Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules is crucial for rational development of immunotherapies and vaccines targeting CD4(+) T cell... Show moreAccurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules is crucial for rational development of immunotherapies and vaccines targeting CD4(+) T cell activation. So far, most prediction methods for HLA class II antigen presentation have focused on HLA-DR because of limited availability of immunopeptidomics data for HLA-DQ and HLA-DP while not taking into account alternative peptide binding modes. We present an update to the NetMHCIIpan prediction method, which closes the performance gap between all three HLA class II loci. We accomplish this by first integrating large immunopeptidomics datasets describing the HLA class II specificity space across all loci using a refined machine learning framework that accommodates inverted peptide binders. Next, we apply targeted immunopeptidomics assays to generate data that covers additional HLA-DP specificities. The final method, NetMHCIIpan-4.3, achieves high accuracy and molecular coverage across all HLA class II allotypes. Show less
Guo, Y.; Du, X.; Krusche, J.; Beck, C.; Ali, S.; Walter, A.; ... ; Stehle, T. 2023
PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of... Show morePARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. We show that PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a marked increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and antiviral PARP13, and displays specific cellular phenotypes. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated antiviral response. Show less
Ubiquitin and ubiquitin-like conjugation cascades consist of dedicated E1, E2, and E3 enzymes with E3s providing substrate specificity. Mass spectrometry–based approaches have enabled the... Show moreUbiquitin and ubiquitin-like conjugation cascades consist of dedicated E1, E2, and E3 enzymes with E3s providing substrate specificity. Mass spectrometry–based approaches have enabled the identification of more than 6500 SUMO2/3 target proteins. The limited number of SUMO E3s provides the unique opportunity to systematically study E3 substrate wiring. We developed SUMO-activated target traps (SATTs) and systematically identified substrates for eight different SUMO E3s, PIAS1, PIAS2, PIAS3, PIAS4, NSMCE2, ZNF451, LAZSUL (ZNF451-3), and ZMIZ2. SATTs enabled us to identify 427 SUMO1 and 961 SUMO2/3 targets in an E3-specific manner. We found pronounced E3 substrate preference. Quantitative proteomics enabled us to measure substrate specificity of E3s, quantified using the SATT index. Furthermore, we developed the Polar SATTs web-based tool to browse the dataset in an interactive manner. Overall, we uncover E3-to-target wiring of 1388 SUMO substrates, highlighting unique and overlapping sets of substrates for eight different SUMO E3 ligases. Show less
Gu, Y.Z.; Zhang, Z.K.; Camps, M.G.M.; Ossendorp, F.; Wijdeven, R.H.; Dijke, P. ten 2023
While global patterns of human genetic diversity are increasingly well characterized, the diversity of human languages remains less systematically described. Here, we outline the Grambank database.... Show moreWhile global patterns of human genetic diversity are increasingly well characterized, the diversity of human languages remains less systematically described. Here, we outline the Grambank database. With over 400,000 data points and 2400 languages, Grambank is the largest comparative grammatical database available. The comprehensiveness of Grambank allows us to quantify the relative effects of genealogical inheritance and geographic proximity on the structural diversity of the world’s languages, evaluate constraints on linguistic diversity, and identify the world’s most unusual languages. An analysis of the consequences of language loss reveals that the reduction in diversity will be strikingly uneven across the major linguistic regions of the world. Without sustained efforts to document and revitalize endangered languages, our linguistic window into human history, cognition, and culture will be seriously fragmented. Show less
As Earth's climate has varied strongly through geological time, studying the impacts of past climate change on biodiversity helps to understand the risks from future climate change. However, it... Show moreAs Earth's climate has varied strongly through geological time, studying the impacts of past climate change on biodiversity helps to understand the risks from future climate change. However, it remains unclear how paleoclimate shapes spatial variation in biodiversity. Here, we assessed the influence of Quaternary climate change on spatial dissimilarity in taxonomic, phylogenetic, and functional composition among neighboring 200-kilometer cells (beta-diversity) for angiosperm trees worldwide. We found that larger glacial-interglacial temperature change was strongly associated with lower spatial turnover (species replacements) and higher nestedness (richness changes) components of beta-diversity across all three biodiversity facets. Moreover, phylogenetic and functional turnover was lower and nestedness higher than random expectations based on taxonomic beta-diversity in regions that experienced large temperature change, reflecting phylogenetically and functionally selective processes in species replacement, extinction, and colonization during glacial-interglacial oscillations. Our results suggest that future human-driven climate change could cause local homogenization and reduction in taxonomic, phylogenetic, and functional diversity of angiosperm trees worldwide. Show less
Humans work together in groups to tackle shared problems and contribute to local club goods that benefit other group members. Whereas benefits from club goods remain group bound, groups are often... Show moreHumans work together in groups to tackle shared problems and contribute to local club goods that benefit other group members. Whereas benefits from club goods remain group bound, groups are often nested in overarching collectives that face shared problems like pandemics or climate change. Such challenges require individuals to cooperate across group boundaries, raising the question how cooperation can transcend beyond confined groups. Here, we show how frequent intergroup interactions allow groups to transition from group-bound to universal cooperation. With frequent intergroup interactions, reciprocity of cooperative acts permeates group boundaries and enables the evolution of universal cooperation. As soon as intergroup interactions take place frequently, people start to selectively reward cooperation aimed at benefitting everyone, irrespective of their group membership. Simulations further show that it becomes more difficult to overcome group-bound cooperation when populations are fragmented into many small groups. Our findings reveal important prerequisites for the evolution of universal cooperation. Show less
Gaudzinski-Windheuser, S.; Kindler, L.; MacDonald, K.; Roebroeks, W. 2023
Straight-tusked elephants (Palaeoloxodon antiquus) were the largest terrestrial mammals of the Pleistocene, present in Eurasian landscapes between 800,000 and 100,000 years ago. The occasional co... Show moreStraight-tusked elephants (Palaeoloxodon antiquus) were the largest terrestrial mammals of the Pleistocene, present in Eurasian landscapes between 800,000 and 100,000 years ago. The occasional co-occurrence of their skeletal remains with stone tools has generated rich speculation about the nature of interactions between these elephants and Pleistocene humans: Did hominins scavenge on elephants that died a natural death or maybe even hunt some individuals? Our archaeozoological study of the largest P. antiquus assemblage known, excavated from 125,000-year-old lake deposits in Germany, shows that hunting of elephants weighing up to 13 metric tons was part of the cultural repertoire of Last Interglacial Neanderthals there, over >2000 years, many dozens of generations. The intensity and nutritional yields of these well-documented butchering activities, combined with previously reported data from this Neumark-Nord site complex, suggest that Neanderthals were less mobile and operated within social units substantially larger than commonly envisaged. Show less
The extent of vegetation openness in past European landscapes is widely debated. In particular, the temperate forest biome has traditionally been defined as dense, closed-canopy forest; however,... Show moreThe extent of vegetation openness in past European landscapes is widely debated. In particular, the temperate forest biome has traditionally been defined as dense, closed-canopy forest; however, some argue that large herbivores maintained greater openness or even wood-pasture conditions. Here, we address this question for the Last Interglacial period (129,000–116,000 years ago), before Homo sapiens–linked megafauna declines and anthropogenic landscape transformation. We applied the vegetation reconstruction method REVEALS to 96 Last Interglacial pollen records. We found that light woodland and open vegetation represented, on average, more than 50% cover during this period. The degree of openness was highly variable and only partially linked to climatic factors, indicating the importance of natural disturbance regimes. Our results show that the temperate forest biome was historically heterogeneous rather than uniformly dense, which is consistent with the dependency of much of contemporary European biodiversity on open vegetation and light woodland. Show less
IFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering... Show moreIFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotentderived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulinproducing EndoC-0H1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation-related genes, and chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of 0 cell neoantigens, suggesting that it is a central player of the effects of IFNa on 0 cells that contribute to trigger and amplify autoimmunity in T1D. Show less
Mammalian mastication represents a vital initial step in digestion with any change in its relative energetic cost detracting from the net energy gain from foods. Although the energetic efficiency... Show moreMammalian mastication represents a vital initial step in digestion with any change in its relative energetic cost detracting from the net energy gain from foods. Although the energetic efficiency of masticatory effort is one of the fundamental concepts through which the functional morphology and evolution of the human masticatory system is explored, nothing is known currently about the associated metabolic costs and how this is influenced by the item being chewed. Here, using respirometry and electromyography of M. masseter, we demonstrate that chewing by human subjects represents a measurable energy sink. Chewing a tasteless odorless gum elevates metabolic rate by 10-15% above basal levels. The energy expenditure increases with gum stiffness and is paid for by greater muscle recruitment. For modern humans it is likely that mastication represents a small part of the daily energy budget. However, for our ancestors, before the onset of cooking and sophisticated food processing methods, the costs must have been relatively high, adding a novel energetic dimension to the interpretation of hominin dentofacial fossils. Show less
Corbeski, I.; Guo, X.H.; Eckhardt, B.V.; Fasci, D.; Wiegant, W.; Graewert, M.A.; ... ; Ingen, H. van 2022
Nucleosome assembly requires the coordinated deposition of histone complexes H3-H4 and H2A-H2B to form a histone octamer on DNA. In the current paradigm, specific histone chaperones guide the... Show moreNucleosome assembly requires the coordinated deposition of histone complexes H3-H4 and H2A-H2B to form a histone octamer on DNA. In the current paradigm, specific histone chaperones guide the deposition of first H3-H4 and then H2A-H2B. Here, we show that the acidic domain of DNA repair factor APLF (APLF(AD)) can assemble the histone octamer in a single step and deposit it on DNA to form nucleosomes. The crystal structure of the APLF(AD)-histone octamer complex shows that APLF(AD) tethers the histones in their nucleosomal conformation. Mutations of key aromatic anchor residues in APLF(AD) affect chaperone activity in vitro and in cells. Together, we propose that chaperoning of the histone octamer is a mechanism for histone chaperone function at sites where chromatin is temporarily disrupted. Show less
Hoffmann, L A..; Carenza, L.N..; Eckert, J.; Giomi, L. 2022
Growing experimental evidence indicates that topological defects could serve as organizing centers in the morphogenesis of tissues. Here, we provide a quantitative explanation for this phenomenon,... Show moreGrowing experimental evidence indicates that topological defects could serve as organizing centers in the morphogenesis of tissues. Here, we provide a quantitative explanation for this phenomenon, rooted in the buckling theory of deformable active polar liquid crystals. Using a combination of linear stability analysis and computational fluid dynamics, we demonstrate that active layers, such as confined cell monolayers, are unstable to the formation of protrusions in the presence of disclinations. The instability originates from an interplay between the focusing of the elastic forces, mediated by defects, and the renormalization of the system's surface tension by the active flow. The posttransitional regime is also characterized by several complex morphodynamical processes, such as oscillatory deformations, droplet nucleation, and active turbulence. Our findings offer an explanation of recent observations on tissue morphogenesis and shed light on the dynamics of active surfaces in general. Show less
The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation... Show moreThe hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease. Show less
The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation... Show moreThe hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hyper-mutation, and their presence is predictive for disease development. However, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease. Show less
Baaske Martin, D.; Asgari Nasrin; Punj Deep; Orrit Michel 2022
Optical detection of individual proteins with high bandwidth holds great promise for understanding important biological processes on the nanoscale and for high-throughput fingerprinting... Show moreOptical detection of individual proteins with high bandwidth holds great promise for understanding important biological processes on the nanoscale and for high-throughput fingerprinting applications. As fluorescent labels impose restrictions on detection bandwidth and require time-intensive and invasive processes, label-free optical techniques are highly desirable. Here, we read out changes in the resonantly scattered field of individual gold nanorods interferometrically and use photothermal spectroscopy to optimize the experiment's parameters. This interferometric plasmonic scattering enables the observation of single proteins as they traverse plasmonic near fields of gold nanorods with unprecedented temporal resolution in the nanosecond-to-microsecond range. Show less
