A fast and easy approach to the simulation of binary mixtures sorption kinetics

Diffusivity of a component in a binary mixture is affected by the presence of a second component. The knowledge of the influence on each other component diffusivity is very useful for the prediction of sorption kinetics of binary mixtures. In this work kinetic studies of Cr(VI) and Cu(II) binary mixtures sorption onto exhausted coffee encapsulated in calcium alginate beads were carried out in both bench and pilot scale experiments. The spectroscopic analysis evidenced the complexity of the process since different mechanisms such as adsorption, redox reaction and ion exchange are involved. Experimental data were fitted to the Linear Adsorption Model (LAM). An empirical quadratic model was developed to estimate LAM parameters (De) and α = Cf/(Ci − Cf) as a function of the initial concentration of metals in the mixture. The empirical model developed enables to estimate the LAM parameters (De and α) of metal ions binary mixtures provided that the initial concentration of the metal ions is included in the range of concentrations studied. The estimated parameters introduced in LAM equation allow simulating the corresponding binary mixtures sorption kinetics. This study constitutes a fast and easy approach to the modelling of sorption kinetics of complex systems in which different processes take place simultaneously

Over-expression of the Arabidopsis AtMYB41 gene alters cell expansion and leaf surface permeability

The Arabidopsis AtMYB41 gene encodes an R2R3-MYB transcription factor whose expression is not detectable under normal growth conditions in any organ or at any developmental stage analysed. It is expressed at high levels in response to drought, ABA and salt treatments, suggesting a possible role in stress responses. Transgenic lines over-expressing this transcription factor showed a pleiotropic phenotype similar to that exhibited by some mutants that affect cuticle biosynthesis. This includes a dwarf appearance, dependent on smaller cells with abnormal morphology, enhanced sensitivity to desiccation, and enhanced permeability of leaf surfaces, suggesting discontinuity in the cuticle. The expression of genes involved in lipid metabolism and transport, in cell-wall modifications and cell expansion, genes coding for membrane-associated proteins and genes specifically involved in cuticle metabolism was differentially modulated between wild-type and transgenic plants, suggesting a direct or indirect role of AtMYB41 in the regulation of their transcription. Taken together, our results suggest that AtMYB41 is part of a complex network of transcription factors controlling cell expansion and cuticle deposition in response to abiotic stress

Nature-based solutions as enablers of circularity in water systems: A review on assessment methodologies, tools and indicators

Water has been pushed into a linear model, which is increasingly acknowledged of causing cumulative emissions of pollutants, waste stocks, and impacting on the irreversible deterioration of water and other resources. Moving towards a circular model in the water sector, the configuration of future water infrastructure changes through the integration of grey and green infrastructure, forming Nature-based Solutions (NBS) as an integral component that connects human-managed to nature-managed water systems. In this study, a thorough appraisal of the latest literature is conducted, providing an overview of the existing tools, methodologies and indicators that have been used to assess NBS for water management, as well as complete water systems considering the need of assessing both anthropogenic and natural elements. Furthermore, facilitators and barriers with respect to existing policies and regulations on NBS and circularity have been identified. The study concludes that the co-benefits of NBS for water management are not adequately assessed. A holistic methodology assessing complete water systems from a circularity perspective is still needed integrating existing tools (i.e. hydro-biogeochemical models), methods (i.e. MFA-based and LCA) and incorporating existing and/or newly-developed indicators.Horizon 2020 research and innovation program; CERCA program; Slovenian Research Agenc

Neurospora COP9 Signalosome Integrity Plays Major Roles for Hyphal Growth, Conidial Development, and Circadian Function

The COP9 signalosome (CSN) is a highly conserved multifunctional complex that has two major biochemical roles: cleaving NEDD8 from cullin proteins and maintaining the stability of CRL components. We used mutation analysis to confirm that the JAMM domain of the CSN-5 subunit is responsible for NEDD8 cleavage from cullin proteins in Neurospora crassa. Point mutations of key residues in the metal-binding motif (EXnHXHX10D) of the CSN-5 JAMM domain disrupted CSN deneddylation activity without interfering with assembly of the CSN complex or interactions between CSN and cullin proteins. Surprisingly, CSN-5 with a mutated JAMM domain partially rescued the phenotypic defects observed in a csn-5 mutant. We found that, even without its deneddylation activity, the CSN can partially maintain the stability of the SCFFWD-1 complex and partially restore the degradation of the circadian clock protein FREQUENCY (FRQ) in vivo. Furthermore, we showed that CSN containing mutant CSN-5 efficiently prevents degradation of the substrate receptors of CRLs. Finally, we found that deletion of the CAND1 ortholog in N. crassa had little effect on the conidiation circadian rhythm. Our results suggest that CSN integrity plays major roles in hyphal growth, conidial development, and circadian function in N. crassa

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63–1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70–1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19

Identification and Characterization of NF-Y Transcription Factor Families in the Monocot Model Plant Brachypodium distachyon

BACKGROUND: Nuclear Factor Y (NF-Y) is a heterotrimeric transcription factor composed of NF-YA, NF-YB and NF-YC proteins. Using the dicot plant model system Arabidopsis thaliana (Arabidopsis), NF-Y were previously shown to control a variety of agronomically important traits, including drought tolerance, flowering time, and seed development. The aim of the current research was to identify and characterize NF-Y families in the emerging monocot model plant Brachypodium distachyon (Brachypodium) with the long term goal of assisting in the translation of known dicot NF-Y functions to the grasses. METHODOLOGY/PRINCIPAL FINDINGS: We identified, annotated, and further characterized 7 NF-YA, 17 NF-YB, and 12 NF-YC proteins in Brachypodium (BdNF-Y). By examining phylogenetic relationships, orthology predictions, and tissue-specific expression patterns for all 36 BdNF-Y, we proposed numerous examples of likely functional conservation between dicots and monocots. To test one of these orthology predictions, we demonstrated that a BdNF-YB with predicted orthology to Arabidopsis floral-promoting NF-Y proteins can rescue a late flowering Arabidopsis mutant. CONCLUSIONS/SIGNIFICANCE: The Brachypodium genome encodes a similar complement of NF-Y to other sequenced angiosperms. Information regarding NF-Y phylogenetic relationships, predicted orthologies, and expression patterns can facilitate their study in the grasses. The current data serves as an entry point for translating many NF-Y functions from dicots to the genetically tractable monocot model system Brachypodium. In turn, studies of NF-Y function in Brachypodium promise to be more readily translatable to the agriculturally important grasses

CSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses

The Hedgehog (Hh) morphogen directs distinct cell responses according to its distinct signalling levels. Hh signalling stabilizes transcription factor cubitus interruptus (Ci) by prohibiting SCFSlimb-dependent ubiquitylation and proteolysis of Ci. How graded Hh signalling confers differential SCFSlimb-mediated Ci proteolysis in responding cells remains unclear. Here, we show that in COP9 signalosome (CSN) mutants, in which deneddylation of SCFSlimb is inactivated, Ci is destabilized in low-to-intermediate Hh signalling cells. As a consequence, expression of the low-threshold Hh target gene dpp is disrupted, highlighting the critical role of CSN deneddylation on low-to-intermediate Hh signalling response. The status of Ci phosphorylation and the level of E1 ubiquitin-activating enzyme are tightly coupled to this CSN regulation. We propose that the affinity of substrate–E3 interaction, ligase activity and E1 activity are three major determinants for substrate ubiquitylation and thereby substrate degradation in vivo

Pathogen and Circadian Controlled 1 (PCC1) Protein Is Anchored to the Plasma Membrane and Interacts with Subunit 5 of COP9 Signalosome in Arabidopsis

The Pathogen and Circadian Controlled 1 (PCC1) gene, previously identified and further characterized as involved in defense to pathogens and stress-induced flowering, codes for an 81-amino acid protein with a cysteine-rich C-terminal domain. This domain is essential for homodimerization and anchoring to the plasma membrane. Transgenic plants with the ß- glucuronidase (GUS) reporter gene under the control of 1.1 kb promoter sequence of PCC1 gene display a dual pattern of expression. At early post-germination, PCC1 is expressed only in the root vasculature and in the stomata guard cells of cotyledons. During the transition from vegetative to reproductive development, PCC1 is strongly expressed in the vascular tissue of petioles and basal part of the leaf, and it further spreads to the whole limb in fully expanded leaves. This developmental pattern of expression together with the late flowering phenotype of long-day grown RNA interference (iPCC1) plants with reduced PCC1 expression pointed to a regulatory role of PCC1 in the photoperiod-dependent flowering pathway. iPCC1 plants are defective in light perception and signaling but are not impaired in the function of the core CO-FT module of the photoperiod-dependent pathway. The regulatory effect exerted by PCC1 on the transition to flowering as well as on other reported phenotypes might be explained by a mechanism involving the interaction with the subunit 5 of the COP9 signalosome (CSN).This work was funded by grants BIO2008-00839, BIO2011-27526 and CSD2007-0057 from Ministerio de Ciencia e Innovacion of Spain to J.L. A fellowship/contract of the FPU program of the Ministerio de Educacion y Ciencia (Spain) funded R.M. work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Mir Moreno, R.; Leon Ramos, J. (2014). Pathogen and Circadian Controlled 1 (PCC1) Protein Is Anchored to the Plasma Membrane and Interacts with Subunit 5 of COP9 Signalosome in Arabidopsis. PLoS ONE. 1(9):1-14. https://doi.org/10.1371/journal.pone.0087216S11419Sauerbrunn, N., & Schlaich, N. L. (2004). PCC1 : a merging point for pathogen defence and circadian signalling in Arabidopsis. Planta, 218(4), 552-561. doi:10.1007/s00425-003-1143-zSEGARRA, S., MIR, R., MARTÍNEZ, C., & LEÓN, J. (2009). Genome-wide analyses of the transcriptomes of salicylic acid-deficient versus wild-type plants uncover Pathogen and Circadian Controlled 1 (PCC1) as a regulator of flowering time in Arabidopsis. Plant, Cell & Environment, 33(1), 11-22. doi:10.1111/j.1365-3040.2009.02045.xVenancio, T. M., & Aravind, L. (2009). CYSTM, a novel cysteine-rich transmembrane module with a role in stress tolerance across eukaryotes. Bioinformatics, 26(2), 149-152. doi:10.1093/bioinformatics/btp647Lau, O. S., & Deng, X. W. (2010). Plant hormone signaling lightens up: integrators of light and hormones. Current Opinion in Plant Biology, 13(5), 571-577. doi:10.1016/j.pbi.2010.07.001Seo, M., Nambara, E., Choi, G., & Yamaguchi, S. (2008). Interaction of light and hormone signals in germinating seeds. Plant Molecular Biology, 69(4), 463-472. doi:10.1007/s11103-008-9429-yDe Lucas, M., Davière, J.-M., Rodríguez-Falcón, M., Pontin, M., Iglesias-Pedraz, J. M., Lorrain, S., … Prat, S. (2008). A molecular framework for light and gibberellin control of cell elongation. Nature, 451(7177), 480-484. doi:10.1038/nature06520Feng, S., Martinez, C., Gusmaroli, G., Wang, Y., Zhou, J., Wang, F., … Deng, X. W. (2008). Coordinated regulation of Arabidopsis thaliana development by light and gibberellins. Nature, 451(7177), 475-479. doi:10.1038/nature06448Mutasa-Gottgens, E., & Hedden, P. (2009). Gibberellin as a factor in floral regulatory networks. Journal of Experimental Botany, 60(7), 1979-1989. doi:10.1093/jxb/erp040Bastian, R., Dawe, A., Meier, S., Ludidi, N., Bajic, V. B., & Gehring, C. (2010). Gibberellic acid and cGMP-dependent transcriptional regulation inArabidopsis thaliana. Plant Signaling & Behavior, 5(3), 224-232. doi:10.4161/psb.5.3.10718Yu, S., Galvão, V. C., Zhang, Y.-C., Horrer, D., Zhang, T.-Q., Hao, Y.-H., … Wang, J.-W. (2012). Gibberellin Regulates the Arabidopsis Floral Transition through miR156-Targeted SQUAMOSA PROMOTER BINDING–LIKE Transcription Factors. The Plant Cell, 24(8), 3320-3332. doi:10.1105/tpc.112.101014Arc, E., Galland, M., Cueff, G., Godin, B., Lounifi, I., Job, D., & Rajjou, L. (2011). Reboot the system thanks to protein post-translational modifications and proteome diversity: How quiescent seeds restart their metabolism to prepare seedling establishment. PROTEOMICS, 11(9), 1606-1618. doi:10.1002/pmic.201000641Dill, A., Thomas, S. G., Hu, J., Steber, C. M., & Sun, T. (2004). The Arabidopsis F-Box Protein SLEEPY1 Targets Gibberellin Signaling Repressors for Gibberellin-Induced Degradation. The Plant Cell, 16(6), 1392-1405. doi:10.1105/tpc.020958Wang, F., & Deng, X. W. (2011). Plant ubiquitin-proteasome pathway and its role in gibberellin signaling. Cell Research, 21(9), 1286-1294. doi:10.1038/cr.2011.118Hotton, S. K., & Callis, J. (2008). Regulation of Cullin RING Ligases. Annual Review of Plant Biology, 59(1), 467-489. doi:10.1146/annurev.arplant.58.032806.104011Cope, G. A. (2002). Role of Predicted Metalloprotease Motif of Jab1/Csn5 in Cleavage of Nedd8 from Cul1. Science, 298(5593), 608-611. doi:10.1126/science.1075901Gusmaroli, G., Figueroa, P., Serino, G., & Deng, X. W. (2007). Role of the MPN Subunits in COP9 Signalosome Assembly and Activity, and Their Regulatory Interaction with Arabidopsis Cullin3-Based E3 Ligases. The Plant Cell, 19(2), 564-581. doi:10.1105/tpc.106.047571Serino, G., & Deng, X.-W. (2003). THECOP9 SIGNALOSOME: Regulating Plant Development Through the Control of Proteolysis. Annual Review of Plant Biology, 54(1), 165-182. doi:10.1146/annurev.arplant.54.031902.134847Stratmann, J. W., & Gusmaroli, G. (2012). Many jobs for one good cop – The COP9 signalosome guards development and defense. Plant Science, 185-186, 50-64. doi:10.1016/j.plantsci.2011.10.004Lozano-Juste, J., & León, J. (2011). Nitric Oxide Regulates DELLA Content and PIF Expression to Promote Photomorphogenesis in Arabidopsis. Plant Physiology, 156(3), 1410-1423. doi:10.1104/pp.111.177741Nakagawa, T., Kurose, T., Hino, T., Tanaka, K., Kawamukai, M., Niwa, Y., … Kimura, T. (2007). Development of series of gateway binary vectors, pGWBs, for realizing efficient construction of fusion genes for plant transformation. Journal of Bioscience and Bioengineering, 104(1), 34-41. doi:10.1263/jbb.104.34Fromont-Racine, M., Rain, J.-C., & Legrain, P. (1997). Toward a functional analysis of the yeast genome through exhaustive two-hybrid screens. Nature Genetics, 16(3), 277-282. doi:10.1038/ng0797-277Belda-Palazón B, Ruiz L, Martí E, Tárraga S, Tiburcio AF, et al.. (2012) Aminopropyltransferases involved in polyamine biosynthesis localize preferentially in the nucleus of plant cells. PLoS One 7(10), e46907.Simon, R., Igeño, M. I., & Coupland, G. (1996). Activation of floral meristem identity genes in Arabidopsis. Nature, 384(6604), 59-62. doi:10.1038/384059a0Martínez, C., Pons, E., Prats, G., & León, J. (2003). Salicylic acid regulates flowering time and links defence responses and reproductive development. The Plant Journal, 37(2), 209-217. doi:10.1046/j.1365-313x.2003.01954.xKyte, J., & Doolittle, R. F. (1982). A simple method for displaying the hydropathic character of a protein. Journal of Molecular Biology, 157(1), 105-132. doi:10.1016/0022-2836(82)90515-0Marmagne, A., Rouet, M.-A., Ferro, M., Rolland, N., Alcon, C., Joyard, J., … Ephritikhine, G. (2004). Identification of New Intrinsic Proteins inArabidopsisPlasma Membrane Proteome. Molecular & Cellular Proteomics, 3(7), 675-691. doi:10.1074/mcp.m400001-mcp200Nühse, T. S., Stensballe, A., Jensen, O. N., & Peck, S. C. (2004). Phosphoproteomics of the Arabidopsis Plasma Membrane and a New Phosphorylation Site Database. The Plant Cell, 16(9), 2394-2405. doi:10.1105/tpc.104.023150Kobayashi, Y., & Weigel, D. (2007). Move on up, it’s time for change mobile signals controlling photoperiod-dependent flowering. Genes & Development, 21(19), 2371-2384. doi:10.1101/gad.1589007Jaeger, K. E., & Wigge, P. A. (2007). FT Protein Acts as a Long-Range Signal in Arabidopsis. Current Biology, 17(12), 1050-1054. doi:10.1016/j.cub.2007.05.008Mathieu, J., Warthmann, N., Küttner, F., & Schmid, M. (2007). Export of FT Protein from Phloem Companion Cells Is Sufficient for Floral Induction in Arabidopsis. Current Biology, 17(12), 1055-1060. doi:10.1016/j.cub.2007.05.009Mir, R., Hernández, M. L., Abou-Mansour, E., Martínez-Rivas, J. M., Mauch, F., Métraux, J.-P., & León, J. (2013). Pathogen and Circadian Controlled 1 (PCC1) regulates polar lipid content, ABA-related responses, and pathogen defence in Arabidopsis thaliana. Journal of Experimental Botany, 64(11), 3385-3395. doi:10.1093/jxb/ert177Nordgård, O., Dahle, Ø., Andersen, T. Ø., & Gabrielsen, O. S. (2001). JAB1/CSN5 interacts with the GAL4 DNA binding domain: A note of caution about two-hybrid interactions. Biochimie, 83(10), 969-971. doi:10.1016/s0300-9084(01)01329-3Kwok, S. F., Staub, J. M., & Deng, X.-W. (1999). Characterization of two subunits of Arabidopsis 19S proteasome regulatory complex and its possible interaction with the COP9 complex 1 1Edited by J. Karn. Journal of Molecular Biology, 285(1), 85-95. doi:10.1006/jmbi.1998.2315Nezames, C. D., & Deng, X. W. (2012). The COP9 Signalosome: Its Regulation of Cullin-Based E3 Ubiquitin Ligases and Role in Photomorphogenesis. Plant Physiology, 160(1), 38-46. doi:10.1104/pp.112.198879Moon, J., Parry, G., & Estelle, M. (2004). The Ubiquitin-Proteasome Pathway and Plant Development. The Plant Cell, 16(12), 3181-3195. doi:10.1105/tpc.104.161220Dreher, K., & Callis, J. (2007). Ubiquitin, Hormones and Biotic Stress in Plants. Annals of Botany, 99(5), 787-822. doi:10.1093/aob/mcl255Parry, G., & Estelle, M. (2004). Regulation of cullin-based ubiquitin ligases by the Nedd8/RUB ubiquitin-like proteins. Seminars in Cell & Developmental Biology, 15(2), 221-229. doi:10.1016/j.semcdb.2003.12.003Wee, S., Geyer, R. K., Toda, T., & Wolf, D. A. (2005). CSN facilitates Cullin–RING ubiquitin ligase function by counteracting autocatalytic adapter instability. Nature Cell Biology, 7(4), 387-391. doi:10.1038/ncb1241Kuramata, M., Masuya, S., Takahashi, Y., Kitagawa, E., Inoue, C., Ishikawa, S., … Kusano, T. (2008). Novel Cysteine-Rich Peptides from Digitaria ciliaris and Oryza sativa Enhance Tolerance to Cadmium by Limiting its Cellular Accumulation. Plant and Cell Physiology, 50(1), 106-117. doi:10.1093/pcp/pcn175Zeng, W., Melotto, M., & He, S. Y. (2010). Plant stomata: a checkpoint of host immunity and pathogen virulence. Current Opinion in Biotechnology, 21(5), 599-603. doi:10.1016/j.copbio.2010.05.006Wigge, P. A. (2011). FT, A Mobile Developmental Signal in Plants. Current Biology, 21(9), R374-R378. doi:10.1016/j.cub.2011.03.038Kardailsky, I. (1999). Activation Tagging of the Floral Inducer FT. Science, 286(5446), 1962-1965. doi:10.1126/science.286.5446.1962Srikanth, A., & Schmid, M. (2011). Regulation of flowering time: all roads lead to Rome. Cellular and Molecular Life Sciences, 68(12), 2013-2037. doi:10.1007/s00018-011-0673-yGalvao, V. C., Horrer, D., Kuttner, F., & Schmid, M. (2012). Spatial control of flowering by DELLA proteins in Arabidopsis thaliana. Development, 139(21), 4072-4082. doi:10.1242/dev.080879Cerdán, P. D., & Chory, J. (2003). Regulation of flowering time by light quality. Nature, 423(6942), 881-885. doi:10.1038/nature01636Guo, H. (1998). Regulation of Flowering Time by Arabidopsis Photoreceptors. Science, 279(5355), 1360-1363. doi:10.1126/science.279.5355.1360Liu, B., Zuo, Z., Liu, H., Liu, X., & Lin, C. (2011). Arabidopsis cryptochrome 1 interacts with SPA1 to suppress COP1 activity in response to blue light. Genes & Development, 25(10), 1029-1034. doi:10.1101/gad.2025011Weidler, G., zur Oven-Krockhaus, S., Heunemann, M., Orth, C., Schleifenbaum, F., Harter, K., … Batschauer, A. (2012). Degradation of Arabidopsis CRY2 Is Regulated by SPA Proteins and Phytochrome A. The Plant Cell, 24(6), 2610-2623. doi:10.1105/tpc.112.09821

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons