Odgaardlindsay4040

Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.Producing hydrogen by water electrolysis suffers from the kinetic barriers in the oxygen evolution reaction (OER) that limits the overall efficiency. With spin-dependent kinetics in OER, to manipulate the spin ordering of ferromagnetic OER catalysts (e.g., by magnetization) can reduce the kinetic barrier. However, most active OER catalysts are not ferromagnetic, which makes the spin manipulation challenging. In this work, we report a strategy with spin pinning effect to make the spins in paramagnetic oxyhydroxides more aligned for higher intrinsic OER activity. The spin pinning effect is established in oxideFM/oxyhydroxide interface which is realized by a controlled surface reconstruction of ferromagnetic oxides. Under spin pinning, simple magnetization further increases the spin alignment and thus the OER activity, which validates the spin effect in rate-limiting OER step. The spin polarization in OER highly relies on oxyl radicals (O∙) created by 1st dehydrogenation to reduce the barrier for subsequent O-O coupling.Neuronal activity in sensory cortex fluctuates over time and across repetitions of the same input. This variability is often considered detrimental to neural coding. The theory of neural sampling proposes instead that variability encodes the uncertainty of perceptual inferences. In primary visual cortex (V1), modulation of variability by sensory and non-sensory factors supports this view. However, it is unknown whether V1 variability reflects the statistical structure of visual inputs, as would be required for inferences correctly tuned to the statistics of the natural environment. Here we combine analysis of image statistics and recordings in macaque V1 to show that probabilistic inference tuned to natural image statistics explains the widely observed dependence between spike count variance and mean, and the modulation of V1 activity and variability by spatial context in images. Our results show that the properties of a basic aspect of cortical responses-their variability-can be explained by a probabilistic representation tuned to naturalistic inputs.The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.Multitudinous topological configurations spawn oases of many physical properties and phenomena in condensed-matter physics. Nano-sized ferroelectric bubble domains with various polar topologies (e.g., vortices, skyrmions) achieved in ferroelectric films present great potential for valuable physical properties. However, experimentally manipulating bubble domains has remained elusive especially in the bulk form. Here, in any bulk material, we achieve self-confined bubble domains with multiple polar topologies in bulk Bi0.5Na0.5TiO3 ferroelectrics, especially skyrmions, as validated by direct Z-contrast imaging. This phenomenon is driven by the interplay of bulk, elastic and electrostatic energies of coexisting modulated phases with strong and weak spontaneous polarizations. We demonstrate reversable and tip-voltage magnitude/time-dependent donut-like domain morphology evolution towards continuously and reversibly modulated high-density nonvolatile ferroelectric memories.U5 snRNP is a complex particle essential for RNA splicing. U5 snRNPs undergo intricate biogenesis that ensures that only a fully mature particle assembles into a splicing competent U4/U6•U5 tri-snRNP and enters the splicing reaction. During splicing, U5 snRNP is substantially rearranged and leaves as a U5/PRPF19 post-splicing particle, which requires re-generation before the next round of splicing. Here, we show that a previously uncharacterized protein TSSC4 is a component of U5 snRNP that promotes tri-snRNP formation. We provide evidence that TSSC4 associates with U5 snRNP chaperones, U5 snRNP and the U5/PRPF19 particle. Specifically, TSSC4 interacts with U5-specific proteins PRPF8, EFTUD2 and SNRNP200. We also identified TSSC4 domains critical for the interaction with U5 snRNP and the PRPF19 complex, as well as for TSSC4 function in tri-snRNP assembly. TSSC4 emerges as a specific chaperone that acts in U5 snRNP de novo biogenesis as well as post-splicing recycling.Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. selleck kinase inhibitor Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5, and that VSDI measurements do not capture individual spikes. Furthermore, we test the capacity of VSD image sequences to discriminate between afferent thalamic inputs at various spatial locations to estimate a lower bound on the functional resolution of VSDI. Our approach underscores the power of a bottom-up computational approach for relating scales of cortical processing.We present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. Finally, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants at transcription start sites of active genes in lymphoid leukaemia, distinct from a general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. In summary, TensorSignatures elucidates complex mutational footprints by characterising their underlying processes with respect to a multitude of genomic variables.Dzyaloshinskii-Moriya interaction (DMI) is vital to form various chiral spin textures, novel behaviors of magnons and permits their potential applications in energy-efficient spintronic devices. Here, we realize a sizable bulk DMI in a transition metal dichalcogenide (TMD) 2H-TaS2 by intercalating Fe atoms, which form the chiral supercells with broken spatial inversion symmetry and also act as the source of magnetic orderings. Using a newly developed protonic gate technology, gate-controlled protons intercalation could further change the carrier density and intensely tune DMI via the Ruderman-Kittel-Kasuya-Yosida mechanism. The resultant giant topological Hall resistivity [Formula see text] of [Formula see text] at [Formula see text] (about [Formula see text] larger than the zero-bias value) is larger than most known chiral magnets. Theoretical analysis indicates that such a large topological Hall effect originates from the two-dimensional Bloch-type chiral spin textures stabilized by DMI, while the large anomalous Hall effect comes from the gapped Dirac nodal lines by spin-orbit interaction. Dual-intercalation in 2H-TaS2 provides a model system to reveal the nature of DMI in the large family of TMDs and a promising way of gate tuning of DMI, which further enables an electrical control of the chiral spin textures and related electromagnetic phenomena.KIF14 is a mitotic kinesin whose malfunction is associated with cerebral and renal developmental defects and several cancers. Like other kinesins, KIF14 couples ATP hydrolysis and microtubule binding to the generation of mechanical work, but the coupling mechanism between these processes is still not fully clear. Here we report 20 high-resolution (2.7-3.9 Å) cryo-electron microscopy KIF14-microtubule structures with complementary functional assays. Analysis procedures were implemented to separate coexisting conformations of microtubule-bound monomeric and dimeric KIF14 constructs. The data provide a comprehensive view of the microtubule and nucleotide induced KIF14 conformational changes. It shows that 1) microtubule binding, the nucleotide species, and the neck-linker domain govern the transition between three major conformations of the motor domain; 2) an undocked neck-linker prevents the nucleotide-binding pocket to fully close and dampens ATP hydrolysis; 3) 13 neck-linker residues are required to assume a stable docked conformation; 4) the neck-linker position controls the hydrolysis rather than the nucleotide binding step; 5) the two motor domains of KIF14 dimers adopt distinct conformations when bound to the microtubule; and 6) the formation of the two-heads-bound-state introduces structural changes in both motor domains of KIF14 dimers.