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Abstract An ultrapure deep-blue multi-resonance-induced thermally activated delayed fluorescence material (DOB2-DABNA-A) is designed and synthesized. Benefiting from a fully resonating extended helical π-conjugated system, this compound has a small ΔE ST value of 3.6 meV and sufficient spin–orbit coupling to exhibit a high-rate constant for reverse intersystem crossing (k RISC = 1.1 × 106 s–1). Furthermore, an organic light-emitting diode employing DOB2-DABNA-A as an emitter is fabricated; it exhibits ultrapure deep-blue emission at 452 nm with a small full width at half maximum of 24 nm, corresponding to Commission Internationale de l’Éclairage (CIE) coordinates of (0.145, 0.049). The high k RISC value reduces the efficiency roll-off, resulting in a high external quantum efficiency (EQE) of 21.6% at 1000 cd m–2.

Abstract Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody–drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.

Abstract A superconductor-insulator transition (SIT) in two dimensions is a prototypical quantum phase transition (QPT) with a clear quantum critical point (QCP) at zero temperature (T = 0). The SIT is induced by a field B and observed in disordered thin films. In some of weakly disordered or crystalline thin films, however, an anomalous metallic (AM) ground state emerges over a wide B range between the superconducting and insulating phases. It remains a fundamental open question how the QPT picture of the SIT is modified when the AM state appears. Here we present measurements of the Nernst effect N, which has great sensitivity to the fluctuations of the superconducting order parameter. From a thorough contour map of N in the B-T plane, we found a thermal-to-quantum crossover line of the superconducting fluctuations, a so-called ghost-temperature line associated with the QPT, as well as a ghost-field line associated with a thermal transition. The QCP is identified as a T = 0 intercept of the ghost-temperature line inside the AM state, which verifies that the AM state is a broadened critical state of the SIT.

Abstract In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Abstract In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

Transcription termination is generally accompanied by the 3′-end processing of transcripts. Here the authors demonstrate a role for Mediator in transcript end site proximal pausing of replication-dependent histone genes.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.

Cortical excitatory/inhibitory (E/I) imbalance is a feature of autism spectrum disorder (ASD). Here, the authors show that FoxG1 regulates the formation of cortical GABAergic circuits affecting social behaviour during a specific postnatal time window in mouse models of ASD.

Mediator subunit MED26 was shown to help recruit Super Elongation Complex (SEC) or Little Elongation Complex (LEC) to control the expression of certain genes. Here, the authors provide evidence that MED26 recruits LEC to regulate transcription termination of non-polyadenylated genes, including snRNA and replication-dependent histone (RDH) genes at Cajal bodies.

High-temperature solid oxide electrolysis cells are a promising technology for energy conversion, but higher current density is needed to increase efficiency. Here the authors design nanocomposite electrodes to improve electronic and ionic conductivity to achieve a high current density.

Spin current generation in organic materials is hindered by the light elements in the molecules. Here the authors predict a class of organic antiferromagnets with checker-plate type molecular arrangements can be spin current generator under thermal gradient or an electric field, even without spin-orbit coupling.

Samarium hexaboride has unusual electronic properties that have been suggested to arise from topological effects. Here the authors present spin-resolved ARPES measurements of the (111) surface and observe surface states that may give insight into the bulk topological properties.

MHC class I and II molecules generally present endogenous and exogenous peptides, respectively, through distinct mechanisms. Here, the authors show that the class II molecule HLA-DP84Glyuses both class I and II mechanisms to constitutively present peptides.

Dynamically controlling the conformations of 1D elongated supramolecular polymers can induce functions comparable to protein folding/unfolding. Here the authors show light-induced conformational changes of azobenzene-based supramolecular polymers from helically coiled to extended/randomly coiled conformations.

Plant immune responses are often associated with reduced growth. Here, the authors show that combining mutations in transcriptional repressors of the defense and light perception pathways can confer both robust growth and strong herbivore defense, demonstrating that growth-defense tradeoffs can be uncoupled.

Electrode degradation due to metal-ion dissolution in conventional electrolyte hampers the performance of 5 V-class lithium ion batteries. Here, the authors employ a high concentration electrolyte to inhibit metal-ion dissolution and realize a stable high voltage LiNi0.5Mn1.5O4/graphite battery.

PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance. Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies., (© 2024. The Author(s).)

RNA surveillance systems degrade aberrant RNAs that result from defective transcriptional termination, splicing, and polyadenylation. Defective RNAs in the nucleus are recognized by RNA-binding proteins and MTR4, and are degraded by the RNA exosome complex. Here, we detect aberrant RNAs in MTR4-depleted cells using long-read direct RNA sequencing and 3' sequencing. MTR4 destabilizes intronic polyadenylated transcripts generated by transcriptional read-through over one or more exons, termed 3' eXtended Transcripts (3XTs). MTR4 also associates with hnRNPK, which recognizes 3XTs with multiple exons. Moreover, the aberrant protein translated from KCTD13 3XT is a target of the hnRNPK-MTR4-RNA exosome pathway and forms aberrant condensates, which we name KCTD13 3eXtended Transcript-derived protein (KeXT) bodies. Our results suggest that RNA surveillance in human cells inhibits the formation of condensates of a defective polyadenylated transcript-derived protein., (© 2024. The Author(s).)

Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization., (© 2024. The Author(s).)

Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design., (© 2024. The Author(s).)

We previously reported that normothermic ex vivo kidney  perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation., (© 2024. The Author(s).)

Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca 2+ ) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca 2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca 2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca 2+ -activated K + channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca 2+ stimulation, along with Kcnn4 activation., (© 2024. The Author(s).)

Imaging antiferromagnetic 180° domains with actively controlled visibility is vital for both fundamental science and sophisticated applications. While optical second-harmonic generation (SHG) is a well-known technique for distinguishing such domains in non-centrosymmetric antiferromagnets, a general material-based strategy to control domain contrast remains elusive. Using van der Waals antiferromagnet MnPS 3 as a proof of concept, we demonstrate the tuning of nonreciprocity-induced domain contrast in SHG through applying an in-plane electric field that transforms the magnetic point group to its unitary subgroup. The interference among intrinsic electric-dipole, magnetic-dipole, and field-induced electric-dipole transitions, each carrying distinct characters under space-inversion ( P ) and time-reversal ( T ) operations, enables large tuning of domain contrast and nonreciprocity in a broad spectral range. This strategy, generically applicable to systems characterized by P T -symmetric magnetic groups with a polar unitary subgroup, offers a path to fast electrical modulation of nonlinear nonreciprocal photonic behaviors using antiferromagnets., (© 2024. The Author(s).)

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates., (© 2024. The Author(s).)

Voltage-sensing phosphatase (VSP) exhibits voltage-dependent phosphatase activity toward phosphoinositides. VSP generates a specialized phosphoinositide environment in mammalian sperm flagellum. However, the voltage-sensing mechanism of VSP in spermatozoa is not yet characterized. Here, we found that VSP is activated during sperm maturation, indicating that electric signals in immature spermatozoa are essential. Using a heterologous expression system, we show the voltage-sensing property of mouse VSP (mVSP). The voltage-sensing threshold of mVSP is approximately -30 mV, which is sensitive enough to activate mVSP in immature spermatozoa. We also report several knock-in mice in which we manipulate the voltage-sensitivity or electrochemical coupling of mVSP. Notably, the V312R mutant, with a minor voltage-sensitivity change, exhibits abnormal sperm motility after, but not before, capacitation. Additionally, the V312R mutant shows a significant change in the acyl-chain profile of phosphoinositide. Our findings suggest that electrical signals during sperm maturation are crucial for establishing the optimal phosphoinositide environment in spermatozoa., (© 2024. The Author(s).)

Resting memory B cells can be divided into classical or atypical groups, but the heterogenous marker expression on activated memory B cells makes similar classification difficult. Here, by longitudinal analysis of mass cytometry and CITE-seq data from cohorts with COVID-19, bacterial sepsis, or BNT162b2 mRNA vaccine, we observe that resting B cell memory consist of classical CD45RB + memory and CD45RB lo memory, of which the latter contains of two distinct groups of CD11c + atypical and CD23 + non-classical memory cells. CD45RB levels remain stable in these cells after activation, thereby enabling the tracking of activated B cells and plasmablasts derived from either CD45RB + or CD45RB lo memory B cells. Moreover, in both COVID-19 patients and mRNA vaccination, CD45RB lo B cells formed the majority of SARS-CoV2 specific memory B cells and correlated with serum antibodies, while CD45RB + memory are activated by bacterial sepsis. Our results thus identify that stably expressed CD45RB levels can be exploited to trace resting memory B cells and their activated progeny, and suggest that atypical and non-classical CD45RB lo memory B cells contribute to SARS-CoV-2 infection and vaccination., (© 2024. The Author(s).)

Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y 1 receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca 2+ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders., (© 2024. The Author(s).)

The temperature measurement of material inside of an object is one of the key technologies for control of dynamical processes. For this purpose, various techniques such as laser-based thermography and phase-contrast imaging thermography have been studied. However, it is, in principle, impossible to measure the temperature of an element inside of an object using these techniques. One of the possible solutions is measurements of Doppler brooding effect in neutron resonance absorption (NRA). Here we present a method to measure the temperature of an element or an isotope inside of an object using NRA with a single neutron pulse of approximately 100 ns width provided from a high-power laser. We demonstrate temperature measurements of a tantalum (Ta) metallic foil heated from the room temperature up to 617 K. Although the neutron energy resolution is fluctuated from shot to shot, we obtain the temperature dependence of resonance Doppler broadening using a reference of a silver (Ag) foil kept to the room temperature. A free gas model well reproduces the results. This method enables element(isotope)-sensitive thermometry to detect the instantaneous temperature rise in dynamical processes., (© 2024. The Author(s).)

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates., (© 2024. The Author(s).)

Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2 VHL - or CRL4 CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4-PROTAC-CRL2 VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors., (© 2024. The Author(s).)

Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO) 3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions., (© 2024. The Author(s).)

During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos., (© 2024. The Author(s).)

Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000-50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner. Academically open-sourced ( https://github.com/dbsb-juntendo/descSPIM ), descSPIM allows routine three-dimensional imaging of cleared samples in minutes. Thus, the dissemination of descSPIM will accelerate biomedical discoveries driven by tissue clearing technologies., (© 2024. The Author(s).)

The stratum corneum is the outermost skin layer with a vital role in skin barrier function. It is comprised of dead keratinocytes (corneocytes) and is known to maintain its thickness by shedding cells, although, the precise mechanisms that safeguard stratum corneum maturation and homeostasis remain unclear. Previous ex vivo studies have suggested a neutral-to-acidic pH gradient in the stratum corneum. Here, we use intravital pH imaging at single-corneocyte resolution to demonstrate that corneocytes actually undergo differentiation to develop three distinct zones in the stratum corneum, each with a distinct pH value. We identified a moderately acidic lower, an acidic middle, and a pH-neutral upper layer in the stratum corneum, with tight junctions playing a key role in their development. The upper pH neutral zone can adjust its pH according to the external environment and has a neutral pH under steady-state conditions owing to the influence of skin microbiota. The middle acidic pH zone provides a defensive barrier against pathogens. With mathematical modeling, we demonstrate the controlled protease activation of kallikrein-related peptidases on the stratum corneum surface that results in proper corneocyte shedding in desquamation. This work adds crucial information to our understanding of how stratum corneum homeostasis is maintained., (© 2024. The Author(s).)

Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s -1 ) impact of a micrometeoroid with a diameter ranging from 2 to 20 μm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid., (© 2024. The Author(s).)

The DEAD-box RNA helicase (DDX) plays a central role in many aspects of RNA metabolism by remodeling the defined structure of RNA molecules. While a number of structural studies have revealed the atomistic details of the interaction between DDX and RNA ligands, the molecular mechanism of how this molecule unwinds a structured RNA into an unstructured single-stranded RNA (ssRNA) has largely remained elusive. This is due to challenges in structurally characterizing the unwinding intermediate state and the lack of thermodynamic details underlying this process. In this study, we use solution nuclear magnetic resonance (NMR) spectroscopy to characterize the interaction of human DDX3X, a member of the DDX family, with various RNA ligands. Our results show that the inherent binding affinity of DDX3X for ssRNA is significantly higher than that for structured RNA elements. This preferential binding, accompanied by the formation of a domain-closed conformation in complex with ssRNA, effectively stabilizes the denatured ssRNA state and thus underlies the unwinding activity of DDX3X. Our results provide a thermodynamic and structural basis for the DDX function, whereby DDX can recognize and remodel a distinct set of structured RNAs to participate in a wide range of physiological processes., (© 2024. The Author(s).)

The capability of focus control has been central to optical technologies that require both high temporal and spatial resolutions. However, existing varifocal lens schemes are commonly limited to the response time on the microsecond timescale and share the fundamental trade-off between the response time and the tuning power. Here, we propose an ultrafast holographic focusing method enabled by translating the speed of a fast 1D beam scanner into the speed of the complex wavefront modulation of a relatively slow 2D spatial light modulator. Using a pair of a digital micromirror device and a resonant scanner, we demonstrate an unprecedented refresh rate of focus control of 31 MHz, which is more than 1,000 times faster than the switching rate of a digital micromirror device. We also show that multiple micrometer-sized focal spots can be independently addressed in a range of over 1 MHz within a large volume of 5 mm × 5 mm × 5.5 mm, validating the superior spatiotemporal characteristics of the proposed technique - high temporal and spatial precision, high tuning power, and random accessibility in a three-dimensional space. The demonstrated scheme offers a new route towards three-dimensional light manipulation in the 100 MHz regime., (© 2024. The Author(s).)

An ultrapure deep-blue multi-resonance-induced thermally activated delayed fluorescence material (DOB2-DABNA-A) is designed and synthesized. Benefiting from a fully resonating extended helical π-conjugated system, this compound has a small ΔE ST value of 3.6 meV and sufficient spin-orbit coupling to exhibit a high-rate constant for reverse intersystem crossing (k RISC  = 1.1 × 10 6  s -1 ). Furthermore, an organic light-emitting diode employing DOB2-DABNA-A as an emitter is fabricated; it exhibits ultrapure deep-blue emission at 452 nm with a small full width at half maximum of 24 nm, corresponding to Commission Internationale de l'Éclairage (CIE) coordinates of (0.145, 0.049). The high k RISC value reduces the efficiency roll-off, resulting in a high external quantum efficiency (EQE) of 21.6% at 1000 cd m -2 ., (© 2024. The Author(s).)

A superconductor-insulator transition (SIT) in two dimensions is a prototypical quantum phase transition (QPT) with a clear quantum critical point (QCP) at zero temperature (T = 0). The SIT is induced by a field B and observed in disordered thin films. In some of weakly disordered or crystalline thin films, however, an anomalous metallic (AM) ground state emerges over a wide B range between the superconducting and insulating phases. It remains a fundamental open question how the QPT picture of the SIT is modified when the AM state appears. Here we present measurements of the Nernst effect N, which has great sensitivity to the fluctuations of the superconducting order parameter. From a thorough contour map of N in the B-T plane, we found a thermal-to-quantum crossover line of the superconducting fluctuations, a so-called ghost-temperature line associated with the QPT, as well as a ghost-field line associated with a thermal transition. The QCP is identified as a T = 0 intercept of the ghost-temperature line inside the AM state, which verifies that the AM state is a broadened critical state of the SIT., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody-drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC., (© 2024. The Author(s).)

Van der Waals layered transition-metal chalcogenides are drawing significant attention owing to their intriguing physical properties. This group of materials consists of abundant members with various elements, having a variety of different structures. However, they are all crystalline materials, and the physical properties of van der Waals layered quasicrystals have never been studied to date. Here, we report on the discovery of superconductivity in a van der Waals layered quasicrystal of Ta 1.6 Te. The electrical resistivity, magnetic susceptibility, and specific heat of the quasicrystal unambiguously validate the occurrence of bulk superconductivity at a transition temperature of ~1 K. This discovery can promote new research on assessing the physical properties of novel van der Waals layered quasicrystals as well as two-dimensional quasicrystals; moreover, it paves the way toward new frontiers of superconductivity in thermodynamically stable quasicrystals., (© 2024. The Author(s).)

Although the domestic dog's origin is still unclear, this lineage is believed to have been domesticated from an extinct population of gray wolves, which is expected to be more closely related to dogs than to other populations of gray wolves. Here, we sequence the whole genomes of nine Japanese wolves (7.5-100x: Edo to Meiji periods) and 11 modern Japanese dogs and analyze them together with those from other populations of dogs and wolves. A phylogenomic tree shows that, among the gray wolves, Japanese wolves are closest to the dog, suggesting that the ancestor of dogs is closely related to the ancestor of the Japanese wolf. Based on phylogenetic and geographic relationships, the dog lineage has most likely originated in East Asia, where it diverged from a common ancestor with the Japanese wolf. Since East Eurasian dogs possess Japanese wolf ancestry, we estimate an introgression event from the ancestor of the Japanese wolf to the ancestor of the East Eurasian dog that occurred before the dog's arrival in the Japanese archipelago., (© 2024. The Author(s).)

Plasma membrane (PM) H + -ATPase is crucial for light-induced stomatal opening and phosphorylation of a penultimate residue, Thr948 (pen-Thr, numbering according to Arabidopsis AHA1) is required for enzyme activation. In this study, a comprehensive phosphoproteomic analysis using guard cell protoplasts from Vicia faba shows that both red and blue light increase the phosphorylation of Thr881, of PM H + -ATPase. Light-induced stomatal opening and the blue light-induced increase in stomatal conductance are reduced in transgenic Arabidopsis plants expressing mutant AHA1-T881A in aha1-9, whereas the blue light-induced phosphorylation of pen-Thr is unaffected. Auxin and photosynthetically active radiation induce the phosphorylation of both Thr881 and pen-Thr in etiolated seedlings and leaves, respectively. The dephosphorylation of phosphorylated Thr881 and pen-Thr are mediated by type 2 C protein phosphatase clade D isoforms. Taken together, Thr881 phosphorylation, in addition of the pen-Thr phosphorylation, are important for PM H + -ATPase function during physiological responses, such as light-induced stomatal opening in Arabidopsis thaliana., (© 2024. The Author(s).)

Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5., (© 2024. The Author(s).)

In angiosperms, the transition from floral-organ maintenance to abscission determines reproductive success and seed dispersion. For petal abscission, cell-fate decisions specifically at the petal-cell base are more important than organ-level senescence or cell death in petals. However, how this transition is regulated remains unclear. Here, we identify a jasmonic acid (JA)-regulated chromatin-state switch at the base of Arabidopsis petals that directs local cell-fate determination via autophagy. During petal maintenance, co-repressors of JA signaling accumulate at the base of petals to block MYC activity, leading to lower levels of ROS. JA acts as an airborne signaling molecule transmitted from stamens to petals, accumulating primarily in petal bases to trigger chromatin remodeling. This allows MYC transcription factors to promote chromatin accessibility for downstream targets, including NAC DOMAIN-CONTAINING PROTEIN102 (ANAC102). ANAC102 accumulates specifically at the petal base prior to abscission and triggers ROS accumulation and cell death via AUTOPHAGY-RELATED GENEs induction. Developmentally induced autophagy at the petal base causes maturation, vacuolar delivery, and breakdown of autophagosomes for terminal cell differentiation. Dynamic changes in vesicles and cytoplasmic components in the vacuole occur in many plants, suggesting JA-NAC-mediated local cell-fate determination by autophagy may be conserved in angiosperms., (© 2024. The Author(s).)

Highly pathogenic avian influenza virus (HPAIV) A H5, particularly clade 2.3.4.4, has caused worldwide outbreaks in domestic poultry, occasional spillover to humans, and increasing deaths of diverse species of wild birds since 2014. Wild bird migration is currently acknowledged as an important ecological process contributing to the global dispersal of HPAIV H5. However, this mechanism has not been quantified using bird movement data from different species, and the timing and location of exposure of different species is unclear. We sought to explore these questions through phylodynamic analyses based on empirical data of bird movement tracking and virus genome sequences of clade 2.3.4.4 and 2.3.2.1. First, we demonstrate that seasonal bird migration can explain salient features of the global dispersal of clade 2.3.4.4. Second, we detect synchrony between the seasonality of bird annual cycle phases and virus lineage movements. We reveal the differing exposed bird orders at geographical origins and destinations of HPAIV H5 clade 2.3.4.4 lineage movements, including relatively under-discussed orders. Our study provides a phylodynamic framework that links the bird movement ecology and genomic epidemiology of avian influenza; it highlights the importance of integrating bird behavior and life history in avian influenza studies., (© 2024. The Author(s).)