Osteoarthritis is the most prevalent joint disease worldwide, yet progress in development of effective disease-modifying treatments is slow because of lack of insight into the underlying disease... Show moreOsteoarthritis is the most prevalent joint disease worldwide, yet progress in development of effective disease-modifying treatments is slow because of lack of insight into the underlying disease pathways. Therefore, we aimed to identify the causal pathogenic mutation in an early-onset osteoarthritis family, followed by functional studies in human induced pluripotent stem cells (hiPSCs) in an in vitro organoid cartilage model. We demonstrated that the identified causal missense mutation in the gelatin-binding domain of the extracellular matrix protein fibronectin resulted in significant decreased binding capacity to collagen type II. Further analyses of formed hiPSC-derived neo-cartilage tissue highlighted that mutated fibronectin affected chondrogenic capacity and propensity to a procatabolic osteoarthritic state. Together, we demonstrate that binding of fibronectin to collagen type II is crucial for fibronectin downstream gene expression of chondrocytes. We advocate that effective treatment development should focus on restoring or maintaining proper binding between fibronectin and collagen type II. Show less
The origin, development, and legacy of the enigmatic Etruscan civilization from the central region of the Italian peninsula known as Etruria have been debated for centuries. Here we report a... Show moreThe origin, development, and legacy of the enigmatic Etruscan civilization from the central region of the Italian peninsula known as Etruria have been debated for centuries. Here we report a genomic time transect of 82 individuals spanning almost two millennia (800 BCE to 1000 CE) across Etruria and southern Italy. During the Iron Age, we detect a component of Indo-European-associated steppe ancestry and the lack of recent Anatolian-related admixture among the putative non-Indo-European-speaking Etruscans. Despite comprising diverse individuals of central European, northern African, and Near Eastern ancestry, the local gene pool is largely maintained across the first millennium BCE. This drastically changes during the Roman Imperial period where we report an abrupt population-wide shift to similar to 50% admixture with eastern Mediterranean ancestry. Last, we identify northern European components appearing in central Italy during the Early Middle Ages, which thus formed the genetic landscape of present-day Italian populations. Show less
Sieber, S.; Mathew, A.J.C.; Kohler, T.; Bar, M.; Carrion Bravo, V.J.; Cazorla, F.M.; ... ; Gademann, K. 2021
Pseudomonas syringae is an important plant pathogen of many valuable crops worldwide, with more than 60 identified pathovars. The phytotoxins produced by these organisms were related to the... Show morePseudomonas syringae is an important plant pathogen of many valuable crops worldwide, with more than 60 identified pathovars. The phytotoxins produced by these organisms were related to the severity of the damage caused to the plant. An emerging strategy to treat bacterial infections relies on interference with their signaling systems. In this study, we investigated P. syringae pv. syringae, which produces the virulence factor mangotoxin that causes bacterial apical necrosis on mango leaves. A previously unknown signaling molecule named leudiazen was identified, determined to be unstable and volatile, and responsible for mangotoxin production. A strategy using potassium permanganate, compatible with organic farming, was developed to degrade leudiazen and thus to attenuate the pathogenicity of P. syringae pv. syringae. Show less
Schendel, R. van; Romeijn, R.; Buijs, H.; Tijsterman, M. 2021
During genome duplication, the replication fork encounters a plethora of obstacles in the form of damaged bases, DNA-cross-linked proteins, and secondary structures. How cells protect DNA integrity... Show moreDuring genome duplication, the replication fork encounters a plethora of obstacles in the form of damaged bases, DNA-cross-linked proteins, and secondary structures. How cells protect DNA integrity at sites of stalled replication is currently unknown. Here, by engineering "primase deserts" into the Caenorhabditis elegans genome close to replication-impeding G-quadruplexes, we show that de novo DNA synthesis downstream of the blocked fork suppresses DNA loss. We next identify the pol alpha-primase complex to limit deletion mutagenesis, a conclusion substantiated by whole-genome analysis of animals carrying mutated POLA2/DIV-1. We subsequently identify a new role for the 9-1-1 checkpoint clamp in protecting Okazaki fragments from resection by EXO1. Together, our results provide a mechanistic model for controlling the fate of replication intermediates at sites of stalled replication. Show less
Allergic rhinitis is an inflammation in the nose caused by overreaction of the immune system to allergens in the air. Managing allergic rhinitis symptoms is challenging and requires timely... Show moreAllergic rhinitis is an inflammation in the nose caused by overreaction of the immune system to allergens in the air. Managing allergic rhinitis symptoms is challenging and requires timely intervention. The following are major questions often posed by those with allergic rhinitis: How should I prepare for the forthcoming season? How will the season's severity develop over the years? No country yet provides clear guidance addressing these questions. We propose two previously unexplored approaches for forecasting the severity of the grass pollen season on the basis of statistical and mechanistic models. The results suggest annual severity is largely governed by preseasonal meteorological conditions. The mechanistic model suggests climate change will increase the season severity by up to 60%, in line with experimental chamber studies. These models can be used as forecasting tools for advising individuals with hay fever and health care professionals how to prepare for the grass pollen season. Show less
Little is known about the antiquity, nature, and scale of Pleistocene hunter-gatherer impact on their ecosystems, despite the importance for studies of conservation and human evolution. Such impact... Show moreLittle is known about the antiquity, nature, and scale of Pleistocene hunter-gatherer impact on their ecosystems, despite the importance for studies of conservation and human evolution. Such impact is likely to be limited, mainly because of low population densities, and challenging to detect and interpret in terms of cause-effect dynamics. We present high-resolution paleoenvironmental and archaeological data from the Last Interglacial locality of Neumark-Nord (Germany). Among the factors that shaped vegetation structure and succession in this lake landscape, we identify a distinct ecological footprint of hominin activities, including fire use. We compare these data with evidence from archaeological and baseline sites from the same region. At Neumark-Nord, notably open vegetation coincides with a virtually continuous c. 2000-year-long hominin presence, and the comparative data strongly suggest that hominins were a contributing factor. With an age of c. 125,000 years, Neumark-Nord provides an early example of a hominin role in vegetation transformation. Show less
Bertelli, I.; Carmiggelt, J.J.; Yu, T.; Simon, B.G.; Pothoven, C.C.; Bauer, G.E.W.; ... ; Sar, T. van der 2020
Spin waves—the elementary excitations of magnetic materials—are prime candidate signal carriers for low-dissipation information processing. Being able to image coherent spin-wave transport is... Show moreSpin waves—the elementary excitations of magnetic materials—are prime candidate signal carriers for low-dissipation information processing. Being able to image coherent spin-wave transport is crucial for developing interference-based spin-wave devices. We introduce magnetic resonance imaging of the microwave magnetic stray fields that are generated by spin waves as a new approach for imaging coherent spin-wave transport. We realize this approach using a dense layer of electronic sensor spins in a diamond chip, which combines the ability to detect small magnetic fields with a sensitivity to their polarization. Focusing on a thin-film magnetic insulator, we quantify spin-wave amplitudes, visualize spin-wave dispersion and interference, and demonstrate time-domain measurements of spin-wave packets. We theoretically explain the observed anisotropic spin-wave patterns in terms of chiral spin-wave excitation and stray-field coupling to the sensor spins. Our results pave the way for probing spin waves in atomically thin magnets, even when embedded between opaque materials. Show less
T cell factor 1 (Tcf1) is the first T cell-specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results... Show moreT cell factor 1 (Tcf1) is the first T cell-specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell-committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program. Show less
Around 40% of humans and Tasmanian devils (Sarcophilus harrisii) develop cancer in their lifetime, compared to less than 10% for most species. In addition, devils are affected by two of the three... Show moreAround 40% of humans and Tasmanian devils (Sarcophilus harrisii) develop cancer in their lifetime, compared to less than 10% for most species. In addition, devils are affected by two of the three known transmissible cancers in mammals. Immune checkpoint immunotherapy has transformed human medicine, but a lack of species-specific reagents has limited checkpoint immunology in most species. We developed a cut-and-paste reagent development system and used the fluorescent fusion protein system to show that immune checkpoint interactions are conserved across 160,000,000 years of evolution, CD200 is highly expressed on transmissible tumor cells, and coexpression of CD200R1 can block CD200 surface expression. The system’s versatility across species was demonstrated by fusing a fluorescent reporter to a camelid-derived nanobody that binds human programmed death ligand 1. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can be used to advance our understanding of cancer and immunological tolerance. Show less
Sen, P.; Wilkie, A.R.; Ji, F.; Yang, Y.M.; Taylor, I.J.; Velazquez-Palafox, M.; ... ; Khoury, J. el 2020
Cytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed... Show moreCytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed to immune modulation by CMV, including increased mortality from fungal disease, allograft dysfunction and rejection in solid organ transplantation, and graft-versus-host-disease in stem cell transplantation. Monocytes, key cellular targets of CMV, are permissive to primary, latent and reactivated CMV infection. Here, pairing unbiased bulk and single cell transcriptomics with functional analyses we demonstrate that human monocytes infected with CMV do not effectively phagocytose fungal pathogens, a functional deficit which occurs with decreased expression of fungal recognition receptors. Simultaneously, CMV-infected monocytes upregulate antiviral, pro-inflammatory chemokine, and inflammasome responses associated with allograft rejection and graft-versus-host disease. Our study demonstrates that CMV modulates both immunosuppressive and immunostimulatory monocyte phenotypes, explaining in part, its paradoxical "indirect effects" in transplantation. These data could provide innate immune targets for the stratification and treatment of CMV disease. Show less
