Kappelfrom1493

Therefore, OPN is a potential target for the treatment of IAV infection.Learning to avoid dangerous signals while preserving normal responses to safe stimuli is essential for everyday behavior and survival. Following identical experiences, subjects exhibit fear specificity ranging from high (specializing fear to only the dangerous stimulus) to low (generalizing fear to safe stimuli), yet the neuronal basis of fear specificity remains unknown. Here, we identified the neuronal code that underlies inter-subject variability in fear specificity using longitudinal imaging of neuronal activity before and after differential fear conditioning in the auditory cortex of mice. Neuronal activity prior to, but not after learning predicted the level of specificity following fear conditioning across subjects. Stimulus representation in auditory cortex was reorganized following conditioning. However, the reorganized neuronal activity did not relate to the specificity of learning. These results present a novel neuronal code that determines individual patterns in learning.Despite several approved therapeutic modalities, multiple myeloma (MM) remains an incurable blood malignancy and only a small fraction of patients achieves prolonged disease control. The common anti-MM treatment targets proteasome with specific inhibitors (PI). The resulting interference with protein degradation is particularly toxic to MM cells as they typically accumulate large amounts of toxic proteins. However, MM cells often acquire resistance to PIs through aberrant expression or mutations of proteasome subunits such as PSMB5, resulting in disease recurrence and further treatment failure. Here we propose CuET-a proteasome-like inhibitor agent that is spontaneously formed in-vivo and in-vitro from the approved alcohol-abuse drug disulfiram (DSF), as a readily available treatment effective against diverse resistant forms of MM. We show that CuET efficiently kills also resistant MM cells adapted to proliferate under exposure to common anti-myeloma drugs such as bortezomib and carfilzomib used as the first-line therapy, as well as to other experimental drugs targeting protein degradation upstream of the proteasome. Furthermore, CuET can overcome also the adaptation mechanism based on reduced proteasome load, another clinically relevant form of treatment resistance. Data obtained from experimental treatment-resistant cellular models of human MM are further corroborated using rather unique advanced cytotoxicity experiments on myeloma and normal blood cells obtained from fresh patient biopsies including newly diagnosed as well as relapsed and treatment-resistant MM. Overall our findings suggest that disulfiram repurposing particularly if combined with copper supplementation may offer a promising and readily available treatment option for patients suffering from relapsed and/or therapy-resistant multiple myeloma.Increased exposure of Antarctica's coastal environment to open ocean and waves due to loss of a protective sea-ice "buffer" has important ramifications for ice-shelf stability, coastal erosion, important ice-ocean-atmosphere interactions and shallow benthic ecosystems. Here, we introduce a climate and environmental metric based on the ongoing long-term satellite sea-ice concentration record, namely Coastal Exposure Length. This is a daily measure of change and variability in the length and incidence of Antarctic coastline lacking any protective sea-ice buffer offshore. For 1979-2020, ~50% of Antarctica's ~17,850-km coastline had no sea ice offshore each summer, with minimal exposure in winter. Regional summer/maximum contributions vary from 45% (Amundsen-Bellingshausen seas) to 58% (Indian Ocean and Ross Sea), with circumpolar annual exposure ranging from 38% (2019) to 63% (1993). The annual maximum length of Antarctic coastal exposure decreased by ~30 km (~0.32%) per year for 1979-2020, composed of distinct regional and seasonal contributions.Neutrons are a valuable tool for non-destructive material investigation as their interaction cross sections with matter are isotope sensitive and can be used complementary to x-rays. So far, most neutron applications have been limited to large-scale facilities such as nuclear research reactors, spallation sources, and accelerator-driven neutron sources. Here we show the design and optimization of a laser-driven neutron source in the epi-thermal and thermal energy range, which is used for non-invasive material analysis. Neutron resonance spectroscopy, neutron radiography, and neutron resonance imaging with moderated neutrons are demonstrated for investigating samples in terms of isotope composition and thickness. The experimental results encourage applications in non-destructive and isotope-sensitive material analysis and pave the way for compact laser-driven neutron sources with high application potential.As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enables identification of ~2,000 previously undescribed mobile element insertions without previous description, nearly 5 Mb of genomic segments absent from the human genome reference, and over 140 alleles from HLA genes absent from public resources. We reclassify and curate pathogenicity assertions for nearly four hundred variants in genes associated with dominantly-inherited Mendelian disorders and calculate the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observe that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS.Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 μM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. DL-Thiorphan In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.Keyhole porosity is a key concern in laser powder-bed fusion (LPBF), potentially impacting component fatigue life. However, some keyhole porosity formation mechanisms, e.g., keyhole fluctuation, collapse and bubble growth and shrinkage, remain unclear. Using synchrotron X-ray imaging we reveal keyhole and bubble behaviour, quantifying their formation dynamics. The findings support the hypotheses that (i) keyhole porosity can initiate not only in unstable, but also in the transition keyhole regimes created by high laser power-velocity conditions, causing fast radial keyhole fluctuations (2.5-10 kHz); (ii) transition regime collapse tends to occur part way up the rear-wall; and (iii) immediately after keyhole collapse, bubbles undergo rapid growth due to pressure equilibration, then shrink due to metal-vapour condensation. Concurrent with condensation, hydrogen diffusion into the bubble slows the shrinkage and stabilises the bubble size. The keyhole fluctuation and bubble evolution mechanisms revealed here may guide the development of control systems for minimising porosity.Heavy alcohol consumption has been associated with brain atrophy, neuronal loss, and poorer white matter fiber integrity. However, there is conflicting evidence on whether light-to-moderate alcohol consumption shows similar negative associations with brain structure. To address this, we examine the associations between alcohol intake and brain structure using multimodal imaging data from 36,678 generally healthy middle-aged and older adults from the UK Biobank, controlling for numerous potential confounds. Consistent with prior literature, we find negative associations between alcohol intake and brain macrostructure and microstructure. Specifically, alcohol intake is negatively associated with global brain volume measures, regional gray matter volumes, and white matter microstructure. Here, we show that the negative associations between alcohol intake and brain macrostructure and microstructure are already apparent in individuals consuming an average of only one to two daily alcohol units, and become stronger as alcohol intake increases.Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.Controlling and programming quantum devices to process quantum information by the unit of quantum dit, i.e., qudit, provides the possibilities for noise-resilient quantum communications, delicate quantum molecular simulations, and efficient quantum computations, showing great potential to enhance the capabilities of qubit-based quantum technologies. Here, we report a programmable qudit-based quantum processor in silicon-photonic integrated circuits and demonstrate its enhancement of quantum computational parallelism. The processor monolithically integrates all the key functionalities and capabilities of initialisation, manipulation, and measurement of the two quantum quart (ququart) states and multi-value quantum-controlled logic gates with high-level fidelities. By reprogramming the configuration of the processor, we implemented the most basic quantum Fourier transform algorithms, all in quaternary, to benchmark the enhancement of quantum parallelism using qudits, which include generalised Deutsch-Jozsa and Bernstein-Vazirani algorithms, quaternary phase estimation and fast factorization algorithms.