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Emicizumab binds to activated factor IX and factor X, reproducing the bridging function of the missing factor VIII. In a trial of emicizumab prophylaxis, emicizumab every 1 or 2 weeks led to a lower bleeding rate than no prophylaxis.

The basic unit of genome packaging is the nucleosome, and nucleosomes have long been proposed to restrict DNA accessibility both to damage and to transcription. Nucleosome number in cells was considered fixed, but recently aging yeast and mammalian cells were shown to contain fewer nucleosomes. We show here that mammalian cells lacking High Mobility Group Box 1 protein (HMGB1) contain a reduced amount of core, linker, and variant histones, and a correspondingly reduced number of nucleosomes, possibly because HMGB1 facilitates nucleosome assembly. Yeast nhp6 mutants lacking Nhp6a and -b proteins, which are related to HMGB1, also have a reduced amount of histones and fewer nucleosomes. Nucleosome limitation in both mammalian and yeast cells increases the sensitivity of DNA to damage, increases transcription globally, and affects the relative expression of about 10% of genes. In yeast nhp6 cells the loss of more than one nucleosome in four does not affect the location of nucleosomes and their spacing, but nucleosomal occupancy. The decrease in nucleosomal occupancy is non-uniform and can be modelled assuming that different nucleosomal sites compete for available histones. Sites with a high propensity to occupation are almost always packaged into nucleosomes both in wild type and nucleosome-depleted cells; nucleosomes on sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells. We suggest that variation in nucleosome number, by affecting nucleosomal occupancy both genomewide and gene-specifically, constitutes a novel layer of epigenetic regulation.

We discuss a small-scale experiment, called ν -cleus, for the first detection of coherent neutrino–nucleus scattering by probing nuclear-recoil energies down to the 10 eV regime. The detector consists of low-threshold CaWO 4 and Al 2 O 3 calorimeter arrays with a total mass of about 10 g and several cryogenic veto detectors operated at millikelvin temperatures. Realizing a fiducial volume and a multi-element target, the detector enables active discrimination of γ , neutron and surface backgrounds. A first prototype Al 2 O 3 device, operated above ground in a setup without shielding, has achieved an energy threshold of ∼ 20  eV and further improvements are in reach. A sensitivity study for the detection of coherent neutrino scattering at nuclear power plants shows a unique discovery potential (5 σ ) within a measuring time of ≲ 2  weeks. Furthermore, a site at a thermal research reactor and the use of a radioactive neutrino source are investigated. With this technology, real-time monitoring of nuclear power plants is feasible.

Models for light dark matter particles with masses below 1 GeV/c 2 are a natural and well-motivated alternative to so-far unobserved weakly interacting massive particles. Gram-scale cryogenic calorimeters provide the required detector performance to detect these particles and extend the direct dark matter search program of CRESST. A prototype 0.5 g sapphire detector developed for the ν -cleus experiment has achieved an energy threshold of E t h = ( 19.7 ± 0.9 )  eV. This is one order of magnitude lower than for previous devices and independent of the type of particle interaction. The result presented here is obtained in a setup above ground without significant shielding against ambient and cosmogenic radiation. Although operated in a high-background environment, the detector probes a new range of light-mass dark matter particles previously not accessible by direct searches. We report the first limit on the spin-independent dark matter particle-nucleon cross section for masses between 140 and 500 MeV/c 2 .

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.

COSINUS is a dark matter (DM) direct search experiment that uses sodium iodide (NaI) crystals as cryogenic calorimeters. Thanks to the low nuclear recoil energy threshold and event-by-event discrimination capability, COSINUS will address the long-standing DM claim made by the DAMA/LIBRA collaboration. The experiment is currently under construction at the Laboratori Nazionali del Gran Sasso, Italy, and employs a large cylindrical water tank as a passive shield to meet the required background rate. However, muon-induced neutrons can mimic a DM signal therefore requiring an active veto system, which is achieved by instrumenting the water tank with an array of photomultiplier tubes (PMTs). This study optimizes the number, arrangement, and trigger conditions of the PMTs as well as the size of an optically invisible region. The objective was to maximize the muon veto efficiency while minimizing the accidental trigger rate due to the ambient and instrumental background. The final configuration predicts a veto efficiency of 99.63 ± 0.16% and 44.4 ± 5.6% in the tagging of muon events and showers of secondary particles, respectively. The active veto will reduce the cosmogenic neutron background rate to 0.11 ± 0.02 cts · kg - 1 · year - 1 , corresponding to less than one background event in the region of interest for the whole COSINUS-1 π exposure of 1000 kg · days.

Models for light dark matter particles with masses below 1 GeV/c [Formula omitted] are a natural and well-motivated alternative to so-far unobserved weakly interacting massive particles. Gram-scale cryogenic calorimeters provide the required detector performance to detect these particles and extend the direct dark matter search program of CRESST. A prototype 0.5 g sapphire detector developed for the [Formula omitted]-cleus experiment has achieved an energy threshold of [Formula omitted] eV. This is one order of magnitude lower than for previous devices and independent of the type of particle interaction. The result presented here is obtained in a setup above ground without significant shielding against ambient and cosmogenic radiation. Although operated in a high-background environment, the detector probes a new range of light-mass dark matter particles previously not accessible by direct searches. We report the first limit on the spin-independent dark matter particle-nucleon cross section for masses between 140 and 500 MeV/c [Formula omitted].

Background Glioblastoma is the most aggressive and most lethal primary brain tumor in the adulthood. Current standard therapies are not curative and novel therapeutic options are urgently required. Present knowledge suggests that the continued glioblastoma growth and recurrence is determined by glioblastoma stem-like cells (GSCs), which display self-renewal, tumorigenic potential, and increased radio- and chemo-resistance. The G-quadruplex ligand RHPS4 displays in vitro radiosensitizing effect in GBM radioresistant cells through the targeting and dysfunctionalization of telomeres but RHPS4 and Ionizing Radiation (IR) combined treatment efficacy in vivo has not been explored so far. Methods RHPS4 and IR combined effects were tested in vivo in a heterotopic mice xenograft model and in vitro in stem-like cells derived from U251MG and from four GBM patients. Cell growth assays, cytogenetic analysis, immunoblotting, gene expression and cytofluorimetric analysis were performed in order to characterize the response of differentiated and stem-like cells to RHPS4 and IR in single and combined treatments. Results RHPS4 administration and IR exposure is very effective in blocking tumor growth in vivo up to 65 days. The tumor volume reduction and the long-term tumor control suggested the targeting of the stem cell compartment. Interestingly, RHPS4 treatment was able to strongly reduce cell proliferation in GSCs but, unexpectedly, did not synergize with IR. Lack of radiosensitization was supported by the GSCs telomeric-resistance observed as the total absence of telomere-involving chromosomal aberrations. Remarkably, RHPS4 treatment determined a strong reduction of CHK1 and RAD51 proteins and transcript levels suggesting that the inhibition of GSCs growth is determined by the impairment of the replication stress (RS) response and DNA repair. Conclusions We propose that the potent antiproliferative effect of RHPS4 in GSCs is not determined by telomeric dysfunction but is achieved by the induction of RS and by the concomitant depletion of CHK1 and RAD51, leading to DNA damage and cell death. These data open to novel therapeutic options for the targeting of GSCs, indicating that the combined inhibition of cell-cycle checkpoints and DNA repair proteins provides the most effective means to overcome resistance of GSC to genotoxic insults.

Coherent elastic neutrino–nucleus scattering (CEνNS) offers a unique way to study neutrino properties and to search for new physics beyond the Standard Model. Nuclear reactors are promising sources to explore this process at low energies since they deliver large fluxes of anti-neutrinos with typical energies of a few MeV. In this paper, a new-generation experiment to study CEνNS is described. The NUCLEUS experiment will use cryogenic detectors which feature an unprecedentedly low-energy threshold and a time response fast enough to be operated under above-ground conditions. Both sensitivity to low-energy nuclear recoils and a high event rate tolerance are stringent requirements to measuring CEνNS of reactor anti-neutrinos. A new experimental site, the Very-Near-Site (VNS), at the Chooz nuclear power plant in France is described. The VNS is located between the two 4.25 GWth reactor cores and matches the requirements of NUCLEUS. First results of on-site measurements of neutron and muon backgrounds, the expected dominant background contributions, are given. In this paper a preliminary experimental set-up with dedicated active and passive background reduction techniques and first background estimations are presented. Furthermore, the feasibility to operate the detectors in coincidence with an active muon veto at shallow overburden is studied. The paper concludes with a sensitivity study pointing out the physics potential of NUCLEUS at the Chooz nuclear power plant.

The COSINUS (Cryogenic Observatory for SIgnatures seen in Next-generation Underground Searches) experiment aims at the detection of dark matter-induced recoils in sodium iodide (NaI) crystals operated as scintillating cryogenic calorimeters. The detection of both scintillation light and phonons allows performing an event-by-event signal to background discrimination, thus enhancing the sensitivity of the experiment. The choice of using NaI crystals is motivated by the goal of probing the long-standing DAMA/LIBRA results using the same target material. The construction of the experimental facility is foreseen to start by 2021 at the INFN Gran Sasso National Laboratory (LNGS) in Italy. It consists of a cryostat housing the target crystals shielded from the external radioactivity by a water tank acting, at the same time, as an active veto against cosmic ray-induced events. Taking into account both environmental radioactivity and intrinsic contamination of materials used for cryostat, shielding and infrastructure, we performed a careful background budget estimation. The goal is to evaluate the number of events that could mimic or interfere with signal detection while optimising the geometry of the experimental setup. In this paper we present the results of the detailed Monte Carlo simulations we performed, together with the final design of the setup that minimises the residual amount of background particles reaching the detector volume.