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The MICOS complex subunit MIC13 is essential for mitochondrial cristae organization. Mutations in MIC13 cause severe mitochondrial hepato-encephalopathy displaying defective cristae morphology and loss of the MIC10-subcomplex. Here we identified stomatin-like protein 2 (SLP2) as an interacting partner of MIC13 and decipher a critical role of SLP2 as an auxiliary MICOS subunit, modulating cristae morphology. SLP2 provides a large interaction hub for MICOS subunits and loss of SLP2 leads to drastic alterations in cristae morphology. Double deletion of SLP2 and MIC13 showed reduced assembly of core MICOS subunit, MIC60 into MICOS and dispersion of MIC60-specific puncta, demonstrating a critical role of SLP2-MIC13 in MICOS assembly and crista junction (CJ) formation. We further identified that the mitochondrial i-AAA protease YME1L in coordination either with MIC13 or SLP2 differentially regulates MICOS assembly pathways thereby interlinking MIC13-specific or scaffolding-specific role of SLP2 with quality control and assembly of the MICOS complex. YME1L- depletion in MIC13 KO could restore MIC10-subcomplex and reform the nascent CJ. Taken together, we propose ‘seeder’ model for MICOS assembly and CJ formation, where SLP2- MIC13 seed the assembly of MIC60 into MICOS complex and promote the formation of CJ by regulating the quality and stability of MIC10-subcomplex.
Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement “hotspot” loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.
Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.
Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00×10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22×10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78×10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.
Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
Objective: To investigate whether regional white matter hyperintensities (WMHs) relate to alpha oscillations (AO) in a large population-based sample of elderly individuals.
Methods: We associated voxel-wise WMHs from high-resolution 3-Tesla MRI with neuronal alpha oscillations (AO) from resting-state multichannel EEG at sensor (N=907) and source space (N=855) in older participants of the LIFE-Adult study (60–80 years). In EEG, we computed relative alpha power (AP), individual alpha peak frequency (IAPF), as well as long-range temporal correlations (LRTC) that represent dynamic properties of the signal. We implemented whole-brain voxel-wise regression models to identify regions where parameters of AO were linked to probability of WMH occurrence. We further used mediation analyses to examine whether WMH volume mediated the relationship between age and AO.
Results: Higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. The age-related increase of relative AP in the right temporal brain region was shown to be mediated by total WMH volume.
Conclusion: A high relative AP corresponding to increased regional WMHs was not associated with age per se, in fact, this relationship was mediated by WMHs. We argue that the WMH-associated increase of AP reflects a generalized and likely compensatory spread of AO leading to a larger number of synchronously recruited neurons. Our findings thus suggest that longitudinal EEG recordings might be sensitive to detect functional changes due to WMHs.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2021)
Aging is associated with increased white matter hyperintensities (WMHs) and with the alterations of alpha oscillations (7–13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N=907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and LRTC. Finally, higher age was associated with elevated alpha power via total WMH volume. Although an increase in alpha oscillations due to WMH can have a compensatory nature, we rather suggest that an elevated alpha power is a consequence of WMH affecting a spatial organization of alpha sources.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
White matter hyperintensities (WMHs) in the cerebral white matter and attenuation of alpha oscillations (AO; 7–13 Hz) occur with the advancing age. However, a crucial question remains, whether changes in AO relate to aging per se or they rather reflect the impact of age-related neuropathology like WMHs. In this study, using a large cohort (N=907) of elderly participants (60-80 years), we assessed relative alpha power (AP), individual alpha peak frequency (IAPF) and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. In contrast, we observed no significant relation of probability of WMH occurrence with IAPF and LRTC. We argue that the WMH-associated increase of AP reflects generalized and likely compensatory changes of AO leading to a larger number of synchronously recruited neurons.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
RNA-binding proteins (RBPs) control every RNA metabolic process by multiple protein-RNA and protein-protein interactions. Their roles have largely been analyzed by crude mutations, which abrogate multiple functions at once and likely impact the structural integrity of the large messenger ribonucleoprotein particle (mRNP) assemblies, these proteins often function in. Using UV-induced RNA-protein crosslinking and subsequent mass spectrometric analysis, we first identified more than 100 in vivo RNA crosslinks in 16 nuclear mRNP components in S. cerevisiae. For functional analysis, we chose Npl3, for which we determined crosslinks in its two RNA recognition motifs (RRM) and in the flexible linker region connecting the two. Using NMR and structural analyses, we show that both RRM domains and the linker uniquely contribute to RNA recognition. Interestingly, mutations in these regions cause different phenotypes, indicating distinct functions of the different RNA-binding domains of Npl3. Notably, the npl3-Linker mutation strongly impairs recruitment of several mRNP components to chromatin and incorporation of further mRNP components into nuclear mRNPs, establishing a function of Npl3 in nuclear mRNP assembly. Taken together, we determined the specific function of the RNA-binding activity of the nuclear mRNP component Npl3, an approach that can be applied to many RBPs in any RNA metabolic process.
Zinc finger (ZnF) domains appear in a pool of structural contexts and despite their small size achieve varying target specificities, covering single-stranded and double-stranded DNA and RNA as well as proteins. Combined with other RNA-binding domains, ZnFs enhance affinity and specificity of RNA-binding proteins (RBPs). The ZnF-containing immunoregulatory RBP Roquin initiates mRNA decay, thereby controlling the adaptive immune system. Its unique ROQ domain shape-specifically recognizes stem-looped cis-elements in mRNA 3’-untranslated regions (UTR). The N-terminus of Roquin contains a RING domain for protein-protein interactions and a ZnF, which was suggested to play an essential role in RNA decay by Roquin. The ZnF domain boundaries, its RNA motif preference and its interplay with the ROQ domain have remained elusive, also driven by the lack of high-resolution data of the challenging protein. We provide the solution structure of the Roquin-1 ZnF and use an RBNS-NMR pipeline to show that the ZnF recognizes AU-rich elements (ARE). We systematically refine the contributions of adenines in a poly(U)-background to specific complex formation. With the simultaneous binding of ROQ and ZnF to a natural target transcript of Roquin, our study for the first time suggests how Roquin integrates RNA shape and sequence specificity through the ROQ-ZnF tandem.
G protein-coupled receptors (GPCRs) play a crucial role in modulating physiological responses and serve as the main drug target. Specifically, salmeterol and salbutamol which are used for the treatment of pulmonary diseases, exert their effects by activating the GPCR β2-adrenergic receptor (β2AR). In our study, we employed coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the dynamics of drug molecules in membranes in presence and absence of β2AR. Our simulations reveal that in more than 50% of the flip-flop events the drug molecules use the β2AR surface to permeate the membrane. The pathway along the GPCR surface is significantly more energetically favorable for the drug molecules, which was revealed by umbrella sampling simulations along spontaneous flip-flop pathways. Furthermore, we assessed the behavior of drugs with intracellular targets, such as kinase inhibitors, whose therapeutic efficacy could benefit from this observation. In summary, our results show that β2AR surface interactions can significantly enhance membrane permeation of drugs, emphasizing their potential for consideration in future drug development strategies.
Hadron lists based on experimental studies summarized by the Particle Data Group (PDG) are a crucial input for the equation of state and thermal models used in the study of strongly-interacting matter produced in heavy-ion collisions. Modeling of these strongly-interacting systems is carried out via hydrodynamical simulations, which are followed by hadronic transport codes that also require a hadronic list as input. To remain consistent throughout the different stages of modeling of a heavy-ion collision, the same hadron list with its corresponding decays must be used at each step. It has been shown that even the most uncertain states listed in the PDG from 2016 are required to reproduce partial pressures and susceptibilities from Lattice Quantum Chromodynamics with the hadronic list known as the PDG2016+. Here, we update the hadronic list for use in heavy-ion collision modeling by including the latest experimental information for all states listed in the Particle Data Booklet in 2021. We then compare our new list, called PDG2021+, to Lattice Quantum Chromodynamics results and find that it achieves even better agreement with the first principles calculations than the PDG2016+ list. Furthermore, we develop a novel scheme based on intermediate decay channels that allows for only binary decays, such that PDG2021+ will be compatible with the hadronic transport framework SMASH. Finally, we use these results to make comparisons to experimental data and discuss the impact on particle yields and spectra.
Muller's ratchet, in its prototype version, models a haploid, asexual population whose size~N is constant over the generations. Slightly deleterious mutations are acquired along the lineages at a constant rate, and individuals carrying less mutations have a selective advantage. The classical variant considers {\it fitness proportional} selection, but other fitness schemes are conceivable as well. Inspired by the work of Etheridge et al. ([EPW09]) we propose a parameter scaling which fits well to the ``near-critical'' regime that was in the focus of [EPW09] (and in which the mutation-selection ratio diverges logarithmically as N→∞). Using a Moran model, we investigate the``rule of thumb'' given in [EPW09] for the click rate of the ``classical ratchet'' by putting it into the context of new results on the long-time evolution of the size of the best class of the ratchet with (binary) tournament selection, which (other than that of the classical ratchet) follows an autonomous dynamics up to the time of its extinction. In [GSW23] it was discovered that the tournament ratchet has a hierarchy of dual processes which can be constructed on top of an Ancestral Selection graph with a Poisson decoration. For a regime in which the mutation/selection-ratio remains bounded away from 1, this was used in [GSW23] to reveal the asymptotics of the click rates as well as that of the type frequency profile between clicks. We will describe how these ideas can be extended to the near-critical regime in which the mutation-selection ratio of the tournament ratchet converges to 1 as N→∞.
Motivated by the question of the impact of selective advantage in populations with skewed reproduction mechanims, we study a Moran model with selection. We assume that there are two types of individuals, where the reproductive success of one type is larger than the other. The higher reproductive success may stem from either more frequent reproduction, or from larger numbers of offspring, and is encoded in a measure Λ for each of the two types. Our approach consists of constructing a Λ-asymmetric Moran model in which individuals of the two populations compete, rather than considering a Moran model for each population. Under certain conditions, that we call the "partial order of adaptation", we can couple these measures. This allows us to construct the central object of this paper, the Λ−asymmetric ancestral selection graph, leading to a pathwise duality of the forward in time Λ-asymmetric Moran model with its ancestral process. Interestingly, the construction also provides a connection to the theory of optimal transport. We apply the ancestral selection graph in order to obtain scaling limits of the forward and backward processes, and note that the frequency process converges to the solution of an SDE with discontinous paths. Finally, we derive a Griffiths representation for the generator of the SDE and use it to find a semi-explicit formula for the probability of fixation of the less beneficial of the two types.
Motivated by the question of the impact of selective advantage in populations with skewed reproduction mechanims, we study a Moran model with selection. We assume that there are two types of individuals, where the reproductive success of one type is larger than the other. The higher reproductive success may stem from either more frequent reproduction, or from larger numbers of offspring, and is encoded in a measure Λ for each of the two types. Our approach consists of constructing a Λ-asymmetric Moran model in which individuals of the two populations compete, rather than considering a Moran model for each population. Under certain conditions, that we call the ``partial order of adaptation'', we can couple these measures. This allows us to construct the central object of this paper, the Λ−asymmetric ancestral selection graph, leading to a pathwise duality of the forward in time Λ-asymmetric Moran model with its ancestral process. Interestingly, the construction also provides a connection to the theory of optimal transport. We apply the ancestral selection graph in order to obtain scaling limits of the forward and backward processes, and note that the frequency process converges to the solution of an SDE with discontinous paths. Finally, we derive a Griffiths representation for the generator of the SDE and use it to find a semi-explicit formula for the probability of fixation of the less beneficial of the two types.
Mollusca is the second-largest animal phylum with over 100,000 species among eight distinct taxonomic classes. Across 1000 living species in the class Polyplacophora, chitons have a relatively constrained morphology but with some notable deviations. Several genera possess “shell eyes”, true eyes with a lens and retina that are embedded within the dorsal shells, which represent the most recent evolution of animal eyes. The phylogeny of major chiton clades is mostly well established, in a set of superfamily and higher-level taxa supported by various approaches including multiple gene markers, mitogenome-phylogeny and phylotranscritomic approaches as well as morphological studies. However, one critical lineage has remained unclear: Schizochiton was controversially suggested as a potential independent origin of chiton shell eyes. Here, with the draft genome sequencing of Schizochiton incisus (superfamily Schizochitonoidea) plus assembly of transcriptome data from other polyplacophorans, we present phylogenetic reconstructions using both mitochondrial genomes and phylogenomic approaches with multiple methods. Phylogenetic trees from mitogenomic data are inconsistent, reflecting larger scale confounding factors in molluscan mitogenomes. A consistent robust topology was generated with protein coding genes using different models and methods. Our results support Schizochitonoidea is a sister group to other Chitonoidea in Chitonina, in agreement with established classification. This suggests that the earliest origin of shell eyes is in Schizochitonoidea, which were also gained secondarily in other genera in Chitonoidea. Our results have generated a holistic review of the internal relationship within Polyplacophora, and a better understanding on the evolution of Polyplacophora.
Understanding effects of emotional valence and stress on children’s memory is important for educational and legal contexts. This study disentangles the effects of emotional content of to-be-remembered information (i.e., items differing in emotional valence and arousal), stress exposure, and associated cortisol secretion on children’s memory. We also examine whether girls’ memory is more affected by stress induction. 143 6-to-7-year-old children were randomly allocated to the Trier Social Stress Test for Children (n = 103) or a control condition (n = 40). 25 minutes after stressor onset, children incidentally encoded 75 objects varying in emotional valence (crossed with arousal) together with neutral scene backgrounds. We found that response-bias corrected memory was worse for low arousing negative items than neutral and positive items, with the latter two categories not being different from each other. Whilst boys’ memory was largely unaffected by stress, girls in the stress condition showed worse memory for negative items, especially the low arousing ones, than girls in the control condition. Girls, compared to boys, reported higher subjective stress increases following stress exposure, and had higher cortisol stress responses. Whilst a higher cortisol stress response was associated with better emotional memory in girls in the stress condition, boys’ memory was not associated with their cortisol secretion. Taken together, our study suggests that 6-to-7-year-old children, more so girls, show memory suppression for negative information. Girls’ memory for negative information, compared to boys, is also more strongly modulated by stress experience and the associated cortisol response.
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
Pseudomonas aeruginosa is a human pathogen that causes health-care associated blood stream infections (BSI). Although P. aeruginosa BSI are associated with high mortality rates, the clinical relevance of pathogen-derived prognostic biomarker to identify patients at risk for unfavorable outcome remains largely unexplored. We found novel pathogen-derived prognostic biomarker candidates by applying a multi-omics approach on a multicenter sepsis patient cohort. Multi-level Cox regression was used to investigate the relation between patient characteristics and pathogen features (2298 accessory genes, 1078 core protein levels, 107 parsimony-informative variations in reported virulence factors) with 30-day mortality. Our analysis revealed that presence of the helP gene encoding a putative DEAD-box helicase was independently associated with a fatal outcome (hazard ratio 2.01, p = 0.05). helP is located within a region related to the pathogenicity island PAPI-1 in close proximity to a pil gene cluster, which has been associated with horizontal gene transfer. Besides helP, elevated protein levels of the bacterial flagellum protein FliL (hazard ratio 3.44, p < 0.001) and of a bacterioferritin-like protein (hazard ratio 1.74, p = 0.003) increased the risk of death, while high protein levels of a putative aminotransferase were associated with an improved outcome (hazard ratio 0.12, p < 0.001). The prognostic potential of biomarker candidates and clinical factors was confirmed with different machine learning approaches using training and hold-out datasets. The helP genotype appeared the most attractive biomarker for clinical risk stratification due to its relevant predictive power and ease of detection.
The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different length, linkage-type and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying length, as well as, homotypic and heterotypic branched chains of the two most abundant linkage types – K48- and K63-linked Ub. We identified some of the first K48/K63 branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4 and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50 and p97-adaptor FAF1. Crucially, we compared datasets collected using two common DUB inhibitors – Chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.
The human growth factor receptor MET is a receptor tyrosine kinase involved in cell proliferation, migration, and survival. MET is also hijacked by the intracellular pathogen Listeria monocytogenes. Its invasion protein, internalin B (InlB), binds to MET and promotes the formation of a signaling dimer that triggers the internalization of the pathogen. Here, we use a combination of structural biology, modeling, molecular dynamics simulations, and in situ single-molecule Förster resonance energy transfer (smFRET) experiments to elucidate the early events in MET activation by Listeria. Simulations show that InlB binding stabilizes MET in a conformation that promotes dimer formation. smFRET identifies the organization of the in situ signaling dimer. Further MD simulations of the dimer model are in quantitative agreement with smFRET. We accurately describe the structural dynamics underpinning an important cellular event and introduce a powerful methodological pipeline applicable to studying the activation of other plasma membrane receptors.