, and conservation biology. Seriously confronting the complexity of spatiotemporal heterogeneity could push many of these subdisciplines forward.

ecology↗

bioRxiv2023

Macrophages sense ECM mechanics and growth factor availability through cytoskeletal remodeling to regulate their tissue repair program

Tissue resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM in order to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a non-canonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by CSF1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study suggests a distinct mode of ECM mechanosensing and growth factor signaling through which macrophages may regulate tissue repair and fibrosis.

immunology↗

bioRxiv2023

Cross-species transmission and PB2 mammalian adaptations of highly pathogenic avian influenza A/H5N1 viruses in Chile

H5N1 highly pathogenic avian influenza viruses (HPAIV) emerged in wild birds in Chile in December 2022 and spilled over into poultry, marine mammals, and one human. Between December 9, 2022 - March 14, 2023, a coordinated government/academic response detected HPAIV by real-time RT-PCR in 8.5% (412/4735) of samples from 23 avian and 3 mammal orders. Whole-genome sequences obtained from 77 birds and 8 marine mammals revealed that all Chilean H5N1 viruses belong to lineage 2.3.4.4b and cluster monophyletically with viruses from Peru, indicating a single introduction from North America into Peru/Chile. Mammalian adaptations were identified in the PB2 segment: D701N in two sea lions, one human, and one shorebird, and Q591K in the human and one sea lion. Minor variant analysis revealed that D701N was present in 52.9 - 70.9% of sequence reads, indicating the presence of both genotypes within hosts. Further surveillance of spillover events is warranted to assess the emergence and potential onward transmission of mammalian adapted H5N1 HPAIV in South America.

microbiology↗

bioRxiv2023

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

Brains are highly metabolically active organs, consuming 20% of an organisms energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, its unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimers disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

neuroscience↗

bioRxiv2023

Serine ubiquitination of p62 regulates Nrf2 dependent redox homeostasis

The KEAP1-Nrf2 axis is essential for the cellular response against metabolic and oxidative stress. KEAP1 is an adaptor protein of Cullin-3 ubiquitin ligase that controls the cellular levels of Nrf2, a critical transcription factor of several cytoprotective genes. Oxidative stress, defective autophagy and pathogenic infections activate Nrf2 signaling through phosphorylation of the adaptor protein p62, which competes with Nrf2 for binding to KEAP1. Here we show that phosphoribosyl-linked serine ubiquitination of p62 catalyzed by SidE effectors of Legionella pneumophila controls Nrf2 signaling and cell metabolism upon Legionella infection. Serine ubiquitination of p62 sterically blocks its binding to KEAP1, resulting in Nrf2 ubiquitination and degradation. This reduces Nrf2-dependent antioxidant synthesis in the early phase of infection. Levels of serine ubiquitinated p62 diminish in the later stage of infection allowing the expression of Nrf2-target genes; resulting in a differential regulation of the host metabolome and proteome in a Nrf2 dependent manner.

cell biology↗