Showing papers by "University of Würzburg published in 2020"

Pan-cancer analysis of whole genomes

Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium

Abstract: BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

TRY plant trait database : Enhanced coverage and open access

Abstract: Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.

KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma

Abstract: Background Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton’s tyrosine kinase (BTK) inhibitor therapy have a poo...

Generalized bulk–boundary correspondence in non-Hermitian topolectrical circuits

Abstract: The study of the laws of nature has traditionally been pursued in the limit of isolated systems, where energy is conserved. This is not always a valid approximation, however, as the inclusion of features such as gain and loss, or periodic driving, qualitatively amends these laws. A contemporary frontier of metamaterial research is the challenge open systems pose to the characterization of topological matter1,2. Here, one of the most relied upon principles is the bulk–boundary correspondence (BBC), which intimately relates the surface states to the topological classification of the bulk3,4. The presence of gain and loss, in combination with the violation of reciprocity, has been predicted to affect this principle dramatically5,6. Here, we report the experimental observation of BBC violation in a non-reciprocal topolectric circuit7, which is also referred to as the non-Hermitian skin effect. The circuit admittance spectrum exhibits an unprecedented sensitivity to the presence of a boundary, displaying an extensive admittance mode localization despite a translationally invariant bulk. Intriguingly, we measure a non-local voltage response due to broken BBC. Depending on the a.c. current feed frequency, the voltage signal accumulates at the left or right boundary, and increases as a function of nodal distance to the current feed. Boundary-localized bulk eigenstates given by the non-Hermitian skin effect are observed in a non-reciprocal topological circuit. A fundamental revision of the bulk–boundary correspondence in an open system is required to understand the underlying physics.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Abstract: Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

Topological Funneling of Light

Abstract: Dissipation is a general feature of non-Hermitian systems. But rather than being an unavoidable nuisance, non-Hermiticity can be precisely controlled and hence used for sophisticated applications, such as optical sensors with enhanced sensitivity. In our work, we implement a non-Hermitian photonic mesh lattice by tailoring the anisotropy of the nearest-neighbor coupling. The appearance of an interface results in a complete collapse of the entire eigenmode spectrum, leading to an exponential localization of all modes at the interface. As a consequence, any light field within the lattice travels toward this interface, irrespective of its shape and input position. On the basis of this topological phenomenon, called the "non-Hermitian skin effect," we demonstrate a highly efficient funnel for light.

The genetic architecture of the human cerebral cortex

Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Implicit Functions in Feature Space for 3D Shape Reconstruction and Completion

Abstract: While many works focus on 3D reconstruction from images, in this paper, we focus on 3D shape reconstruction and completion from a variety of 3D inputs, which are deficient in some respect: low and high resolution voxels, sparse and dense point clouds, complete or incomplete. Processing of such 3D inputs is an increasingly important problem as they are the output of 3D scanners, which are becoming more accessible, and are the intermediate output of 3D computer vision algorithms. Recently, learned implicit functions have shown great promise as they produce continuous reconstructions. However, we identified two limitations in reconstruction from 3D inputs: 1) details present in the input data are not retained, and 2) poor reconstruction of articulated humans. To solve this, we propose Implicit Feature Networks (IF-Nets), which deliver continuous outputs, can handle multiple topologies, and complete shapes for missing or sparse input data retaining the nice properties of recent learned implicit functions, but critically they can also retain detail when it is present in the input data, and can reconstruct articulated humans. Our work differs from prior work in two crucial aspects. First, instead of using a single vector to encode a 3D shape, we extract a learnable 3-dimensional multi-scale tensor of deep features, which is aligned with the original Euclidean space embedding the shape. Second, instead of classifying x-y-z point coordinates directly, we classify deep features extracted from the tensor at a continuous query point. We show that this forces our model to make decisions based on global and local shape structure, as opposed to point coordinates, which are arbitrary under Euclidean transformations. Experiments demonstrate that IF-Nets outperform prior work in 3D object reconstruction in ShapeNet, and obtain significantly more accurate 3D human reconstructions. Code and project website is available at https://virtualhumans.mpi-inf.mpg.de/ifnets/.

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

Abstract: Background RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and sa...

Aggregation-Induced Emission (AIE): A Historical Perspective.

Abstract: Aggregation-induced emission (AIE) has attracted considerable interest over the last twenty years. In contrast to the large number of available reviews focusing specifically on AIE, this Essay discusses the AIE phenomenon from a broader perspective, with an emphasis on early observations related to AIE made long before the term was coined. Illustrative examples are highlighted from the 20th century where fluorescence enhancement upon rigidification of dyes in viscous or solid environments or J-aggregate formation was studied. It is shown that these examples already include typical AIE luminogens such as tetraphenylethylene (TPE) as well as stilbenes and oligo- or polyphenylenevinylenes and -ethynylenes, which became important fluorescent solid-state materials in OLED research in the 1990s. Further examples include cyanine dyes such as thiazole orange (TO) or its dimers (TOTOs), which have been widely applied as molecular probes in nucleic acid research. The up to 10 000-fold fluorescence enhancement of such dyes upon intercalation into double-stranded DNA, attributable to the restricted intramolecular motion (RIM) concept, afforded commercial products for bioimaging and fluorescence sensing applications already in the early 1990s.

Search for electroweak production of charginos and sleptons decaying into final states with two leptons and missing transverse momentum in √s = 13 TeV pp collisions using the ATLAS detector

Abstract: A search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented. The analysis is based on 139 fb$^{-1}$ of proton–proton collisions recorded by the ATLAS detector at the Large Hadron Collider at $\sqrt{s}=13$ $\text {TeV}$. Three R-parity-conserving scenarios where the lightest neutralino is the lightest supersymmetric particle are considered: the production of chargino pairs with decays via either W bosons or sleptons, and the direct production of slepton pairs. The analysis is optimised for the first of these scenarios, but the results are also interpreted in the others. No significant deviations from the Standard Model expectations are observed and limits at 95% confidence level are set on the masses of relevant supersymmetric particles in each of the scenarios. For a massless lightest neutralino, masses up to 420 $\text {Ge}\text {V}$ are excluded for the production of the lightest-chargino pairs assuming W-boson-mediated decays and up to 1 $\text {TeV}$ for slepton-mediated decays, whereas for slepton-pair production masses up to 700 $\text {Ge}\text {V}$ are excluded assuming three generations of mass-degenerate sleptons.

Supramolecular polymerization through kinetic pathway control and living chain growth

Abstract: Supramolecular polymers exhibit fascinating structures, and their properties, and thus applications, depend both on the strength and dynamics of the non-covalent bonds and on the functional properties of the monomeric building blocks. In this Review, we highlight the progress in methods developed to control supramolecular polymerization based on physicochemical insights into the thermodynamics and kinetics of non-covalent interactions. Prerequisites for polymer formation and stability, such as high binding strength (thermodynamics) between complementary receptor units, are briefly discussed, while the main focus is on the kinetic control of pathway selectivity, which in recent years has allowed seed-induced living supramolecular polymerization, chain growth-type supramolecular polymerization and the preparation of specific supramolecular polymer polymorphs and supramolecular block copolymers. Beginning with a historical retrospective, this Review highlights the progress from thermodynamically and kinetically controlled self-assembly processes towards seed-induced living supramolecular polymerization, which allows the formation of highly ordered, functional materials such as supramolecular block copolymers.

Initialization and read-out of intrinsic spin defects in a van der Waals crystal at room temperature

Abstract: Optically addressable spins in wide-bandgap semiconductors are a promising platform for exploring quantum phenomena. While colour centres in three-dimensional crystals such as diamond and silicon carbide were studied in detail, they were not observed experimentally in two-dimensional (2D) materials. Here, we report spin-dependent processes in the 2D material hexagonal boron nitride (hBN). We identify fluorescence lines associated with a particular defect, the negatively charged boron vacancy ($${\mathrm{V}}_{\mathrm{B}}^ -$$), showing a triplet (S = 1) ground state and zero-field splitting of ~3.5 GHz. We establish that this centre exhibits optically detected magnetic resonance at room temperature and demonstrate its spin polarization under optical pumping, which leads to optically induced population inversion of the spin ground state—a prerequisite for coherent spin-manipulation schemes. Our results constitute a step forward in establishing 2D hBN as a prime platform for scalable quantum technologies, with potential for spin-based quantum information and sensing applications. An ensemble of spins associated with an intrinsic defect of two-dimensional hexagonal boron nitride is shown to be optically addressable, allowing spin polarization of its triplet ground state and providing evidence of spin coherence.

From Shape to Function: The Next Step in Bioprinting

Abstract: In 2013, the "biofabrication window" was introduced to reflect the processing challenge for the fields of biofabrication and bioprinting. At that time, the lack of printable materials that could serve as cell-laden bioinks, as well as the limitations of printing and assembly methods, presented a major constraint. However, recent developments have now resulted in the availability of a plethora of bioinks, new printing approaches, and the technological advancement of established techniques. Nevertheless, it remains largely unknown which materials and technical parameters are essential for the fabrication of intrinsically hierarchical cell-material constructs that truly mimic biologically functional tissue. In order to achieve this, it is urged that the field now shift its focus from materials and technologies toward the biological development of the resulting constructs. Therefore, herein, the recent material and technological advances since the introduction of the biofabrication window are briefly summarized, i.e., approaches how to generate shape, to then focus the discussion on how to acquire the biological function within this context. In particular, a vision of how biological function can evolve from the possibility to determine shape is outlined.

T cell-engaging therapies - BiTEs and beyond.

Abstract: Immuno-oncology approaches have entered clinical practice, with tremendous progress particularly in the field of T cell-engaging therapies over the past decade. Herein, we provide an overview of the current status of bispecific T cell engager (BiTE) therapy, considering the unprecedented new indication for such therapy in combating minimal (or measurable) residual disease in patients with acute lymphoblastic leukaemia, and the development of novel approaches based on this concept. Key aspects that we discuss include the current clinical data, challenges relating to treatment administration and patient monitoring, toxicities and resistance to treatment, and novel strategies to overcome these hurdles as well as to broaden the indications for BiTE therapy, particularly to common solid cancers. Elucidation of mechanisms of resistance and immune escape and new technologies used in drug development pave the way for new and more-effective therapies and rational combinatorial approaches. In particular, we highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells (CART.BiTE cells), designed to integrate various immune functions into one molecule or a single cellular vector and thereby enhance efficacy without compromising safety. We also discuss the targeting of intracellular tumour-associated epitopes using bispecific constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which might broaden the armamentarium of T cell-engaging therapies. The use of bispecific antibodies to engage cells of the immune system that are cytotoxic to cancer cells is a major focus of cancer immunotherapy, with approvals for the treatment of acute lymphoblastic leukaemia. Here, the authors review the clinical results obtained with bispecific antibodies to date. They also discuss the challenges associated with this therapeutic approach and the proposed solutions aimed at preventing or minimizing toxicities, countering immune escape and broadening the indications for these treatments.

The bioprinting roadmap

Abstract: This bioprinting roadmap features salient advances in selected applications of the technique and highlights the status of current developments and challenges, as well as envisioned advances in science and technology, to address the challenges to the young and evolving technique. The topics covered in this roadmap encompass the broad spectrum of bioprinting; from cell expansion and novel bioink development to cell/stem cell printing, from organoid-based tissue organization to bioprinting of human-scale tissue structures, and from building cell/tissue/organ-on-a-chip to biomanufacturing of multicellular engineered living systems. The emerging application of printing-in-space and an overview of bioprinting technologies are also included in this roadmap. Due to the rapid pace of methodological advancements in bioprinting techniques and wide-ranging applications, the direction in which the field should advance is not immediately clear. This bioprinting roadmap addresses this unmet need by providing a comprehensive summary and recommendations useful to experienced researchers and newcomers to the field.

Interpreting insect declines: seven challenges and a way forward

Abstract: 1. Many insect species are under threat from the anthropogenic drivers of global change. There have been numerous well‐documented examples of insect population declines and extinctions in the scientific literature, but recent weaker studies making extreme claims of a global crisis have drawn widespread media coverage and brought unprecedented public attention. This spotlight might be a double‐edged sword if the veracity of alarmist insect decline statements do not stand up to close scrutiny. 2. We identify seven key challenges in drawing robust inference about insect population declines: establishment of the historical baseline, representativeness of site selection, robustness of time series trend estimation, mitigation of detection bias effects, and ability to account for potential artefacts of density dependence, phenological shifts and scale‐dependence in extrapolation from sample abundance to population‐level inference. 3. Insect population fluctuations are complex. Greater care is needed when evaluating evidence for population trends and in identifying drivers of those trends. We present guidelines for best‐practise approaches that avoid methodological errors, mitigate potential biases and produce more robust analyses of time series trends. 4. Despite many existing challenges and pitfalls, we present a forward‐looking prospectus for the future of insect population monitoring, highlighting opportunities for more creative exploitation of existing baseline data, technological advances in sampling and novel computational approaches. Entomologists cannot tackle these challenges alone, and it is only through collaboration with citizen scientists, other research scientists in many disciplines, and data analysts that the next generation of researchers will bridge the gap between little bugs and big data.

Statin therapy is associated with lower prevalence of gut microbiota dysbiosis

Abstract: Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics. A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.

The Fourth Catalog of Active Galactic Nuclei Detected by the Fermi Large Area Telescope

Abstract: The fourth catalog of active galactic nuclei (AGNs) detected by the Fermi Gamma-ray Space Telescope Large Area Telescope (4LAC) between 2008 August 4 and 2016 August 2 contains 2863 objects located at high Galactic latitudes (|b|>10{\deg}). It includes 85% more sources than the previous 3LAC catalog based on 4 years of data. AGNs represent at least 79% of the high-latitude sources in the fourth Fermi-Large Area Telescope Source Catalog (4FGL), which covers the energy range from 50 MeV to 1 TeV. In addition, 344 gamma-ray AGNs are found at low Galactic latitudes. Most of the 4LAC AGNs are blazars (98%), while the remainder are other types of AGNs. The blazar population consists of 24% Flat Spectrum Radio Quasars (FSRQs), 38% BL Lac-type objects (BL Lacs), and 38% blazar candidates of unknown types (BCUs). On average, FSRQs display softer spectra and stronger variability in the gamma-ray band than BL Lacs do, confirming previous findings. All AGNs detected by ground-based atmospheric Cherenkov telescopes are also found in the 4LAC.

Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

Abstract: Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the le...

Glucose transporters in brain in health and disease

Abstract: Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-d-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of d-glucose across the blood-brain barrier and delivery of d-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome.

Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

Abstract: Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression

Abstract: Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome In mice, hematogenous F nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc Intravascularly inoculated Fap2-expressing F nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization Inoculation with F nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment Thus, targeting F nucleatum or Fap2 might be beneficial during treatment of breast cancer High levels of Fusobacterium nucleatum have been associated with poor overall survival in patients with colorectal and esophageal cancer Here, the authors show that F nucleatum is abundant in breast cancer samples and that the colonization by F nucleatum accelerates tumor growth and metastasis in preclinical breast cancer models

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint.

Abstract: Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

Reciprocal skin effect and its realization in a topolectrical circuit

Abstract: A system is non-Hermitian when it exchanges energy with its environment and nonreciprocal when it behaves differently upon the interchange of input and response. Within the field of metamaterial research on synthetic topological matter, the skin effect describes the conspiracy of non-Hermiticity and nonreciprocity to yield extensive anomalous localization of all eigenmodes in a (quasi) one-dimensional geometry. Here, we introduce the reciprocal skin effect, which occurs in non-Hermitian but reciprocal systems in two or more dimensions: Eigenmodes with opposite longitudinal momentum exhibit opposite transverse anomalous localization. We experimentally demonstrate the reciprocal skin effect in a passive RLC circuit, suggesting convenient alternative implementations in optical, acoustic, mechanical, and related platforms. Skin mode localization brings forth potential applications in directional and polarization detectors for electromagnetic waves.