Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.

Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs.

Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.

Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.

Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid.

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 µM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 Mpro. In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

HALL: a comprehensive database for human aging and longevity studies.

Diverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.

N-doped carbon-iron heterointerfaces for boosted electrocatalytic active and selective ammonia production.

The electrochemical conversion of waste nitrate (NO3-) to valuable ammonia (NH3) is an economical and environmentally friendly technology for sustainable NH3 production. It is beneficial for environmental nitrogen pollution management and is also an appealing alternative to the current Haber-Bosch process for NH3 production. However, owing to the competing hydrogen evolution reaction, it is necessary to design highly efficient and stable electrocatalysts with high selectivity. Herein, we report a rational design of Fe nanoparticles wrapped in N-doped carbon (Fe@N10-C) as a high NH3 selective and efficient electrocatalyst using a metal-organic framework precursor. We constructed a catalyst with new active sites by doping with nitrogen, which activated neighboring carbon atoms and enhanced metal-to-carbon electron transfer, resulting in high catalytic activity. These doped N sites play a key role in the NO3- electroreduction. As a result, the Fe@N10-C nanoparticles with optimal doping of N demonstrated remarkable performance, with a record-high NO3- removal capacity of 125.8 ± 0.5 mg N gcat-1 h-1 and nearly 100 % (99.7 ± 0.1%) selectivity. The catalyst also delivers an impressive NH3 production rate of 2647.7 µg h-1 cm-2 and high faradaic efficiency of 91.8 ± 0.1%. This work provides a new route for N-doped carbon-iron catalysis application and paves the way for addressing energy and environmental issues.

Free-standing membrane incorporating single-atom catalysts for ultrafast electroreduction of low-concentration nitrate.

The release of wastewaters containing relatively low levels of nitrate (NO3-) results in sufficient contamination to induce harmful algal blooms and to elevate drinking water NO3- concentrations to potentially hazardous levels. In particular, the facile triggering of algal blooms by ultra-low concentrations of NO3- necessitates the development of efficient methods for NO3- destruction. However, promising electrochemical methods suffer from weak mass transport under low reactant concentrations, resulting in long treatment times (on the order of hours) for complete NO3- destruction. In this study, we present flow-through electrofiltration via an electrified membrane incorporating nonprecious metal single-atom catalysts for NO3- reduction activity enhancement and selectivity modification, achieving near-complete removal of ultra-low concentration NO3- (10 mg-N L-1) with a residence time of only a few seconds (10 s). By anchoring Cu single atoms supported on N-doped carbon in a carbon nanotube interwoven framework, we fabricate a free-standing carbonaceous membrane featuring high conductivity, permeability, and flexibility. The membrane achieves over 97% NO3- removal with high N2 selectivity of 86% in a single-pass electrofiltration, which is a significant improvement over flow-by operation (30% NO3- removal with 7% N2 selectivity). This high NO3- reduction performance is attributed to the greater adsorption and transport of nitric oxide under high molecular collision frequency coupled with a balanced supply of atomic hydrogen through H2 dissociation during electrofiltration. Overall, our findings provide a paradigm of applying a flow-through electrified membrane incorporating single-atom catalysts to improve the rate and selectivity of NO3- reduction for efficient water purification.

A green edge-hosted zinc single-site heterogeneous catalyst for superior Fenton-like activity.

Developing green heterogeneous catalysts with excellent Fenton-like activity is critical for water remediation technologies. However, current catalysts often rely on toxic transitional metals, and their catalytic performance is far from satisfactory as alternatives of homogeneous Fenton-like catalysts. In this study, a green catalyst based on Zn single-atom was prepared in an ammonium atmosphere using ZIF-8 as a precursor. Multiple characterization analyses provided evidence that abundant intrinsic defects due to the edge sites were created, leading to the formation of a thermally stable edge-hosted Zn-N4 single-atom catalyst (ZnN4-Edge). Density functional theory calculations revealed that the edge sites equipped the single-atom Zn with a super catalytic performance, which not only promoted decomposition of peroxide molecule (HSO5-) but also greatly lowered the activation barrier for •OH generation. Consequently, the as-prepared ZnN4-Edge exhibited extremely high Fenton-like performance in oxidation and mineralization of phenol as a representative organic contaminant in a wide range of pH, realizing its quick detoxification. The atom-utilization efficiency of the ZnN4-Edge was ~104 higher than an equivalent amount of the control sample without edge sites (ZnN4), and the turnover frequency was ~103 times of the typical benchmark of homogeneous catalyst (Co2+). This study opens up a revolutionary way to rationally design and optimize heterogeneous catalysts to homogeneous catalytic performance for Fenton-like application.

Leveraging trans-ethnic genetic risk scores to improve association power for complex traits in underrepresented populations.

Trans-ethnic genome-wide association studies have revealed that many loci identified in European populations can be reproducible in non-European populations, indicating widespread trans-ethnic genetic similarity. However, how to leverage such shared information more efficiently in association analysis is less investigated for traits in underrepresented populations. We here propose a statistical framework, trans-ethnic genetic risk score informed gene-based association mixed model (GAMM), by hierarchically modeling single-nucleotide polymorphism effects in the target population as a function of effects of the same trait in well-studied populations. GAMM powerfully integrates genetic similarity across distinct ancestral groups to enhance power in understudied populations, as confirmed by extensive simulations. We illustrate the usefulness of GAMM via the application to 13 blood cell traits (i.e. basophil count, eosinophil count, hematocrit, hemoglobin concentration, lymphocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocyte count, neutrophil count, platelet count, red blood cell count and total white blood cell count) in Africans of the UK Biobank (n = 3204) while utilizing genetic overlap shared in Europeans (n = 746 667) and East Asians (n = 162 255). We discovered multiple new associated genes, which had otherwise been missed by existing methods, and revealed that the trans-ethnic information indirectly contributed much to the phenotypic variance. Overall, GAMM represents a flexible and powerful statistical framework of association analysis for complex traits in underrepresented populations by integrating trans-ethnic genetic similarity across well-studied populations, and helps attenuate health inequities in current genetics research for people of minority populations.

Oxidative Stress Induces E-Selectin Expression through Repression of Endothelial Transcription Factor ERG.

Oxidative stress induces a prothrombotic state through enhancement of adhesion properties of the endothelium. E-selectin, an endothelial cell adhesion molecule, becomes a therapeutic target for venous thrombosis, whereas the regulatory mechanisms of its expression have not been fully understood. In the present study, we report that H2O2 treatment increases expression of E-selectin but decreases expression of the endothelial transcription factor ETS-related gene (ERG) in HUVECs in a dose- and time-dependent manner. In BALB/c mice treated with hypochlorous acid, E-selectin expression is increased and ERG expression is decreased in endothelial cells of the brain and lung. RNA interference of ERG upregulates E-selectin expression, whereas transfection of ERG-expressing plasmid downregulates E-selectin expression in HUVECs. Knockdown or overexpression of ERG comprises H2O2-induced E-selectin expression in HUVECs. Deletion of the Erg gene in mice results in embryonic lethality at embryonic days 10.5-12.5, and E-selectin expression is increased in the Erg-/- embryos. No chromatin loop was found on the E-selectin gene or its promoter region by capture high-throughput chromosome conformation capture. Chromatin immunoprecipitation and luciferase reporter assay determined that the -127 ERG binding motif mediates ERG-repressed E-selectin promoter activity. In addition, ERG decreases H2O2-induced monocyte adhesion. Together, ERG represses the E-selectin gene transcription and inhibits oxidative stress-induced endothelial cell adhesion.

Comprehensive preimplantation genetic testing for balanced insertional translocation carriers.

BACKGROUND: Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate. METHODS: A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis. The balanced insertion segments in euploid embryos were inferred from the haplotypes inherited from the carrier parent. RESULTS: A total of 10 BIT carrier couples were enrolled in our study. 15 in vitro fertilisation cycles were conducted, resulting in 73 blastocysts biopsied and subjected to PGT analysis. Among these, 20 blastocysts displayed rearrangement-related imbalances, 13 exhibited de novo aneuploidies, 15 presented a complex anomaly involving both imbalances and additional aneuploidies, while 25 were euploid. Within the euploid embryos, 12 were balanced carrier embryos and 13 were non-carrier embryos. To date, eight non-carrier and one carrier embryos have been transferred, resulting in seven clinical pregnancies. All pregnancies were recommended to perform prenatal diagnosis, our date revealed complete concordance between fetal genetic testing results and PGT results. Presently, five infants have been born from these pregnancies, and two pregnancies are still ongoing. CONCLUSION: The proposed method facilitates comprehensive chromosome screening and the concurrent identification of balanced insertions or normal karyotypes in embryos. This study offers an effective and universally applicable strategy for BIT carriers to achieve a healthy pregnancy and prevent the transmission of BITs to their offspring.

A novel RHH family transcription factor aCcr1 and its viral homologs dictate cell cycle progression in archaea.

Cell cycle regulation is of paramount importance for all forms of life. Here, we report that a conserved and essential cell cycle-specific transcription factor (designated as aCcr1) and its viral homologs control cell division in Sulfolobales. We show that the transcription level of accr1 reaches peak during active cell division (D-phase) subsequent to the expression of CdvA, an archaea-specific cell division protein. Cells over-expressing the 58-aa-long RHH (ribbon-helix-helix) family cellular transcription factor as well as the homologs encoded by large spindle-shaped viruses Acidianus two-tailed virus (ATV) and Sulfolobus monocaudavirus 3 (SMV3) display significant growth retardation and cell division failure, manifesting as enlarged cells with multiple chromosomes. aCcr1 over-expression results in downregulation of 17 genes (>4-fold), including cdvA. A conserved motif, aCcr1-box, located between the TATA-binding box and the translation initiation site of 13 out of the 17 highly repressed genes, is critical for aCcr1 binding. The aCcr1-box is present in the promoters and 5' UTRs of cdvA genes across Sulfolobales, suggesting that aCcr1-mediated cdvA repression is an evolutionarily conserved mechanism by which archaeal cells dictate cytokinesis progression, whereas their viruses take advantage of this mechanism to manipulate the host cell cycle.

High-ammonia selective metal-organic framework-derived Co-doped Fe/Fe2O3 catalysts for electrochemical nitrate reduction.

Ammonia (NH3) is an ideal carbon-free power source in the future sustainable hydrogen economy for growing energy demand. The electrochemical nitrate reduction reaction (NO3-RR) is a promising approach for nitrate removal and NH3 production at ambient conditions, but efficient electrocatalysts are lacking. Here, we present a metal-organic framework (MOF)-derived cobalt-doped Fe@Fe2O3 (Co-Fe@Fe2O3) NO3-RR catalyst for electrochemical energy production. This catalyst has a nitrate removal capacity of 100.8 mg N gcat-1 h-1 and an ammonium selectivity of 99.0 ± 0.1%, which was the highest among all reported research. In addition, NH3 was produced at a rate of 1,505.9 µg h-1 cm-2, and the maximum faradaic efficiency was 85.2 ± 0.6%. Experimental and computational results reveal that the high performance of Co-Fe@Fe2O3 results from cobalt doping, which tunes the Fe d-band center, enabling the adsorption energies for intermediates to be modulated and suppressing hydrogen production. Thus, this study provides a strategy in the design of electrocatalysts in electrochemical nitrate reduction.

Boosted ammonium production by single cobalt atom catalysts with high Faradic efficiencies.

Efficient n = O bond activation is crucial for the catalytic reduction of nitrogen compounds, which is highly affected by the construction of active centers. In this study, n = O bond activation was achieved by a single-atom catalyst (SAC) with phosphorus anchored on a Co active center to form intermediate N-species for further hydrogenation and reduction. Unique phosphorus-doped discontinuous active sites exhibit better n = O activation performance than conventional N-cooperated single-atom sites, with a high Faradic efficiency of 92.0% and a maximum ammonia yield rate of 433.3 µg NH4·h-1·cm-2. This approach of constructing environmental sites through heteroatom modification significantly improves atom efficiency and will guide the design of future functional SACs with wide-ranging applications.

Intracellular zinc protects Kv7 K+ channels from Ca2+/calmodulin-mediated inhibition.

Zinc (Zn) is an essential trace element; it serves as a cofactor for a great number of enzymes, transcription factors, receptors, and other proteins. Zinc is also an important signaling molecule, which can be released from intracellular stores into the cytosol or extracellular space, for example, during synaptic transmission. Amongst cellular effects of zinc is activation of Kv7 (KCNQ, M-type) voltage-gated potassium channels. Here, we investigated relationships between Kv7 channel inhibition by Ca2+/calmodulin (CaM) and zinc-mediated potentiation. We show that Zn2+ ionophore, zinc pyrithione (ZnPy), can prevent or reverse Ca2+/CaM-mediated inhibition of Kv7.2. In the presence of both Ca2+ and Zn2+, the Kv7.2 channels lose most of their voltage dependence and lock in an open state. In addition, we demonstrate that mutations that interfere with CaM binding to Kv7.2 and Kv7.3 reduced channel membrane abundance and activity, but these mutants retained zinc sensitivity. Moreover, the relative efficacy of ZnPy to activate these mutants was generally greater, compared with the WT channels. Finally, we show that zinc sensitivity was retained in Kv7.2 channels assembled with mutant CaM with all four EF hands disabled, suggesting that it is unlikely to be mediated by CaM. Taken together, our findings indicate that zinc is a potent Kv7 stabilizer, which may protect these channels from physiological inhibitory effects of neurotransmitters and neuromodulators, protecting neurons from overactivity.

Gut microbiota and intestinal immunity-A crosstalk in irritable bowel syndrome.

Irritable bowel syndrome (IBS), one of the most prevalent functional gastrointestinal disorders, is characterized by recurrent abdominal pain and abnormal defecation habits, resulting in a severe healthcare burden worldwide. The pathophysiological mechanisms of IBS are multi-factorially involved, including food antigens, visceral hypersensitivity reactions, and the brain-gut axis. Numerous studies have found that gut microbiota and intestinal mucosal immunity play an important role in the development of IBS in crosstalk with multiple mechanisms. Therefore, based on existing evidence, this paper elaborates that the damage and activation of intestinal mucosal immunity and the disturbance of gut microbiota are closely related to the progression of IBS. Combined with the application prospect, it also provides references for further in-depth exploration and clinical practice.

"Atomic Topping" of MnOx on Al2O3 to Create Electron-Rich, Aperiodic, Lattice Oxygens that Resemble Noble Metals for Catalytic Oxidation.

Enhancing the catalytic oxidation activity of traditional transition-metal oxides to rival that of noble metals has been a prominent focus in the field of catalysis. However, existing synthesis strategies that focus on controlling the electronic states of metal centers have not yet fully succeeded in achieving this goal. Our current research reveals that manipulating the electronic states of oxygen centers can yield unexpected results. By creating electron-rich, aperiodic lattice oxygens through atomic topping of MnOx, we have produced a catalyst with performance that closely resembles supported Pt. Spherical aberration-corrected transmission electron microscopy and X-ray absorption spectra have confirmed that the atomic topping of the MnOx layer on Al2O3 can form an aperiodic arrangement oxide structure. Near-ambient pressure X-ray photoelectron spectroscopy, in situ diffuse reflectance infrared Fourier transform spectroscopy, reaction kinetics test, and theoretical calculations demonstrated that this structure significantly increases the electron density around the oxygen in MnOx, shifting the activation center for CO adsorption from Mn to O, thereby exhibiting catalytic activity and stability close to that of the precious metal Pt. This study presents a fresh perspective on designing efficient oxide catalysts by targeting electron-rich anionic centers, thereby deepening the understanding of how these centers can be altered to enhance catalytic efficiency in oxidation reactions.

BaCu, a Two-Dimensional Electride with Cu Anions.

The electron-rich characteristic and low work function endow electrides with excellent performance in (opto)electronics and catalytic applications; these two features are closely related to the structural topology, constituents, and valence electron concentration of electrides. However, the synthesized electrides, especially two-dimensional (2D) electrides, are limited to specific structural prototypes and anionic p-block elements. Here we synthesize and identify a distinct 2D electride of BaCu with delocalized anionic electrons confined to the interlayer spaces of the BaCu framework. The bonding between Cu and Ba atoms exhibits ionic characteristics, and the adjacent Cu anions form a planar honeycomb structure with metallic Cu-Cu bonding. The negatively charged Cu ions are revealed by the theoretical calculations and experimental X-ray absorption near-edge structure. Physical property measurements reveal that BaCu electride has a high electronic conductivity (ρ = 3.20 µΩ cm) and a low work function (2.5 eV), attributed to the metallic Cu-Cu bonding and delocalized anionic electrons. In contrast to typical ionic 2D electrides with p-block anions, density functional theory calculations find that the orbital hybridization between the delocalized anionic electrons and BaCu framework leads to unique isotropic physical properties, such as mechanical properties, and work function. The freestanding BaCu monolayer with half-metal conductivity exhibits low exfoliation energy (0.84 J/m2) and high mechanical/thermal stability, suggesting the potential to achieve low-dimensional BaCu from the bulk. Our results expand the space for the structure and attributes of 2D electrides, facilitating the discovery and potential application of novel 2D electrides with transition metal anions.

Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation.

BACKGROUND: Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes. METHODS: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI ∼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction. RESULTS: We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern. CONCLUSION: We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.