Potential Neutrino Signals from Galactic Gamma-Ray Sources

The recent progress made in Galactic gamma-ray astronomy using the High Energy Stereoskopic System (H.E.S.S.) instrument provides for the first time a population of Galactic TeV gamma-rays, and hence potential neutrino sources, for which the neutrino flux can be estimated. Using the energy spectra and source morphologies measured by H.E.S.S., together with new parameterisations of pion production and decay in hadronic interactions, we estimate the signal and background rates expected for these sources in a first-generation water Cherenkov detector (ANTARES) and a next-generation neutrino telescope in the Mediterranean Sea, KM3NeT, with an instrumented volume of 1 km^3. We find that the brightest gamma-ray sources produce neutrino rates above 1 TeV, comparable to the background from atmospheric neutrinos. The expected event rates of the brightest sources in the ANTARES detector make a detection unlikely. However, for a 1 km^3 KM3NeT detector, event rates of a few neutrinos per year from these sources are expected, and the detection of individual sources seems possible. Although generally these estimates should be taken as flux upper limits, we discuss the conditions and type of gamma-ray sources for which the neutrino flux predictions can be considered robust.Comment: 20 pages, 4 figures; v2: ERROR in energy scale of KM3NeT effective neutrino area corrected which resulted in event rates being about a factor 3 too low; v3: grammatical changes and update of references after receiving proof

Geotechnical characterization and stability analysis of subaqueous slopes in Lake Lucerne (Switzerland).

Tsunamis occur not only in marine settings but also in lacustrine environments. Most of the lacustrine tsunamis are caused by seismically- or aseismically-triggered mass movements. Therefore, an assessment of the stability of subaqueous slopes is crucial for tsunami hazard assessment in a lake. We selected Lake Lucerne (Switzerland) as a natural laboratory to perform an in-depth geotechnical characterization of its subaqueous slopes. This lake experienced documented tsunamis in 1601 and 1687. Some of its slopes still bear sediment volumes with a potential for tsunamigenic failure. To identify such slopes, we interpreted available reflection seismic data and analyzed the bathymetric map. Then, we performed 152 dynamic Cone Penetration Tests with pore pressure measurement (CPTu) and retrieved 49 sediment cores at different locations in the lake. These data were used to characterize the failure-prone sediments and to evaluate the present-day static stability of subaqueous slopes. Obtained results allowed the definition of three classes of slopes in terms of static stability: unstable slopes, stable slopes close to the unstable state, and stable areas. Non-deltaic slopes with thicker unconsolidated fine-grained sediment drape and moderate-to-high slope gradients (> 5-10°) have the lowest Factor of Safety. In agreement with previous studies, the failure plane for the non-deltaic slopes is embedded within the fine-grained glaciolacustrine sediments. Deltaic slopes with prevailing coarse-grained sediments mostly appear statically stable. Finally, we generalized the measured undrained shear strength profiles into the depth-dependent power-law models. These models define the of Lake Lucerne's sediments and can be applied to other lakes with similar sedimentation history. Supplementary Information The online version contains supplementary material available at 10.1007/s11069-022-05310-1

Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3

Bipotential T/natural killer (NK) progenitor cells are present in the human thymus. Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus. The mechanisms controlling this developmental choice are unknown. Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NK/T cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34+ progenitor cells by retrovirus-mediated gene transfer. Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC). In contrast, development into NK cells in an FTOC is enhanced. Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen. Our results identify a molecular switch for lineage specification in early lymphoid precursors of humans

Femtosecond laser preparation of resin embedded samples for correlative microscopy workflows in life sciences

Correlative multimodal imaging is a useful approach to investigate complex structural relations in life sciences across multiple scales. For these experiments, sample preparation workflows that are compatible with multiple imaging techniques must be established. In one such implementation, a fluorescently labeled region of interest in a biological soft tissue sample can be imaged with light microscopy before staining the specimen with heavy metals, enabling follow-up higher resolution structural imaging at the targeted location, bringing context where it is required. Alternatively, or in addition to fluorescence imaging, other microscopy methods, such as synchrotron x-ray computed tomography with propagation-based phase contrast or serial blockface scanning electron microscopy, might also be applied. When combining imaging techniques across scales, it is common that a volumetric region of interest (ROI) needs to be carved from the total sample volume before high resolution imaging with a subsequent technique can be performed. In these situations, the overall success of the correlative workflow depends on the precise targeting of the ROI and the trimming of the sample down to a suitable dimension and geometry for downstream imaging. Here, we showcase the utility of a femtosecond laser (fs laser) device to prepare microscopic samples (1) of an optimized geometry for synchrotron x-ray tomography as well as (2) for volume electron microscopy applications and compatible with correlative multimodal imaging workflows that link both imaging modalities

Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication

Funding Information: We thank Thorsten Wolff, Daniel Bourquain, Jessica Schulz, and Christian Mache from the Robert-Koch Institute and Martin Beer from the Friedrich Loeffler Institute (FLI) for providing isolates of SARS-CoV-2 variants. We thank Anna Kraft and Gabriele Czerwinski (both FLI) for support in the preparation of samples for pathology, and Catherine Hambly (University of Aberdeen) for help with daily energy expenditure measurements. We would like to thank Cathrin Bierwirth (University Medical Center Göttingen), Isabell Schulz, Anne-Kathrin Donner, and Frank-Thorben Peters for excellent technician assistance and Jasmin Fertey and Alexandra Rockstroh for providing the virus stocks for the mice experiment (Fraunhofer Institute IZI Leipzig). We acknowledge support by the Open Access Publication Funds of the Göttingen University. KMS was a member of the Göttingen Graduate School GGNB during this work. This work was funded by the COVID-19 Forschungsnetzwerk Niedersachsen (COFONI) to MD, by the Federal Ministry of Education and Research Germany ( Bundesministerium für Bildung und Forschung; BMBF ; OrganSARS , 01KI2058 ) to SP and TM, and by a grant of the Max Planck Foundation to DG. Declaration of interests AS, HK, EP, and DV are employees of Immunic AG and own shares and/or stock-options of the parent company of Immunic AG, Immunic Inc. Some of the Immunic AG employees also hold patents for the Immunic compounds described in this manuscript (WO2012/001,148, WO03006425). KMS, AD, and MD are employees of University Medical Center Göttingen, which has signed a License Agreement with Immunic AG covering the combination of DHODH inhibitors and nucleoside analogs to treat viral infections, including COVID-19 (inventors: MD, KMS, and AD). The other authors declare no conflict of interest.Peer reviewedPublisher PD

Short-lived Nuclei in the Early Solar System: Possible AGB Sources

(Abridged) We review abundances of short-lived nuclides in the early solar system (ESS) and the methods used to determine them. We compare them to the inventory for a uniform galactic production model. Within a factor of two, observed abundances of several isotopes are compatible with this model. I-129 is an exception, with an ESS inventory much lower than expected. The isotopes Pd-107, Fe-60, Ca-41, Cl-36, Al-26, and Be-10 require late addition to the solar nebula. Be-10 is the product of particle irradiation of the solar system as probably is Cl-36. Late injection by a supernova (SN) cannot be responsible for most short-lived nuclei without excessively producing Mn-53; it can be the source of Mn-53 and maybe Fe-60. If a late SN is responsible for these two nuclei, it still cannot make Pd-107 and other isotopes. We emphasize an AGB star as a source of nuclei, including Fe-60 and explore this possibility with new stellar models. A dilution factor of about 4e-3 gives reasonable amounts of many nuclei. We discuss the role of irradiation for Al-26, Cl-36 and Ca-41. Conflict between scenarios is emphasized as well as the absence of a global interpretation for the existing data. Abundances of actinides indicate a quiescent interval of about 1e8 years for actinide group production in order to explain the data on Pu-244 and new bounds on Cm-247. This interval is not compatible with Hf-182 data, so a separate type of r-process is needed for at least the actinides, distinct from the two types previously identified. The apparent coincidence of the I-129 and trans-actinide time scales suggests that the last actinide contribution was from an r-process that produced actinides without fission recycling so that the yields at Ba and below were governed by fission.Comment: 92 pages, 14 figure files, in press at Nuclear Physics

USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.</p

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome