![]() ; ; et al in Nature Communications (2023), 14(1), 4392 Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV ... [more ▼] Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice. [less ▲] Detailed reference viewed: 32 (0 UL)![]() Tkatchenko, Alexandre ![]() ![]() ![]() in Nature Communications (2023) Detailed reference viewed: 34 (1 UL)![]() Pavic, Karolina ![]() in Nature communications (2023), 14(1), 1143 The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular ... [more ▼] The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases. [less ▲] Detailed reference viewed: 39 (0 UL)![]() ; ; Tkatchenko, Alexandre ![]() in Nature Communications (2022) Detailed reference viewed: 90 (2 UL)![]() ; ; et al in Nature Communications (2022), 13 COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30 ... [more ▼] COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19. [less ▲] Detailed reference viewed: 50 (5 UL)![]() Tkatchenko, Alexandre ![]() in Nature Communications (2022) Detailed reference viewed: 57 (3 UL)![]() ; ; et al in Nature Communications (2022), 13(607), Detailed reference viewed: 19 (0 UL)![]() ; Guennou, Mael ![]() in NATURE COMMUNICATIONS (2022), 13(1), 443-7 Typically, magnetic phenomena result from the spontaneous order of the sublattices. Here, the cross-talk of two magnetic ions gives rise to an intrinsic, yet non-spontaneous ordering and manifests as ... [more ▼] Typically, magnetic phenomena result from the spontaneous order of the sublattices. Here, the cross-talk of two magnetic ions gives rise to an intrinsic, yet non-spontaneous ordering and manifests as emergent strong spin-phonon coupling in SmFeO3. Many material properties such as superconductivity, magnetoresistance or magnetoelectricity emerge from the non-linear interactions of spins and lattice/phonons. Hence, an in-depth understanding of spin-phonon coupling is at the heart of these properties. While most examples deal with one magnetic lattice only, the simultaneous presence of multiple magnetic orderings yield potentially unknown properties. We demonstrate a strong spin-phonon coupling in SmFeO3 that emerges from the interaction of both, iron and samarium spins. We probe this coupling as a remarkably large shift of phonon frequencies and the appearance of new phonons. The spin-phonon coupling is absent for the magnetic ordering of iron alone but emerges with the additional ordering of the samarium spins. Intriguingly, this ordering is not spontaneous but induced by the iron magnetism. Our findings show an emergent phenomenon from the non-linear interaction by multiple orders, which do not need to occur spontaneously. This allows for a conceptually different approach in the search for yet unknown properties. [less ▲] Detailed reference viewed: 54 (2 UL)![]() ; ; Pozdeev, Vitaly ![]() in Nature Communications (2022) Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells ... [more ▼] Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential. [less ▲] Detailed reference viewed: 32 (0 UL)![]() ; Iñiguez, Jorge ![]() in Nature Communications (2022), 13 Detailed reference viewed: 10 (0 UL)![]() ; Iñiguez, Jorge ![]() in Nature Communications (2022) Detailed reference viewed: 13 (0 UL)![]() ; Iñiguez, Jorge ![]() in Nature Communications (2022) Detailed reference viewed: 17 (1 UL)![]() Freitas, Jose Nahuel ![]() ![]() in Nature Communications (2022), 13(5084), 1--8 Detailed reference viewed: 27 (2 UL)![]() de Nies, Laura ![]() ![]() ![]() in Nature communications (2022), 13(1), 2296 The emergence and spread of antimicrobial resistance (AMR) represent an ever-growing healthcare challenge worldwide. Nevertheless, the mechanisms and timescales shaping this resistome remain elusive ... [more ▼] The emergence and spread of antimicrobial resistance (AMR) represent an ever-growing healthcare challenge worldwide. Nevertheless, the mechanisms and timescales shaping this resistome remain elusive. Using an antibiotic cocktail administered to a murine model along with a longitudinal sampling strategy, we identify the mechanisms by which gut commensals acquire antimicrobial resistance genes (ARGs) after a single antibiotic course. While most of the resident bacterial populations are depleted due to the treatment, Akkermansia muciniphila and members of the Enterobacteriaceae, Enterococcaceae, and Lactobacillaceae families acquire resistance and remain recalcitrant. We identify specific genes conferring resistance against the antibiotics in the corresponding metagenome-assembled genomes (MAGs) and trace their origins within each genome. Here we show that, while mobile genetic elements (MGEs), including bacteriophages and plasmids, contribute to the spread of ARGs, integrons represent key factors mediating AMR in the antibiotic-treated mice. Our findings suggest that a single course of antibiotics alone may act as the selective sweep driving ARG acquisition and incidence in gut commensals over a single mammalian lifespan. [less ▲] Detailed reference viewed: 61 (5 UL)![]() ; ; et al in Nature Communications (2021) Detailed reference viewed: 76 (2 UL)![]() Del Sol Mesa, Antonio ![]() in Nature Communications (2021) Detailed reference viewed: 142 (7 UL)![]() Del Sol Mesa, Antonio ![]() in Nature Communications (2021) Detailed reference viewed: 182 (30 UL)![]() ; Vassilev Galindo, Valentin ![]() in Nature Communications (2021) Detailed reference viewed: 67 (4 UL)![]() Stoehr, Martin ![]() in Nature Communications (2021), 12(1), 137 Mutual Coulomb interactions between electrons lead to a plethora of interesting physical and chemical effects, especially if those interactions involve many fluctuating electrons over large spatial scales ... [more ▼] Mutual Coulomb interactions between electrons lead to a plethora of interesting physical and chemical effects, especially if those interactions involve many fluctuating electrons over large spatial scales. Here, we identify and study in detail the Coulomb interaction between dipolar quantum fluctuations in the context of van der Waals complexes and materials. Up to now, the interaction arising from the modification of the electron density due to quantum van der Waals interactions was considered to be vanishingly small. We demonstrate that in supramolecular systems and for molecules embedded in nanostructures, such contributions can amount to up to 6 kJ/mol and can even lead to qualitative changes in the long-range van der Waals interaction. Taking into account these broad implications, we advocate for the systematic assessment of so-called Dipole-Correlated Coulomb Singles in large molecular systems and discuss their relevance for explaining several recent puzzling experimental observations of collective behavior in nanostructured materials. [less ▲] Detailed reference viewed: 193 (25 UL)![]() ; Kunath, Benoît ![]() in Nature Communications (2021), 12(1), 7305 Abstract Metaproteomics has matured into a powerful tool to assess functional interactions in microbial communities. While many metaproteomic workflows are available, the impact of method choice on ... [more ▼] Abstract Metaproteomics has matured into a powerful tool to assess functional interactions in microbial communities. While many metaproteomic workflows are available, the impact of method choice on results remains unclear. Here, we carry out a community-driven, multi-laboratory comparison in metaproteomics: the critical assessment of metaproteome investigation study (CAMPI). Based on well-established workflows, we evaluate the effect of sample preparation, mass spectrometry, and bioinformatic analysis using two samples: a simplified, laboratory-assembled human intestinal model and a human fecal sample. We observe that variability at the peptide level is predominantly due to sample processing workflows, with a smaller contribution of bioinformatic pipelines. These peptide-level differences largely disappear at the protein group level. While differences are observed for predicted community composition, similar functional profiles are obtained across workflows. CAMPI demonstrates the robustness of present-day metaproteomics research, serves as a template for multi-laboratory studies in metaproteomics, and provides publicly available data sets for benchmarking future developments. 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