Durable CO2 conversion in the proton-exchange membrane system.

Electrolysis that reduces carbon dioxide (CO2) to useful chemicals can, in principle, contribute to a more sustainable and carbon-neutral future1-6. However, it remains challenging to develop this into a robust process because efficient conversion typically requires alkaline conditions in which CO2 precipitates as carbonate, and this limits carbon utilization and the stability of the system7-12. Strategies such as physical washing, pulsed operation and the use of dipolar membranes can partially alleviate these problems but do not fully resolve them11,13-15. CO2 electrolysis in acid electrolyte, where carbonate does not form, has therefore been explored as an ultimately more workable solution16-18. Herein we develop a proton-exchange membrane system that reduces CO2 to formic acid at a catalyst that is derived from waste lead-acid batteries and in which a lattice carbon activation mechanism contributes. When coupling CO2 reduction with hydrogen oxidation, formic acid is produced with over 93% Faradaic efficiency. The system is compatible with start-up/shut-down processes, achieves nearly 91% single-pass conversion efficiency for CO2 at a current density of 600 mA cm-2 and cell voltage of 2.2 V and is shown to operate continuously for more than 5,200 h. We expect that this exceptional performance, enabled by the use of a robust and efficient catalyst, stable three-phase interface and durable membrane, will help advance the development of carbon-neutral technologies.

Constrained C2 adsorbate orientation enables CO-to-acetate electroreduction.

The carbon dioxide and carbon monoxide electroreduction reactions, when powered using low-carbon electricity, offer pathways to the decarbonization of chemical manufacture1,2. Copper (Cu) is relied on today for carbon-carbon coupling, in which it produces mixtures of more than ten C2+ chemicals3-6: a long-standing challenge lies in achieving selectivity to a single principal C2+ product7-9. Acetate is one such C2 compound on the path to the large but fossil-derived acetic acid market. Here we pursued dispersing a low concentration of Cu atoms in a host metal to favour the stabilization of ketenes10-chemical intermediates that are bound in monodentate fashion to the electrocatalyst. We synthesize Cu-in-Ag dilute (about 1 atomic per cent of Cu) alloy materials that we find to be highly selective for acetate electrosynthesis from CO at high *CO coverage, implemented at 10 atm pressure. Operando X-ray absorption spectroscopy indicates in situ-generated Cu clusters consisting of <4 atoms as active sites. We report a 12:1 ratio, an order of magnitude increase compared to the best previous reports, in the selectivity for acetate relative to all other products observed from the carbon monoxide electroreduction reaction. Combining catalyst design and reactor engineering, we achieve a CO-to-acetate Faradaic efficiency of 91% and report a Faradaic efficiency of 85% with an 820-h operating time. High selectivity benefits energy efficiency and downstream separation across all carbon-based electrochemical transformations, highlighting the importance of maximizing the Faradaic efficiency towards a single C2+ product11.

A New Mechanism of Action in Human and Mouse Treg Cells: The Ke(y)to Suppression.

Little is known about how Treg cells mediate suppression, especially in tissues. In this issue of Immunity, Schmidleithner et al. report that Treg cells catabolize PGE2 into 15-keto-PGE2, a T cell-inhibitory metabolite, and that this mechanism controls inflammation in adipose tissue.

Analysis of Genome Architecture during SCNT Reveals a Role of Cohesin in Impeding Minor ZGA.

Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. However, the re-organization of 3D chromatin structure in this process remains poorly understood. Using low-input Hi-C, we revealed that, during SCNT, the transferred nucleus first enters a mitotic-like state (premature chromatin condensation). Unlike fertilized embryos, SCNT embryos show stronger topologically associating domains (TADs) at the 1-cell stage. TADs become weaker at the 2-cell stage, followed by gradual consolidation. Compartments A/B are markedly weak in 1-cell SCNT embryos and become increasingly strengthened afterward. By the 8-cell stage, somatic chromatin architecture is largely reset to embryonic patterns. Unexpectedly, we found cohesin represses minor zygotic genome activation (ZGA) genes (2-cell-specific genes) in pluripotent and differentiated cells, and pre-depleting cohesin in donor cells facilitates minor ZGA and SCNT. These data reveal multi-step reprogramming of 3D chromatin architecture during SCNT and support dual roles of cohesin in TAD formation and minor ZGA repression.

Distribution control enables efficient reduced-dimensional perovskite LEDs.

Light-emitting diodes (LEDs) based on perovskite quantum dots have shown external quantum efficiencies (EQEs) of over 23% and narrowband emission, but suffer from limited operating stability1. Reduced-dimensional perovskites (RDPs) consisting of quantum wells (QWs) separated by organic intercalating cations show high exciton binding energies and have the potential to increase the stability and the photoluminescence quantum yield2,3. However, until now, RDP-based LEDs have exhibited lower EQEs and inferior colour purities4-6. We posit that the presence of variably confined QWs may contribute to non-radiative recombination losses and broadened emission. Here we report bright RDPs with a more monodispersed QW thickness distribution, achieved through the use of a bifunctional molecular additive that simultaneously controls the RDP polydispersity while passivating the perovskite QW surfaces. We synthesize a fluorinated triphenylphosphine oxide additive that hydrogen bonds with the organic cations, controlling their diffusion during RDP film deposition and suppressing the formation of low-thickness QWs. The phosphine oxide moiety passivates the perovskite grain boundaries via coordination bonding with unsaturated sites, which suppresses defect formation. This results in compact, smooth and uniform RDP thin films with narrowband emission and high photoluminescence quantum yield. This enables LEDs with an EQE of 25.6% with an average of 22.1 ±1.2% over 40 devices, and an operating half-life of two hours at an initial luminance of 7,200 candela per metre squared, indicating tenfold-enhanced operating stability relative to the best-known perovskite LEDs with an EQE exceeding 20%1,4-6.

Chelation-directed interface engineering of in-place self-cleaning membranes.

Water-energy sustainability will depend upon the rapid development of advanced pressure-driven separation membranes. Although energy-efficient, water-treatment membranes are constrained by ubiquitous fouling, which may be alleviated by engineering self-cleaning membrane interfaces. In this study, a metal-polyphenol network was designed to direct the armorization of catalytic nanofilms (ca. 18 nm) on inert polymeric membranes. The chelation-directed mineralized coating exhibits high polarity, superhydrophilicity, and ultralow adhesion to crude oil, enabling cyclable crude oil-in-water emulsion separation. The in-place flux recovery rate exceeded 99.9%, alleviating the need for traditional ex situ cleaning. The chelation-directed nanoarmored membrane exhibited 48-fold and 6.8-fold figures of merit for in-place self-cleaning regeneration compared to the control membrane and simple hydraulic cleaning, respectively. Precursor interaction mechanisms were identified by density functional theory calculations. Chelation-directed armorization offers promise for sustainable applications in catalysis, biomedicine, environmental remediation, and beyond.

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis.

The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

A developmental landscape of 3D-cultured human pre-gastrulation embryos.

Our understanding of how human embryos develop before gastrulation, including spatial self-organization and cell type ontogeny, remains limited by available two-dimensional technological platforms1,2 that do not recapitulate the in vivo conditions3-5. Here we report a three-dimensional (3D) blastocyst-culture system that enables human blastocyst development up to the primitive streak anlage stage. These 3D embryos mimic developmental landmarks and 3D architectures in vivo, including the embryonic disc, amnion, basement membrane, primary and primate unique secondary yolk sac, formation of anterior-posterior polarity and primitive streak anlage. Using single-cell transcriptome profiling, we delineate ontology and regulatory networks that underlie the segregation of epiblast, primitive endoderm and trophoblast. Compared with epiblasts, the amniotic epithelium shows unique and characteristic phenotypes. After implantation, specific pathways and transcription factors trigger the differentiation of cytotrophoblasts, extravillous cytotrophoblasts and syncytiotrophoblasts. Epiblasts undergo a transition to pluripotency upon implantation, and the transcriptome of these cells is maintained until the generation of the primitive streak anlage. These developmental processes are driven by different pluripotency factors. Together, findings from our 3D-culture approach help to determine the molecular and morphogenetic developmental landscape that occurs during human embryogenesis.

Development of the Fetal Brain Corticocortical Structural Network during the Second-to-Third Trimester Based on Diffusion MRI.

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.

Genetically Encoded Lizard Color Divergence for Camouflage and Thermoregulation.

Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.

Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model.

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.

A diffusion MRI-based spatiotemporal continuum of the embryonic mouse brain for probing gene-neuroanatomy connections.

The embryonic mouse brain undergoes drastic changes in establishing basic anatomical compartments and laying out major axonal connections of the developing brain. Correlating anatomical changes with gene-expression patterns is an essential step toward understanding the mechanisms regulating brain development. Traditionally, this is done in a cross-sectional manner, but the dynamic nature of development calls for probing gene-neuroanatomy interactions in a combined spatiotemporal domain. Here, we present a four-dimensional (4D) spatiotemporal continuum of the embryonic mouse brain from E10.5 to E15.5 reconstructed from diffusion magnetic resonance microscopy (dMRM) data. This study achieved unprecedented high-definition dMRM at 30- to 35-µm isotropic resolution, and together with computational neuroanatomy techniques, we revealed both morphological and microscopic changes in the developing brain. We transformed selected gene-expression data to this continuum and correlated them with the dMRM-based neuroanatomical changes in embryonic brains. Within the continuum, we identified distinct developmental modes comprising regional clusters that shared developmental trajectories and similar gene-expression profiles. Our results demonstrate how this 4D continuum can be used to examine spatiotemporal gene-neuroanatomical interactions by connecting upstream genetic events with anatomical changes that emerge later in development. This approach would be useful for large-scale analysis of the cooperative roles of key genes in shaping the developing brain.

Self-Assembly Intermetallic PtCu3 Core with High-Index Faceted Pt Shell for High-Efficiency Oxygen Reduction.

Rational design of well-defined active sites is crucial for promoting sluggish oxygen reduction reactions. Herein, leveraging the surfactant-oriented and solvent-ligand effects, we develop a facile self-assembly strategy to construct a core-shell catalyst comprising a high-index Pt shell encapsulating a PtCu3 intermetallic core with efficient oxygen-reduction performance. Without undergoing a high-temperature route, the ordered PtCu3 is directly fabricated through the accelerated reduction of Cu2+, followed by the deposition of the remaining Pt precursor onto its surface, forming high-index steps oriented by the steric hindrance of surfactant. This approach results in a high half-wave potential of 0.911 V versus reversible hydrogen electrode, with negligible deactivation even after 15000-cycle operation. Operando spectroscopies identify that this core-shell catalyst facilitates the conversion of oxygen-involving intermediates and ensures antidissolution ability. Theoretical investigations rationalize that this improvement is attributed to reinforced electronic interactions around high-index Pt, stabilizing the binding strength of rate-determining OHads species.

An Observational Prospective Cohort Study of Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection of an Aerosolized, Inhaled Adenovirus Type 5-Vectored Coronavirus Disease 2019 Vaccine Given as a Second Booster Dose in Guangzhou City, China.

Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.

Spatiotemporal Developmental Gradient of Thalamic Morphology, Microstructure, and Connectivity fromthe Third Trimester to Early Infancy.

Thalamus is a critical component of the limbic system that is extensively involved in both basic and high-order brain functions. However, how the thalamic structure and function develops at macroscopic and microscopic scales during the perinatal period development is not yet well characterized. Here, we used multishell high-angular resolution diffusion MRI of 144 preterm-born and full-term infants in both sexes scanned at 32-44 postmenstrual weeks (PMWs) from the Developing Human Connectome Project database to investigate the thalamic development in morphology, microstructure, associated connectivity, and subnucleus division. We found evident anatomic expansion and linear increases of fiber integrity in the lateral side of thalamus compared with the medial part. The tractography results indicated that thalamic connection to the frontal cortex developed later than the other thalamocortical connections (parieto-occipital, motor, somatosensory, and temporal). Using a connectivity-based segmentation strategy, we revealed that functional partitions of thalamic subdivisions were formed at 32 PMWs or earlier, and the partition developed toward the adult pattern in a lateral-to-medial pattern. Collectively, these findings revealed faster development of the lateral thalamus than the central part as well as a posterior-to-anterior developmental gradient of thalamocortical connectivity from the third trimester to early infancy.SIGNIFICANCE STATEMENT This is the first study that characterizes the spatiotemporal developmental pattern of thalamus during the third trimester to early infancy. We found that thalamus develops in a lateral-to-medial pattern for both thalamic microstructures and subdivisions; and thalamocortical connectivity develops in a posterior-to-anterior gradient that thalamofrontal connectivity appears later than the other thalamocortical connections. These findings may enrich our understanding of the developmental principles of thalamus and provide references for the atypical brain growth in neurodevelopmental disorders.

Genomic and transcriptomic significance of multiple primary lung cancers detected by next-generation sequencing in clinical settings.

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

A splicing-dependent ER retention signal regulates surface expression of the mechanosensitive TMEM63B cation channel.

TMEM63B is a mechanosensitive cation channel activated by hypoosmotic stress and mechanic stimulation. We recently reported a brain-specific alternative splicing of exon 4 in TMEM63B. The short variant lacking exon 4, which constitutes the major isoform in the brain, exhibits enhanced responses to hypoosmotic stimulation compared to the long isoform containing exon 4. However, the mechanisms affecting this differential response are unclear. Here, we showed that the short isoform exhibited stronger cell surface expression compared to the long variant. Using mutagenesis screening of the coding sequence of exon 4, we identified an RXR-type endoplasmic reticulum (ER) retention signal (RER). We found that this motif was responsible for binding to the COPI retrieval vesicles, such that the longer TMEM63B isoforms were more likely to be retrotranslocated to the ER than the short isoforms. In addition, we demonstrated long TMEM63Bs could form heterodimers with short isoforms and reduce their surface expression. Taken together, our findings revealed an ER retention signal in the alternative splicing domain of TMEM63B that regulates the surface expression of TMEM63B protein and channel function.

The role of sirtuins in intervertebral disc degeneration: Mechanisms and therapeutic potential.

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which affects the patients' quality of life and health and imposes a significant socioeconomic burden. Despite great efforts made by researchers to understand the pathogenesis of IDD, effective strategies for preventing and treating this disease remain very limited. Sirtuins are a highly conserved family of (NAD+)-dependent deacetylases in mammals that are involved in a variety of metabolic processes in vivo. In recent years, sirtuins have attracted much attention owing to their regulatory roles in IDD on physiological activities such as inflammation, apoptosis, autophagy, aging, oxidative stress, and mitochondrial function. At the same time, many studies have explored the therapeutic effects of sirtuins-targeting activators or micro-RNA in IDD. This review summarizes the molecular pathways of sirtuins involved in IDD, and summarizes the therapeutic role of activators or micro-RNA targeting Sirtuins in IDD, as well as the current limitations and challenges, with a view to provide possible solutions for the treatment of IDD.

m6A-induced TRIB3 regulates Hippo pathway through interacting with LATS1 to promote the progression of lung adenocarcinoma.

Recent studies have indicated that dysregulation of the Hippo/Yes-associated protein (YAP) axis is associated with tumor progression and therapy resistance in various cancer types, including lung adenocarcinoma (LUAD). Understanding the regulation of Hippo signaling in LUAD is of great significance. Elevated levels of TRIB3, a pseudo kinase, have been observed in certain lung malignancies and are associated with an unfavorable prognosis. Our research aims to investigate whether increased TRIB3 levels enhance the malignant characteristics of LUAD cells and tumor progression through its interaction with the Hippo signaling pathway. In this study, we reported a positive correlation between elevated expression of TRIB3 and LUAD progression. Additionally, TRIB3 has the ability to enhance TEAD luciferase function and suppress Hippo pathway activity. Moreover, TRIB3 increases total YAP protein levels and promotes YAP nuclear localization. Mechanistic experiments revealed that TRIB3 directly interacts with large tumor suppressor kinase 1 (LATS1), thereby suppressing Hippo signaling. Moreover, the decrease in METTL3-mediated N6-methyladenosine modification of TRIB3 results in a substantial elevation of its expression levels in LUAD cells. Collectively, our research unveils a novel discovery that TRIB3 enhances the growth and invasion of LUAD cells by interacting with LATS1 and inhibiting the Hippo signaling pathway. TRIB3 may serve as a potential biomarker for an unfavorable prognosis and a target for novel treatments in YAP-driven lung cancer.