Biology subjects

Weber, P.

Publications and source records attributed to Weber, P..

At least 19 recordsLinked to original sources

bioRxiv2026

A non-retinoid triazolopyrimidine RBP4 antagonist for the treatment of Stargardt disease

Stargardt disease is a juvenile-onset retinal dystrophy characterized by the buildup of cytotoxic lipofuscin deposits in the retinal pigment epithelium (RPE), leading to photoreceptor degeneration and eventual blindness. Currently, there are no FDA-approved treatments for Stargardt disease. Bisretinoids, byproducts of the visual cycle, are the major cytotoxic components of the lipofuscin deposits, and bisretinoid synthesis relies on the traffic of retinol from the bloodstream to the retina. Selective targeting of the key retinol transporter, Retinol-Binding Protein 4 (RBP4), offers an appealing strategy for halting the buildup of lipofuscin in the RPE and arresting the progression of Stargardt disease. Retinol delivery depends on RBP4 interaction with another serum protein, Transthyretin (TTR). We previously reported several libraries of RBP4 antagonists that effectively blocked the association of the TTR-RBP4-retinol tertiary complex, thereby lowering the overall retinol load in the retina; however, some chemotypes displayed off-target activity that warranted further optimization. Here, we report the pharmacological characterization of AKR-XI-85 and its analogs as promising non-retinoid small-molecule RBP4 antagonists. AKR-XI-85 displayed excellent in vitro and in vivo efficacy and desirable pharmacokinetic properties without any limiting off-target activity. In Abca4-/- mice, chronic dosing of the compound induced a prolonged reduction in serum RBP4 levels and achieved a dramatic, 70 % reduction in the accumulation of A2E, a critical component of toxic lipofuscin. As such, AKR-XI-85 may be an attractive drug candidate for the treatment of Stargardt disease and other lipofuscin-dependent retinopathies.

pharmacology and toxicology↗

bioRxiv2025

Inhibition of cell-mediated immunity in type 1 diabetes by beta cell-targeted PD-1 agonists in pancreas tissue slices

Tissue-targeted immunotherapies for type 1 diabetes (T1D) hold potential to protect pancreatic beta cells while minimizing systemic immunosuppression. We used a bispecific agonist called Immune Modulating Monoclonal-TCR Against Autoimmune Disease (ImmTAAI), consisting of a T cell receptor (TCR) targeting domain fused with a PD-1 agonist to specifically bind beta cells and suppress autoreactive T cells. We used live pancreas slices to demonstrate targeting of ImmTAAI molecules to pre-proinsulin peptide-HLA-A2 complexes on human beta cells. ImmTAAI protected beta cells from T cell killing by increasing T cell motility and inhibiting cytokine secretion. ImmTAAI treatment also increased the motility of islet-infiltrating T cells in slices from a donor with recent-onset T1D and preserved insulin secretion in slices co-cultured with T cell avatars transduced with diabetogenic TCRs. These data demonstrate that ImmTAAI molecules have the potential to limit T cell activity locally, making this an attractive platform to elicit targeted immunoregulation in T1D. One Sentence SummaryWe demonstrate inhibition of cellular immunity in human type 1 diabetes using a beta cell-targeting, affinity-enhanced TCR fused to a PD-1 agonist.

bioengineering↗

bioRxiv2025

Composition, growth, succession, and function in the Cladophora microbiome: insights from quantitative Stable Isotope Probing and NanoSIMS imaging

The branching green macroalga Cladophora glomerata and its epiphytic microbiome dominate summer biomass in the Eel River, a Northern California river under Mediterranean (summer drought, winter rain) seasonality. Green Cladophora streamers proliferate in early summer, then change to yellow and then red-brown as epiphyte loads increase. We characterized successional changes in epiphytic bacteria on Cladophora, examining both community composition and growth rates, using quantitative Stable Isotope Probing (qSIP) and16S rRNA gene amplicon sequencing. The number of bacterial taxa increased with succession while growth rates peaked in the middle stage. NanoSIMS imaging confirmed high sulfur (S) concentrations in Cladophora cell walls relative to surrounding biomass, coinciding with a bloom of sulfur bacteria (bacteria that reduce or oxidize sulfur/sulfates). In general, relative abundances and growth rates were independent, indicating that either metric alone is insufficient for understanding how taxonomy and functional groups affect ecosystem processes. For instance, the relative abundance of nitrogen fixers peaked in the late summer when their relative growth rates were slowest. Such patterns may be driven by space competition limiting growth. Together, changes in abundance and relative growth rates suggest different limiting factors for different functional groups in the Cladophora microbiome at multiple successional stages.

microbiology↗

bioRxiv2025

Neural dynamics of proactive and reactive cognitive control in medial and lateral prefrontal cortex

Goal-directed behavior requires adjusting cognitive control to both react to and prepare for conflict. Previous work indicates theta oscillations and population activity in dorsomedial prefrontal cortex (dmPFC) and dorsolateral prefrontal cortex (dlPFC) are critical for reactive control. However, the neural mechanisms supporting proactive control are less clear. Here, we investigated the neural basis of behavioral adaptations when control is prepared in anticipation of conflict using intracranial EEG (iEEG) in dmPFC and dlPFC during a Stroop task where conflict frequency was manipulated across blocks. We observed canonical conflict-driven increases in dmPFC theta and in dmPFC and dlPFC local population activity, as indexed by high frequency activity (HFA). Conflict also suppressed theta power in both regions after the response, accentuated a pre-response beta desynchronization selectively in dlPFC, and increased a post-response beta rebound in both regions. Importantly, we identified a pre-trial marker of proactive control where dmPFC theta power increased before trials when conflict was expected, and theta, beta, and HFA conflict signals in both regions were enhanced when conflict was rare and diminished when conflict was common. These findings reveal shared HFA but dissociable oscillatory dynamics in dmPFC and dlPFC during reactive conflict processing, highlight pre-trial dmPFC theta as a potential substrate for proactive control, and refine the roles of dmPFC and dlPFC in control adaptations.

neuroscience↗

bioRxiv2024

Volatile Organic Compound Specialists in the Phycosphere

Labile dissolved organic carbon (LDOC) in the oceans accounts for [~][1/4] of marine primary production and turns over with a half-life of seconds to days, fueling one of the largest engines of microbial heterotrophic production on the planet. Volatile organic compounds (VOCs) are poorly constrained components of LDOC. Here, we detected 78 m/z signals, corresponding to unique VOCs, including petroleum hydrocarbons, totaling 18.5 nM in the culture medium of a model diatom. In five cocultures with bacteria adapted to grow with this diatom, 1 to 66 VOCs were depleted. Two of the most active VOC consumers, Marinobacter and Roseibium, contained more genes encoding VOC oxidation proteins, and attached to the diatom, suggesting VOC specialism. With NanoSIMS and stable isotope labeling, we confirmed that Marinobacter incorporated carbon from benzene, one of the depleted VOCs detected in the co-culture. Diatom gross carbon production increased by up to 29% in the presence of VOC consumers, indicating that VOC consumption by heterotrophic bacteria in the phycosphere - a region of rapid organic carbon oxidation that surrounds phytoplankton cells - could impact global rates of gross primary production.

microbiology↗

bioRxiv2024

Chronic intermittent fasting impairs β-cell maturation and function in adolescent mice

Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individuals age is unclear. Here, we investigated the effects of IF on systemic metabolism and pancreatic islet function in old, middle-aged, and young mice. Short-term IF improved glucose homeostasis across all age groups, without altering islet function and morphology. In contrast, while chronic IF was beneficial for adult mice, it resulted in impaired {beta}-cell function in the young. Using scRNAseq, we delineated that the {beta}-cell maturation and function score were reduced in young mice. In human islets, a similar pattern was observed in Type 1 (T1D), but not in Type 2 diabetes (T2D), suggesting that the impact of chronic IF in adolescence is linked to the development of {beta}-cell dysfunction. Our study suggests considering the duration of IF in younger people, as it may enhance rather than reduce diabetes outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/590140v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1676dd1org.highwire.dtl.DTLVardef@15ac993org.highwire.dtl.DTLVardef@167f577org.highwire.dtl.DTLVardef@247e4e_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LILong-term IF impairs {beta}-cell function in adolescent mice. C_LIO_LIIF-induced impaired {beta}-cell function is associated with impaired proliferative capacity and lower levels of mature cells. C_LIO_LIIF-induced impaired {beta}-cell function is associated with a transcriptional change highly conserved in type 1-, but not type 2 diabetes. C_LI

physiology↗

bioRxiv2023

THE DUAL ROLE OF THE MICROCYSTIS AERUGINOSA MICROBIOME ON CYANOTOXIN PRODUCTION: COMPETITION FOR AND REMINERALIZATION OF ORGANIC NITROGEN

Nutrient-induced blooms of the globally abundant freshwater toxic cyanobacterium Microcystis are the cause of worldwide public and ecosystem health concerns. The response of Microcystis growth and toxin production to new and recycled nitrogen (N) inputs, and the impact of heterotrophic bacteria in the Microcystis phycosphere on these processes are not well understood. Here, using microbiome transplant experiments, cyanotoxin analysis, and stable isotope tracing to measure N incorporation and exchange at single cell resolution, we monitored the growth, cyanotoxin production, and microbiome community structure of several Microcystis strains grown on amino acids and proteins as the sole N source. We demonstrate that 1) organic N availability shapes the microbiome community structure in the Microcystis phycosphere; 2) external organic N input leads to lower bacterial colonization of the phycosphere; 3) certain Microcystis strains can directly uptake amino acids, but with lower rates than heterotrophic bacteria; 4) biomass-specific microcystin production is not impacted by N source (i.e., nitrate, amino acids and protein) but rather by total N availability; and 5) some bacterial communities compete with Microcystis for organic N, but others remineralize organic N, in the process producing bio-available N for Microcystis. We conclude that organic N input can support Microcystis blooms and toxin production, and Microcystis-associated microbial communities play critical roles by influencing cyanobacterial succession through either decreasing (via competition) or increasing (via remineralization) N availability, especially under inorganic N scarcity.

microbiology↗

bioRxiv2023

Natural genetic variation quantitatively regulates heart-rate and -dimension

The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models, Oryzias latipes, and Oryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In a segregation population of 1192 HO5 x HdrR F2 embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes in loss-of-function models revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart. One-Sentence SummaryKey loci for vertebrate heart function mapped and validated, highlighting diagnostic and potential therapeutic targets for cardiac disorders.

genetics↗

bioRxiv2023

Drosophila macrophages control systemic cytokine levels in response to oxidative stress via a non-canonical DNA damage repair signaling cascade

Environmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, the Drosophila blood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, the Drosophila macrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokine unpaired-3. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adult Drosophila on oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.

immunology↗

bioRxiv2022

Asymmetric coding of reward prediction errors in human insula and dorsomedial prefrontal cortex

The signed value and unsigned salience of reward prediction errors (RPEs) are critical to understanding reinforcement learning (RL) and cognitive control. Dorsomedial prefrontal cortex (dMPFC) and insula (INS) are key regions for integrating reward and surprise information, but conflicting evidence for both signed and unsigned activity has led to competing proposals for the nature of RPE representations in these brain areas. Recently, the distributional RL theory (dRL) has been used to explain RPE coding diversity in the rodent midbrain by proposing that dopaminergic neurons have differential sensitivity to positive and negative RPEs. Here, we use intracranially recorded high frequency activity (HFA) to show that this asymmetric scaling strategy captures RPE coding diversity in human dMPFC and INS. We found neural populations responding to valence-specific positive and negative RPEs, as well as unsigned RPE salience, which are spatially interleaved within each region. Furthermore, directional connectivity estimates suggest a leading role of INS in communicating positive and unsigned RPEs to dMPFC. These findings support asymmetric scaling across distinct but intermingled neural populations as a core principle in RPE coding, expand the scope of dRL, and reconcile longstanding theoretical debates on the role of dMPFC and INS in RL and cognitive control.

neuroscience↗

bioRxiv2022

Synergizing algorithmic design, photoclick chemistry and multi-material volumetric printing for accelerating complex shape engineering

Accelerating the designing and manufacturing of complex shapes has been a driving factor of modern industrialization. This has led to numerous advances in computational design and modeling and novel additive manufacturing (AM) techniques that can create complex shapes for bespoke applications. By combining a new coding-based design approach with high-throughput volumetric printing, we envision a new approach to transform the way we design and fabricate complex shapes. Here, we demonstrate an algorithmic voxel-based approach, which can rapidly generate and analyze porous structures, auxetic meshes and cylinders, or perfusable constructs. We use this design scheme in conjunction with new approaches for multi-material volumetric printing based on thiol-ene photoclick chemistry to rapidly fabricate complex heterogeneous structures. Collectively, the new design and fabrication technique we demonstrate can be used across a wide-spectrum of products such as actuators, biomedical implants and grafts, or tissue and disease models. TeaserA new scheme of rapidly designing and printing complex multi-material structures for implant and tissue graft applications.

bioengineering↗

bioRxiv2022

Dynamics and structural changes of calmodulin upon interaction with its potent antagonist calmidazolium

Calmodulin (CaM) is a eukaryotic multifunctional, calcium-modulated protein that regulates the activity of numerous effector proteins involved in a variety of physiological processes. Calmidazolium (CDZ) is a potent small molecule antagonist of CaM and one the most widely used inhibitors of CaM in cell biology. Here, we report the structural characterization of CaM:CDZ complexes using combined SAXS, X-ray crystallography, HDX-MS and NMR approaches. Our results provide molecular insights into the CDZ-induced dynamics and structural changes of CaM leading to its inhibition. CDZ-binding induces an open-to-closed conformational change of CaM and results in a strong stabilization of its structural elements associated with a reduction of protein dynamics over a large time range. These CDZ-triggered CaM changes mimic those induced by CaM-binding peptides derived from protein targets, despite their distant chemical nature. CaM residues in close contact with CDZ and involved in the stabilization of the CaM:CDZ complex have been identified. These results open the way to rationally design new CaM-selective drugs. Figure and text for the Table of Contents (ToC) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/474921v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@b0c76org.highwire.dtl.DTLVardef@15f462forg.highwire.dtl.DTLVardef@1f8e57forg.highwire.dtl.DTLVardef@1a33575_HPS_FORMAT_FIGEXP M_FIG C_FIG Calmidazolium is a potent and widely used inhibitor of calmodulin, a major mediator of calcium-signaling in eukaryotic cells. Structural characterization of calmidazolium-binding to calmodulin reveals that it triggers open-to-closed conformational changes similar to those induced by calmodulin-binding peptides derived from enzyme targets. These results open the way to rationally design new and more selective inhibitors of calmodulin.

biophysics↗

bioRxiv2021

Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function

ObjectiveFibrotic organ responses have recently been identified as long-term complication in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. MethodsBased on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single cell liver sequencing. ResultsHepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice. Single cell RNA sequencing revealed a distinct gene signature identifying an upregulation of mitochondrial-related processes. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models. ConclusionsTogether, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Cell-specific reduction of TSC22D4 improves hepatic steatosis, inflammation and promotes hepatocyte survival thus paving the way for further preclinical therapy developments.

physiology↗

bioRxiv2021

Community RNA-Seq: Multi-kingdom responses to living versus decaying root inputs in soil

Roots are the primary source of organic carbon inputs to most soils. Decomposition is a multi-trophic process involving multiple kingdoms of microbial life, but typically microbial ecology studies focus on one or two major lineages in isolation. We used Illumina shotgun RNA sequencing to conduct PCR-independent SSU rRNA community analysis ("community RNA-Seq") to simultaneously study the bacteria, archaea, fungi, and microfauna surrounding both living and decomposing roots of the annual grass, Avena fatua. Plants were grown in 13CO2-labeled microcosms amended with 15N-root litter. We identified rhizosphere substrate preferences for 13C-exudates versus 15N-litter using NanoSIMS microarray imaging (Chip-SIP). When litter was available, rhizosphere and bulk soil had significantly more Amoebozoa, which are potentially important yet often overlooked top-down drivers of detritusphere community dynamics and nutrient cycling. Bulk soil containing litter was depleted in Actinobacteria but had significantly more Bacteroidetes and Proteobacteria. While Actinobacteria were abundant in the rhizosphere, Chip-SIP showed Actinobacteria preferentially incorporated litter relative to root exudates, indicating this groups more prominent role in detritus elemental cycling in the rhizosphere. Our results emphasize that decomposition is a multi-trophic process involving cross-kingdom interactions, and the trajectory of carbon through this soil food web likely impacts the fate of carbon in soil.

microbiology↗

bioRxiv2020

A high-affinity calmodulin-binding site in the CyaA toxin translocation domain is essential for invasion into eukaryotic cells

The molecular mechanisms and forces involved in the translocation of bacterial toxins into host cells have thus far remained elusive. The adenylate cyclase (CyaA) toxin from Bordetella pertussis displays a unique intoxication pathway in which its catalytic domain is directly translocated across target cell membranes. We have previously identified a translocation region in CyaA that contains a segment, P454 (residues 454-484), exhibiting membrane-active properties related to antimicrobial peptides. Herein, we show that this peptide is able to translocate across membranes and interact with calmodulin. Structural and biophysical analyses have revealed the key residues of P454 involved in membrane destabilization and calmodulin binding. Mutational analysis demonstrated that these residues play a crucial role in CyaA translocation into target cells. We have also shown that calmidazolium, a calmodulin inhibitor, efficiently blocks CyaA internalization. We propose that after CyaA binding to target cells, the P454 segment destabilizes the plasma membrane, translocates across the lipid bilayer and binds calmodulin. Trapping of the CyaA polypeptide chain by the CaM:P454 interaction in the cytosol may assist the entry of the N-terminal catalytic domain by converting the stochastic process of protein translocation into an efficient vectorial chain transfer into host cells.

biophysics↗

bioRxiv2020

Toxoplasma gondii infections are associated with boldness towards lions in wild hyena hosts

Toxoplasma gondii is widely reported to manipulate the behavior of its non-definitive hosts in ways that promote lethal interactions with the parasites definitive feline hosts. Nonetheless, there is a lack of data on the association between T. gondii infection and costly behavioral interactions with felids in nature. Here, we report that three decades of field observations reveal T. gondii infected hyena cubs approach lions more closely than uninfected peers and have higher rates of lion mortality. Our findings support the hypothesis that T. gondiis manipulation of host boldness is an extended phenotype that promotes parasite transmission from intermediate hosts to feline predators. While upregulating hyena boldness toward lions might achieve this, it may also reflect a collateral influence of manipulative traits that evolved in other hosts (e.g., rodents). In either case, our findings corroborate the potential impacts of a globally distributed and generalist parasite (T. gondii) on fitness-related interaction with felids in a wild host. One Sentence SummaryWild hyenas infected with the parasite T. gondii show evidence of costly behavioral manipulation when interacting with lions.

animal behavior and cognition↗

bioRxiv2019

Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction

Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1s role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.

genomics↗

bioRxiv2019

Genetics and Pathway Analysis of Normative Cognitive Variation in the Philadelphia Neurodevelopmental Cohort

An open challenge in human genetics is to better understand the link between genotype variation and the various molecular, cellular, anatomical and physiological systems that it can affect. To address this challenge, we performed genotype-phenotype-systems analysis for accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (3,319 individuals aged 8-21 years). We report a region of genome-wide significance within the 3 end of the FBLN1 gene (p=4.6x10-8), associated with nonverbal reasoning, a heritable form of complex reasoning ability. Integration of published brain-specific omic maps reveals that FBLN1 shows greatest expression in the fetal brain, is a marker of neural progenitor cells, is differentially expressed in schizophrenia and increases genetic risk for bipolar disorder. These findings suggest that nonverbal reasoning and FBLN1 variation warrant further investigation in studies of neurodevelopmental disorders and psychosis. Using genotype-pathway analysis, we identify pathways related to development and to autonomic nervous system dysfunction associated with working memory accuracy. Top-ranking pathway genes include those genetically associated with multiple diseases with working memory deficits, such as schizophrenia and Parkinsons disease, and that are also markers for specific brain cell types. Our findings identify novel molecular players involved in specific cognitive tasks and link variants to genes, pathways, cell types, diseases and drugs. This work advances the "molecules-to-behaviour" view of cognition, and provides a framework for using systems-level organization of data for other biomedical domains.

genomics↗